Clinical trial NCT03074318
Conditions: Metastatic Leiomyosarcoma Metastatic Liposarcoma Unresectable Leiomyosarcoma Unresectable Liposarcoma
Sponsor: Fred Hutchinson Cancer Center
Start date: 2017-09-28; Completion date: 2020-11-15
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase I/II studies the side effects of avelumab and trabectedin and how well they work in treating patients with leiomyosarcoma or liposarcoma that has spread to other places in the body (metastatic) or cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as trabectedin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving avelumab and trabectedin may work better in treating patients with liposarcoma or leiomyosarcoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of the combination of trabectedin and avelumab in subjects with advanced leiomyosarcoma and liposarcoma.

II. To assess the objective response rate of advanced L-type sarcoma patients receiving the combination regimen of avelumab and trabectedin.

SECONDARY OBJECTIVE:

I. To further explore the clinical activity and safety profile of avelumab and trabectedin as a combination therapy.

OUTLINE:

Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression.

After completion of study treatment, patients are followed up at 30 and 90 days, then every 12 weeks for 2 years.

Arms: arm 1: Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression. arm 2: Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression. arm 3: Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression. arm 4: Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression.
Interventions: intervention 1: Avelumab intervention 2: Trabectedin
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Current Version: 04/FEB/2020 
 
 
Version 8.0, Amendment 7 
04/FEB/2020 
Version 7.0, Amendment 6 
29/AUG/2019 
Version 6.0, Amendment 5 
04/APR/2019 
Version 5.0, Amendment 4 
08/Nov/2018 
Version 4.0, Amendment 3 
31/AUG/2018 
Version 3.0, Amendment 2 
11/APR/2018 
Version 2.0, Amendment 1 
30/OCT/2017 
Version 1.0, Original 
19/JAN/2016 
 
 
Title of Protocol: 
A Phase I/II Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma 
 
 
Sponsor- Investigator: 
Seth Pollack, MD  
Associate Member, FHCRC, Assistant Professor of Medicine, UW 
(206) 667-6629 
Biostatistician: 
Chad He 
Assistant Member, FHCRC 
(206)  667-7004 
 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave 
D3-100 
Seattle, WA 98109 
 
IND Number: 132,920 
 
 
Supported by: 
EMD Serono 
 
Emergency number (24 hours): 206-598-6190 ask for on-call provider. 
 
 
FHCRC IRB Approval  
03 06 2020 
Document Released Date


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PROTOCOL SYNOPSIS 
 
Protocol Title 
A Phase I/II Trial Combining Avelumab and Trabectedin for 
Advanced Liposarcoma and Leiomyosarcoma 
Protocol Number 
FH9717 
Sponsor-Investigator 
Seth Pollack 
Funding Source & 
Collaborator 
EMD Serono 
Trial Phase 
Phase I/II 
Trial Type 
Single-arm, open label 
Clinical Indication 
Advanced Leiomyosarcoma and Liposarcoma 
Study Design 
The study will enroll in two phases. The Phase 1 will evaluate safety 
and tolerability of the combination with the option for dose 
escalation or de-escalation. If the combination is found to be well 
tolerated, Phase 2 will expand enrollment to evaluate efficacy. 
Primary Endpoints 
• 
Safety as measured by CTCAE v5.0. 
• 
Overall Response Rate (PR + CR, best response for each 
subject) by RECIST v1.1. 
Secondary Endpoints 
• 
Adverse event profile (based on National Cancer 
Institute Common Terminology Criteria for Adverse 
Events [CTCAE] v5.0) for all subjects,  
• 
Time to response,  
• 
Duration of response,  
• 
Progression-free survival (PFS) at 12 weeks (based on 
RECIST 1.1),  
• 
Clinical benefit rate (CR+PR+SD) at 12 weeks (based on 
RECIST 1.1),  
• 
Overall survival (OS) at 12 months 
Type of control 
Historical 
Investigational Drug 
Avelumab 
Dose 
800 mg q2wk 
Route of administration 
IV 
Regimen 
Avelumab 800 mg (q2wk) + Trabectedin 1.5 mg/m2 (q4wk) 
Expected number of trial 
subjects 
22, with possible expansion up to 34 (6 up to 18 in Phase 1, 
additional 16 in Phase 2) 
Estimated duration of trial 
2 years 
Duration of Participation 
1-2 year (estimated) 
 
 
 
 


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ABBREVIATIONS 
 
ADL 
AE 
ALT 
AST 
Activities of Daily living 
Adverse Event 
Alanine aminotransferase 
Aspartate aminotransferase 
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 
CT 
Case Report Forms 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T Lymphocyte 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
IB 
ICH 
IFN-g 
irAE 
End of Treatment 
Investigator Brochure 
International Conference on Harmonisation 
Interferon Gamma 
Immune-related adverse event 
IV 
LFT 
LLN 
Intravenous 
Liver function test 
Lower limit of normal 
mAb 
Monoclonal Antibody 
MHC 
MRI 
NCI-CTCAE 
NSAID 
Major Histocompatibility Complex 
Magnetic Resonance Imaging 
National Cancer Institute-Common Terminology Criteria for Adverse Event 
Non-steroidal anti-inflammatory drug 
OS 
Overall Survival 
OTC 
Over the Counter 
PD 
PD-1 
Progressive Disease 
Programed Death Receptor 1 
PD-L1 & 2 
Programed Death Receptor Ligands 1 & 2 
PFS 
Progression-free Survival 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SBRT 
Stereotactic Body Radiation Therapy 
STS 
T4 
Soft Tissue Sarcoma 
Free thyroxine 


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TSH 
Thyroid-Stimulating Hormone 
Treg 
ULN 
Regulatory T cell 
Upper limit of normal 
  
 


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Table of Contents 
1.0 
GENERAL INFORMATION ......................................................................................................................................................... 8 
1.1 
Protocol Title ............................................................................................................................................................... 8 
1.2 
Sponsor-Investigator Information............................................................................................................................... 8 
2.0 
BACKGROUND AND RATIONAL ................................................................................................................................................ 9 
2.1 
Introduction to “L-type” sarcomas ............................................................................................................................. 9 
2.2 
Preliminary Data ......................................................................................................................................................... 9 
2.3 
Clinical Data Using Avelumab in Solid Tumors .......................................................................................................... 10 
2.4 
Study Agent ............................................................................................................................................................... 11 
2.5 
Dose Rationale .......................................................................................................................................................... 13 
2.6 
Trabectedin - Commercially Sourced ........................................................................................................................ 14 
2.7 
Risks/Benefits............................................................................................................................................................ 15 
3.0 
STUDY OBJECTIVES ................................................................................................................................................................. 15 
3.1 
Study Objectives ....................................................................................................................................................... 15 
3.1.1 
Primary Objectives .................................................................................................................................................... 15 
3.1.2 
Primary Endpoints ..................................................................................................................................................... 16 
3.1.3 
Secondary Objectives ................................................................................................................................................ 16 
3.1.4 
Secondary Endpoints ................................................................................................................................................ 16 
4.0 
TRIAL OVERVIEW .................................................................................................................................................................... 17 
4.1 
Study Design ............................................................................................................................................................. 17 
4.1.1 
Introduction .............................................................................................................................................................. 17 
4.1.2 
Definition of dose limiting toxicity (DLT): ................................................................................................................. 17 
4.1.3 
Dosing Administration and Schedule ........................................................................................................................ 18 
4.1.4 
Assessment of Response and duration of therapy ................................................................................................... 18 
4.2 
Estimated Accrual ..................................................................................................................................................... 18 
5.0 
SUBJECT ELIGIBLITY ................................................................................................................................................................ 19 
5.1 
Inclusion criteria: ...................................................................................................................................................... 19 
5.2 
Exclusion criteria: ...................................................................................................................................................... 19 
6.0 
SUBJECT REGISTRATION ......................................................................................................................................................... 20 
7.0 
TREATMENT PLAN .................................................................................................................................................................. 20 
7.1 
Treatment Plan ......................................................................................................................................................... 20 
7.2 
Administration of agents .......................................................................................................................................... 21 
7.3 
Drug Product Information ......................................................................................................................................... 21 
7.4 
Schedule of Treatment Visits .................................................................................................................................... 22 
8.0 
SUBJECT EVALUATION............................................................................................................................................................ 22 
8.1 
Screening Evaluations ............................................................................................................................................... 22 
8.2 
On-Study Clinical Evaluations ................................................................................................................................... 23 
8.3 
End of Treatment (EOT) Procedures ......................................................................................................................... 24 
8.4 
Short Term Follow-Up / 30 Day Safety Assessment ................................................................................................. 25 


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8.5 
Long Term Follow-Up / 90 Day Safety Assessment .................................................................................................. 25 
8.6 
Long-Term Follow-Up for Survival ............................................................................................................................ 25 
8.7 
Imaging Assessments ................................................................................................................................................ 26 
8.8 
Analyte Listing ........................................................................................................................................................... 26 
8.9 
Correlative Studies .................................................................................................................................................... 26 
8.9.1 
Tumor Specimens ..................................................................................................................................................... 26 
8.9.2 
Research Blood Specimens ....................................................................................................................................... 27 
9.0 
SAFETY .................................................................................................................................................................................... 27 
9.1 
Adverse Event ........................................................................................................................................................... 27 
9.2 
Serious Adverse Event .............................................................................................................................................. 27 
9.3 
Unexpected Adverse Event ....................................................................................................................................... 28 
9.4 
Monitoring and Recordings Adverse Events ............................................................................................................. 28 
9.5 
Grading Adverse Event Severity ................................................................................................................................ 28 
9.6 
Attribution of an Adverse Event ............................................................................................................................... 28 
9.7 
Adverse Event Recording Period ............................................................................................................................... 29 
9.7.1 
Extended safety follow-up ........................................................................................................................................ 29 
9.8 
Adverse Event Reporting Requirements ................................................................................................................... 29 
9.8.1 
Reporting to Product Manufacturer (EMD Serono) .................................................................................................. 29 
9.8.2 
SAE/ONSET DATE Reporting to IRB ........................................................................................................................... 29 
9.8.3 
FDA Reporting Requirements ................................................................................................................................... 29 
10.0 
MANAGEMENT OF TOXICITY AND COMPLICATIONS ............................................................................................................. 31 
10.1 
Adverse Drug Reactions (ADRs) Related to Avelumab.............................................................................................. 31 
10.2 
Avelumab-Specific Adverse Events or Adverse Drug Reactions ............................................................................... 31 
10.2.1 
Symptoms of Infusion-Related Reactions ................................................................................................................. 31 
10.2.2 
Management of Infusion-Related Reactions ............................................................................................................ 31 
10.3 
Toxicity of Trabectedin ............................................................................................................................................. 41 
10.4 
Dose Modification of Trabectedin ............................................................................................................................ 41 
11.0 
SUBJECT DISCONTINUATION OF ACTIVE TREATMENT ........................................................................................................... 41 
12.0 
CONCOMITANT MEDICATIONS .............................................................................................................................................. 42 
12.1 
Pre-Medication Treatment with Trabectedin and Avelumab ................................................................................... 42 
12.2 
CYP3A4 Inhibitors and Inducers with Trabectedin ................................................................................................... 42 
13.0 
CONTRACEPTION ................................................................................................................................................................... 43 
14.0 
DATA AND SAFETY MONITORING PLAN ................................................................................................................................. 43 
15.0 
DATA MANAGEMENT/CONFIDENTIALITY .............................................................................................................................. 44 
15.1 
Data Quality Assurance ............................................................................................................................................. 44 
15.2 
Data Documents ....................................................................................................................................................... 44 
15.3 
Data Management .................................................................................................................................................... 44 
15.4 
Investigator Responsibilities for Data Collection ...................................................................................................... 44 
16.0 
STATISTICAL CONSIDERATIONS .............................................................................................................................................. 44 
16.1 
Study Design ............................................................................................................................................................. 44 


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16.2 
Phase I Design ........................................................................................................................................................... 45 
16.3 
Phase II Design .......................................................................................................................................................... 45 
16.4 
Data and Safety Monitoring Board (DSMB) .............................................................................................................. 45 
16.5 
Additional Efficacy Hypotheses ................................................................................................................................. 45 
16.6 
Ethnic and Gender Distribution Chart ....................................................................................................................... 46 
17.0 
INVESTIGATOR OBLIGATIONS ................................................................................................................................................ 46 
18.0 
ADMINISTRATIVE AND REGULATORY CONSIDERATIONS ....................................................................................................... 46 
18.1 
Study Site Training .................................................................................................................................................... 46 
18.2 
Documentation ......................................................................................................................................................... 46 
18.3 
Data Collection .......................................................................................................................................................... 47 
18.4 
Protocol Interpretation and Compliance .................................................................................................................. 47 
18.5 
Study Monitoring and Data Collection ...................................................................................................................... 47 
18.6 
Disclosure of Data/Publication ................................................................................................................................. 47 
18.7 
Ethical Considerations............................................................................................................................................... 47 
18.8 
Informed Consent ..................................................................................................................................................... 47 
18.9 
Institutional Review Board/Ethics Committee .......................................................................................................... 48 
18.10 
Subject Privacy .......................................................................................................................................................... 48 
19.0 
APPENDICES ........................................................................................................................................................................... 49 
19.1 
APPENDIX A: ECOG Performance Status Scale .......................................................................................................... 49 
19.2 
APPENDIX B: Karnofsky Performance Status Scale ................................................................................................... 50 
19.3 
APPENDIX C: Study Calendar .................................................................................................................................... 51 
19.4 
APPENDIX D: Assessment and Initial Management of Tumor Lysis Syndrome......................................................... 54 
19.5 
APPENDIX E: Women and Men of Childbearing Potential Definitions and Methods of Contraception ................... 55 
19.5.1 
Definitions ................................................................................................................................................................. 55 
19.5.2 
Contraception Guidance for Females of Childbearing Potential .............................................................................. 55 
19.5.3 
Contraception Guidance for Males of Childbearing Potential .................................................................................. 56 
19.6 
APPENDIX F: References ........................................................................................................................................... 57 
 
 
 
Table of Figures 
Table 1 - Analyte Listing .................................................................................................................................................................... 26 
 
 


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1.0 
GENERAL INFORMATION 
 
This is a phase I/II trial combining the PD-L1 inhibitory antibody, avelumab, with trabectedin, an FDA approved and 
commercially available drug for the treatment of leiomyosarcoma and liposarcoma (sometimes called “L-type” sarcomas). 
Subjects with advanced “L-type” sarcomas typically have survival in the 12-16 month range.Trabectedin has been proven in a 
phase III trial to improve the progression-free survival (PFS) from 1.5 months with dacarbazine to 4.2 months with trabectedin. 
This trial seeks to improve on the efficacy of trabectedin through a novel combination.  
Trabectedin was discovered through a high through-put screening process and questions remain regarding its primary 
mechanism of action in sarcoma. Trabectedin binds to the minor groove of the DNA helix and some of its mechanism may be 
direct activity preventing tumor replication and through cell-cycle specific toxicity in the tumor. However, trabectedin also clearly 
has potent killing of tumor associated macrophages (TAM) and this may also be related to its efficacy as these macrophages may 
play a critical role allowing tumor evasion of immune recognition tumor specific T cells.1-3 We hypothesize that combining the 
anti-macrophage activity of trabectedin and the T-cell checkpoint inhibition of avelumab will result in synergistic activity because 
the activated T cells will be unencumbered by inhibitory TAM activity. 
An initial 6 subjects (two groups of 3, up to a possible maximum of 18) will be treated in the Phase 1 portion of the study. 
Should two mor more dose limiting toxicities (DLTs) be observed, there will be a de-escalation, with potential for re-escalation. 
The primary objective is to assess the safety and tolerability of the study regimen in subjects with advanced L-type sarcomas, with 
a primary endpoint of safety as measured by CTCAE v5.0. If the combination is determined to have an acceptable toxicity profile, 
the trial will expand to a Phase 2 and enroll an additional 16 subjects, to determine an endpoint of response rate.  
 
This document is a clinical research protocol and the described study will be conducted in compliance with the IRB approved 
protocol, associated Federal regulations and all applicable IRB requirements. 
 
1.1 
Protocol Title 
A Phase I/II Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma  
 
1.2 
Sponsor-Investigator Information 
Seth Pollack 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave D3-100 
Seattle, WA 98109 
 
Funding Source: EMD Serono 
 
 
 
 


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2.0 
BACKGROUND AND RATIONALE 
 
2.1 Introduction to “L-type” sarcomas 
 
Leiomyosarcoma (LMS) and Liposarcoma are among the most common soft-tissue sarcoma (STS) subtypes, together with 
over 4000 new cases diagnosed annually. LMS is a cancer of smooth muscle which arises in the uterus in approximately 1/3 of 
cases4. The other 2/3 of cases frequently originate from the smooth muscles supporting the vascular architecture and can occur 
in the extremities, retroperitoneum and skin, as well as other anatomic locations. Surgical resection can be curative for localized 
disease; however, more than half of subjects with large, high-grade tumors will develop metastatic disease. Liposarcomas are 
cancers of adipocytic origins and are comprised of three subtypes (pleomorphic, myxoid/round cell and well/de-differentiated). 
They may occur in the extremities or retroperitoneal region and frequently recur regionally.  
Currently, the standard front line therapy for advanced sarcoma is single-agent doxorubicin that has an objective 
response rate (CR+PR) of 15% and results in a median progression free survival (PFS) of approximately 4.6 months5-7. The oral 
tyrosine kinase inhibitor, pazopanib (Votrient), was approved by the FDA for second line treatment of STS based on an 
improvement in PFS of 3.2 months was observed compared with placebo8,9. The drugs Eribulin and Trabectedin have recently 
been shown to give subjects several additional months of stable disease.   
Although no immunotherapies have yet been incorporated into the standard of care for STS, we at the sarcoma group of 
the Fred Hutchinson Cancer Research Center have built the most comprehensive sarcoma immunotherapy clinical research 
program in the world, with active clinical trials evaluating checkpoint inhibitors (anti-PD-1/PD-L1), vaccines, intra-tumoral toll-like 
receptor agonist injection and adoptive transfer of NY-ESO-1-specific autologous CD8+ T cells all for subjects with STS. Unlike some 
STS subtypes such as synovial sarcoma, LMS has a highly mutated genome10 suggesting that it has the potential to respond to 
immunotherapies that stimulate endogenous T cells11,12. 
 
2.2 Preliminary Data 
 
LMS tumors are infiltrated by immunosuppressive M2 tumor associated macrophages (TAM) 
We and others have found that LMS tumors have brisk CD11b+, CD68+ tumor associated macrophage (TAM) populations. 
Macrophages can be immune activating or inhibitory: M1 macrophages (HLA-DRhigh) produce IL-12, can lyse tumor and be effective 
antigen presenting cells. However, LMS tumors are generally infiltrated with immune inhibitory, M2 macrophages (CD163+, 
CD206+, CD115+) that produce the inhibitory cytokines IL-10 and TGFβ. Furthermore, these cells have the potential to directly 
promote tumor growth, angiogenesis and metastasis13. It has been found that LMS tumors have gene signatures consistent with 
high levels of M2 TAM infiltration. High TAM numbers correlate with poor prognosis in LMS subjects14. Gene expression profiles 
consistent with M2 phenotypic markers and increased expression of markers associated with M2 have been associated with worse 
outcomes independent of TAM presence15. Preclinical LMS models have demonstrated that elimination of TAM using an anti-
CD47 antibody can result in tumor shrinkage and decreased number of metastasis16. While an extensive body of literature argues 
for the role of TAM in LMS immune evasion, our unpublished data demonstrates that liposarcomas, and myxoid/round cell 
liposarcomas in particular, tend to also have very high levels of infiltrating TAM.  
 
 
 


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LMS tumors frequently express high levels of PD-L1 
 
 
We presented data at the 2014 Connective Tissue Oncology Meeting describing the PD-1 and PD-L1 expression in over 
80 soft tissue sarcoma samples including tumors from 27 LMS subjects. Expression levels in some STS subtypes, including synovial 
sarcoma were relatively low. However, positive PD-L1 expression was seen in 58% of LMS tumors tested and expression was high 
in 32% of the 27 tumors tested, including some subjects with staining in every visible tumor cell. We also saw cells staining for PD-
1 in 84% of these tumors with high levels of expression in 63% of tumors tested. While LMS frequently had high numbers of PD-
L1 and PD-1 expressing cells, 89% of liposarcoma tumors tested also had detectable PD-1 expressing T cells suggesting there may 
be a role in this tumor type as well. 
 
Trabectedin is an FDA approved treatment for L-type sarcomas that also kills TAM 
 
Trabectedin (Yondelis, Janssen Pharmaceuticals) was FDA approved on October 23, 2015 for the treatment of LMS and 
Liposarcoma. This approval was based on an improvement in median progression free survival of 4.2 months versus 1.5 months 
with dacarbazine.17 No statistically significant overall survival benefit has yet been reported. 
Interestingly, although trabectedin has been in clinical use for over a decade, controversy remains regarding its 
mechanism of action18. The standard explanation for trabectedin’s activity is that it binds to the minor groove of DNA and thus 
interferes with DNA repair machinery. However, trabectedin has also been demonstrated to interfere with TAM and this may be 
correlated with clinical activity1-3. Thus, trabectedin may actually function as an immunotherapy by overcoming TAM-induced 
immunosuppression in the tumor microenvironment. We believe this activity could lead to potential synergy with a T cell targeted 
checkpoint inhibitor such as avelumab.  
 
2.3 Clinical Data Using Avelumab in Solid Tumors 
Avelumab is a monoclonal antibody targeting PD-L1 currently in clinical development across Phases I, II, and III. The avelumab 
investigator brochure (IB) includes safety data from the following 4 clinical trials sponsored by the manufacturer, EMD Serono, 
and their industry collaborators: 
• 
EMR 100070-001: A Phase I, open-label, multiple ascending dose trial to investigate the safety, tolerability, 
pharmacokinetics, biological and clinical activity of avelumab in subjects with metastatic or locally advanced solid tumors 
and expansion to selected indications   
• 
EMR 100070-002: A Phase I trial to investigate the tolerability, safety, pharmacokinetics, biological and clinical activity of 
avelumab in Japanese subjects with metastatic or locally advanced solid tumors, with expansion part in Asian subjects 
with gastric cancer   
• 
EMR 100070-003: A Phase II, single arm, open-label, multicenter trial to investigate the clinical activity and safety of 
avelumab in subjects with Merkel cell carcinoma (MCC)   
• 
EMR 100070-004: A Phase III open-label, multicenter trial of avelumab versus docetaxel in subjects with non-small cell 
lung cancer that has progressed after a platinum-containing doublet  
• 
EMR 100070-001 is a Phase I, open-label, multiple ascending dose trial to investigate the safety, tolerability, PK, biological 
and clinical activity of avelumab in subjects with metastatic or locally advanced solid tumors and expansion to selected 
indications. This trial consists of 2 parts. In the dose escalation part, sequential cohorts of subjects were enrolled at 
progressively higher dose levels (ranging from 1.0, 3.0, 10.0, and 20.0 mg/kg once every 2 weeks) with a 3 + 3 algorithm 
design for determination of the maximum tolerated dose (MTD) of avelumab; in the treatment expansion phase, subjects 
in different tumor cohorts are being treated with 10 mg/kg of avelumab once every 2 weeks until, confirmed progression, 
unacceptable toxicity, or any reason for withdrawal occurs. More than 1500 subjects have been enrolled in the EMR 
100070-001 trial. The 3 + 3 dose escalation algorithm to determine the MTD is complete and a dose of 10 mg/kg once 
every 2 weeks was determined for the tumor expansion cohorts on the basis of safety, PK, and PD observations. The 
treatment expansion part of the trial consists of 16 tumor treatment cohorts. As of 05 November 2015 (data cutoff for a 
pre-planned safety data review by the study Safety Monitoring Committee [SMC]), 53 subjects in the dose escalation 
part had received avelumab (4, 13, 15, and 21 subjects had received 1.0, 3.0, 10.0, and 20.0 mg/kg of avelumab, 
respectively) and 1300 subjects in the pooled expansion part had received 10 mg/kg avelumab and were followed up for 


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at least 4 weeks.  
The safety summary for the IB summarizes data from 1300 subjects treated in the pooled treatment expansion cohort 
from the ongoing Phase I Trial EMR 100070-001 (as of 05 November 2015). The pooled data included subjects treated in all tumor 
expansion cohorts, including non-small cell lung cancer (NSCLC), metastatic gastric cancer, breast cancer, colorectal cancer, 
castrate-resistant prostate cancer, adrenocortical carcinoma, melanoma, mesothelioma, urothelial carcinoma, ovarian cancer, 
renal cell carcinoma, and squamous cell cancer of the head and neck. Safety data are also summarized for 52 subjects in the 
ongoing Phase I Trial EMR 100070-002 and for 88 subjects in the ongoing Phase II Trial EMR 100070-003 (as of 17 December 2015). 
For Trial EMR 100070-004, an overview of the serious adverse events (SAEs) is provided.  
Most of the observed adverse events (AEs) were either in line with those expected in subjects with advanced solid tumors 
or with class effects of MoAb blocking the PD-1/PD-L1 axis. Infusion-related reactions including drug hypersensitivity reactions 
and immune-mediated adverse reactions have been identified as important risks for avelumab. Respective risk mitigation 
measures have been implemented in all ongoing clinical studies with avelumab.  
Clinical efficacy in diseases other than sarcoma  
The clinical efficacy information summarized in the IB includes data from the NSCLC and ovarian cancer expansion cohorts 
of the ongoing Phase I Trial EMR 100070-001, and for 20 subjects in the gastric cancer expansion cohort of the ongoing Phase I 
Trial EMR 100070-002.  
The NSCLC expansion cohort in the ongoing Phase I Trial EMR 100070-001 had a cutoff date of 15 January 2015, 6 months 
after start of avelumab treatment of the last subject in this expansion cohort (a total of 184 treated subjects). The objective 
response rate (ORR) based on confirmed and unconfirmed responses for subjects treated in the NSCLC expansion cohort was 
14.1% (26 of 184 NSCLC subjects). Progression free survival (PFS) and overall survival (OS) were all evaluated for all NSCLC subjects 
treated in the expansion phase. As of 15 January 2015, the median PFS and OS for the NSCLC treatment expansion cohort were 
11.6 weeks and 8.4 months, respectively.  
The clinical activity of avelumab was also evaluated by subjects’ tumor PD-L1 expression status in the NSCLC expansion 
cohort. An objective response was observed in 20 of 122 subjects (16.4%) who were PD-L1 positive (defined as having at least 1% 
PD-L1 positive tumor cells) compared with 2 of 20 subjects (10.0%) who were considered PD-L1 negative (defined as having less 
than 1% PD-L1 positive tumor cells). A longer median PFS (12.0 vs 5.9 weeks) and OS (8.9 vs 4.6 months) were both observed in 
PD-L1 positive compared with PD-L1 negative subjects.  
The ovarian cancer expansion cohort had a data cutoff of 13 February 2015, approximately 13 weeks after the start of 
avelumab treatment on the last subject who was included in this pre-planned interim analysis on this expansion cohort. The ORR 
based on confirmed and unconfirmed responses for subjects treated in the ovarian cancer expansion cohort was 10.7% (8 of 75 
subjects). The median PFS for the ovarian cancer expansion cohort was 11.4 weeks (95% confidence interval (CI): 6.3 to 12.0 
weeks).  
The preliminary efficacy data for the ongoing Phase I Trial EMR 100070-002 are based on a data cutoff of 11 March 2015. 
As of the data cutoff, 3 of 20 subjects responded to trial treatment (all responses were partial responses [PRs] and all responses 
were confirmed responses), and the best overall response (BOR) was 15.0% (95% CI: 3.2% to 37.9%). The median PFS of this group 
was 11.9 weeks (95% CI: 6.0 to 12.3 weeks).  
 
2.4 Study Agent 
 
Because of the known role of programmed death ligand 1 (PD-L1) in the suppression of T cell responses and the strong correlation 
between PD-L1 expression and prognosis in cancer, the blockade of the PD-L1/programmed death 1 (PD-1) interaction presents 
a highly promising strategy for cancer immunotherapy. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and PD-
1. This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, resulting in the restoration of cytotoxic T cell response.  
Nonclinical pharmacology  


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The nonclinical pharmacology studies have shown that avelumab functionally enhances T cell activation in vitro and 
significantly inhibits the growth of PD-L1 expressing tumors in vivo. Avelumab binds to human PD-L1 with a high affinity of 0.7 nM 
and not to any other B7 family proteins, and competitively blocks the interaction of PD-L1 with PD-1. The in vitro study results 
have shown that by binding to PD-L1, avelumab effectively enhances T cell activation as measured by interleukin (IL)-2 or 
interferon-gamma (IFN-g) production. In addition, as a fully human IgG1 antibody, avelumab has the potential to trigger the 
antibody-dependent cell-mediated cytotoxicity (ADCC) against target cells expressing PD-L1.  
As a monotherapy, avelumab has demonstrated anti-tumor activity against murine MC38 colon carcinoma tumors that 
are characterized by a high level of PD-L1 expression. A dose-dependent trend was observed, and 400 μg per dose (20 mg/kg, 
approximately) was identified as the optimally effective dose when given every third day for 3 total doses. The in vivo anti-tumor 
effects were found to be primarily mediated by CD8+ T cells as evidenced by the observation that in vivo depletion of this cell 
type completely abrogated the anti-tumor efficacy of avelumab. The contribution of ADCC as a potential mechanism of anti-tumor 
activity was further demonstrated in vivo using a deglycosylated version of avelumab to abrogate fragment crystalline (Fc) 
receptor binding or via the systemic depletion of natural killer (NK) cells. In both settings, loss of in vivo ADCC potential significantly 
reduced the anti-tumor activity.  
The combination of avelumab with commonly used cancer treatments, such as cytotoxic agents and radiation therapy, 
resulted in an improved anti-tumor activity. Chemotherapy with combination therapy (with folinic acid, 5-fluorouracil, and 
oxaliplatin [FOLFOX], and radiation therapy showed the better tumor growth inhibition. In particular, radiation therapy was found 
to be a highly synergistic combination with avelumab capable of causing complete regression of established tumors probably 
through generating anti-tumor immune memory.  Various immunomonitoring assays were incorporated into the in vivo studies. 
Treatment with avelumab resulted in a consistent increase in the percentage of CD8+PD-1+ T cells and an increased frequency of 
CD8+ T cells with an effector memory (TEM) phenotype as determined by flow cytometry. Furthermore, these changes correlated 
with the anti-tumor effect. Increases in tumor antigen-specific T cell responses, as measured by enzyme-linked immunosorbent 
spot and pentamer immunoassays, were evident following treatment with avelumab and these responses were enhanced when 
combined with FOLFOX or radiation. Hence, increases in CD8+PD-1+ T cells, CD8+ TEM cells, and antigen-specific T cell responses, 
may be leveraged as pharmacodynamics (PD) biomarkers with translational relevance to the clinical setting.  
 
Nonclinical pharmacokinetics and metabolism  
As expected for a monoclonal antibody (MoAb) binding to a cellular target, avelumab demonstrated pronounced non-
linear pharmacokinetic (PK) characteristics in mice and monkeys in single dose studies at doses below 20 mg/kg, suggesting a 
combination of first order catabolic clearance and saturable target-mediated clearance. Toxicokinetic data from repeated dose 
toxicity studies in mice, rats, and monkeys indicated that the PK of avelumab was linear within the dose range of 20 to 140 mg/kg, 
suggesting that the target mediated clearance could be saturated when higher doses than 20 mg/kg are administered. Similar 
terminal half-lives (t1/2) of approximately 60 to 70 hours were observed in toxicity studies in mice and monkeys.  A PK/ PD study 
in C57BL/6 mice was used to correlate receptor occupancy data of avelumab in blood with drug concentrations. A plasma 
concentration of 58.5 μg/mL was calculated as required for 95% target occupancy (TO) in this model.  
Avelumab is immunogenic in mice, rats, and monkeys with a lower incidence of anti-drug antibodies (ADAs) at higher 
doses. The latter is probably due to interference of free avelumab with the immunogenicity assay (drug interference). In animals, 
the generated ADAs seem to have the potential to increase the clearance of the avelumab. As the fully human avelumab 
represents a foreign protein to the immune system of animals, the observed immunogenicity of avelumab in rodents and non-
human primates is not deemed predictive for an immune response to avelumab in humans.  
 
Nonclinical toxicology  
The toxicological profile of avelumab was evaluated in repeat-dose toxicity studies of 4-week duration with once weekly 
IV bolus injection/infusion of avelumab in mice, rats, and cynomolgus monkeys. A repeat-dose toxicity study with intermittent 
once weekly IV infusion of avelumab over 13 weeks followed by an 8-week recovery period in cynomolgus monkeys was also 
conducted. In addition, in vitro cytokine release assays (CRA) in human and cynomolgus monkey whole blood and peripheral blood 
mononuclear cells (PBMCs) followed by an optimized CRA in phytohemagglutinin (PHA) pre-stimulated PBMCs from 16 human 
volunteers was completed. Tissue cross reactivity (TCR) studies in normal human and cynomolgus monkey tissues have also been 
was performed.  


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On the basis of the binding affinity data, the cynomolgus monkey and the mouse were selected as relevant species for 
the nonclinical safety testing of avelumab. Due to severe hypersensitivity reactions after repeated administration of avelumab in 
mice and the low binding affinity in rats, rodent species are not considered appropriate for nonclinical safety testing of avelumab 
and therefore, a single species approach (cynomolgus monkey only) is applied. In cynomolgus monkeys neither in the pilot 4-week 
Iv repeat-dose toxicity study nor in the pivotal 13-week study have clinical signs of hypersensitivity been seen after repeated 
treatment with avelumab at dose levels of 20, 60, and 140 mg/kg, respectively. For the pilot 4-week study as well as for the pivotal 
13-week Iv repeat-dose toxicity study, a no observed adverse effect level (NOAEL) of 140 mg/kg for systemic toxicity was 
established.  Initial CRA in human and cynomolgus monkey whole blood and PBMCs revealed no clear-cut evidence for release of 
pro-inflammatory cytokines. However, a subsequent, optimized CRA demonstrated evidence of potential cytokine release in PHA 
pre-stimulated PBMCs.  
 
2.5 Dose Rationale 
 
A dose of 10 mg/kg of avelumab, intravenous (IV) once every 2 weeks, was selected in this trial as well as other on-going trials 
around the country. This starting dose is based on the preliminary pharmacokinetic (PK), target occupancy, and preliminary 
clinical safety data collected in the clinical trials. Modeling and simulation in > 1700 patients have been used to provide a 
rationale for changing the regimen for avelumab from the currently approved 10 mg/kg every 2 weeks to a proposed flat dose 
of 800 mg every 2 weeks for adults. For patients <18 years of age, the body weight based dosing will still be employed. A flat 
dose regimen is expected to provide more consistent dosing across body weights, minimize drug wastage, facilitate preparation 
and administration, and reduce pharmacy errors.  
Pharmacokinetics and Target Occupancy  
Avelumab plasma levels leading to full programmed death ligand 1 (PD-L1) receptor target occupancy (TO) on PBMCs 
resulted in tumor growth inhibition in a murine disease model. Therefore, full TO on PBMCs can be considered a PD marker for 
the ability of avelumab to act on its target and to show clinical activity. Preliminary PK data from EMR 100070-001 show that the 
concentration at the end of dose interval (Cmin) increased more than proportionally to dose between 1 to 10 mg/kg, but 
proportionally for doses above 10 mg/kg. Consistently the t1/2 also increased with the dose. However, the average value was 102 
and 120 hours for 10 mg/kg and 20 mg/kg, respectively, with no significant difference between these two dose groups. This PK 
characteristic suggests that target mediated drug disposition is involved in the clearance of avelumab and a high PD-L1 TO is likely 
achieved at the trough concentration for doses of 10 mg/kg and 20 mg/kg.  
The in vitro target occupancy data further support that a high TO is likely achieved at 10 mg/kg and above: 
• 
Target occupancy was measured ex vivo by flow cytometry on peripheral blood CD3+ T cells from subjects (n=9) treated 
with avelumab. After the first dose of the initial dose-escalation portion of Trial EMR 100070-001, the observed mean 
target occupancy reached a plateau of about 90% on Day 15 pre-dose for dose levels of 3 mg/kg and above.   
• 
In addition, in vitro target occupancy was measured using flow cytometry on peripheral blood CD3+ T cells from 8 healthy 
volunteers after spiking avelumab over a concentration range of 0.003 to 10 μg/mL. A 50% target occupancy was 
observed at a drug concentration (standard deviation [StD]) of 0.122 (0.042) μg/mL, and a concentration of 1 μg/mL 
avelumab was required for > 95% target occupancy. Based on these data and the trough serum levels observed in EMR 
100070-001, target occupancy was projected to reach or exceed > 95% throughout the entire dosing interval for 10/13 
subjects at 3 mg/kg, and for all (15/15) subjects at 10 mg/kg group from dose escalation group in EMR 1000700-001. 
Based on the ex vivo peripheral blood CD3+ T cell and in vitro target occupancy results, the dose of 10 mg/kg every 2 
weeks is expected to achieve target saturation during the entire dosing interval in the majority of subjects.  Clinical 
Safety Data Related to Dose  As of the safety cutoff date of 05 November 2015, 1353 subjects have received at least 1 
dose of avelumab at doses ranging from 1.0 to 20 mg/kg in the Phase I Trial EMR 100070-001, of which 1315 have 
received the proposed dose of 10 mg/kg (15 in the dose escalation part of the study and 1300 subjects in the pooled 
expansion cohort).   
In the dose escalation portion of the Phase I study, there was no evidence of differences in the safety profile across all 
administered dose levels from 1 mg/kg to 20 mg/kg. The MTD was not reached. Ongoing review of the safety data by the Safety 
Monitoring Committee (SMC) suggests an acceptable safety profile of avelumab administered at the 10 mg/kg every 2 weeks dose 
and schedule. Treatment-related treatment-emergent adverse events (TEAEs) were observed in 813 (62.5%) subjects in the 


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pooled expansion cohort. The most frequently observed treatment related TEAEs (incidence > 5%) were fatigue (212 subjects, 
16.3%), infusion-related reaction (209 subjects, 16.1%), nausea (108 subjects, 8.3%), chills (102 subjects, 7.8%), diarrhea (79 
subjects, 6.1%), and pyrexia (72 subjects, 5.5%). Grade ≥ 3 treatment-related TEAEs were observed in 124 subjects (9.5%) in the 
pooled expansion cohort. The most frequently reported Grade ≥ 3 treatment- related TEAEs were gamma-glutamyl transferase 
increased (GGT) and infusion-related reaction (each occurred in 9 subjects; 0.7%). Infusion-related reactions including drug 
hypersensitivity reactions and immune-mediated adverse reactions have been identified as expected adverse drug reactions of 
avelumab. The safety profile of avelumab is consistent with findings reported for other anti-PD-1 or anti-PD-L1 antibodies. 
Preliminary data from EMR 100070-001 showed that avelumab at doses up to 20mg/kg Iv every 2 weeks was well tolerated, and 
the dose of 10 mg/kg Iv every 2 weeks was considered to have an acceptable safety profile for further investigation in clinical 
studies.  
In conclusion, based on the PK results and the receptor occupancy data, sufficient trough concentrations appear to be 
achieved for full TO in the blood in the majority of subjects receiving the 10 mg/kg dose. Within the dose range of 1 mg/kg to 20 
mg/kg, avelumab was well tolerated and is deemed to have an acceptable safety profile. Based on the above analyses, a dose of 
10 mg/kg Iv once every 2 weeks was considered to have a favorable risk benefit profile and thus represents an appropriate dose 
for further investigation in registration studies of avelumab.  
 
2.6 Trabectedin - Commercially Sourced 
 
Trabectedin is an FDA approved synthetic, marine-derived alkylating agent discovered in a high through-put screen of 
compounds from the Caribbean tunicate, Ecteinascidia turbinate20. With limited systemic therapy options available for sarcomas 
as a whole, trabectedin has the opportunity to be significantly beneficial for subjects with metastatic disease. Evidence shows 
that disruption of DNA by trabectedin ultimately causes apoptosis and sensitization of cell lines to Fas-mediated cell death 21.  
Multiple studies, including specific experiments in soft tissue sarcomas, have also validated that trabectedin works at the 
level of the tumor microenvironment with selective activity against monocytes and tumor-associated macrophages 22,23. The 
inhibition of these immune factors allows for the prevention of angiogenesis and further disease progression 24,25. Deprivation of 
inflammatory-mediated support in the tumor microenvironment may be one of the most important aspects of trabectedin’s 
mechanism of action, making the drug efficacious as a cancer treatment. Other mechanisms for the chemotherapeutic actions of 
trabectedin may include modulation of the cell cycle and interaction with transcription factors 26,27. 
 
Phase I Trials 
 
A number of Phase I trials have assessed differential dosing and infusion schedules for the administration of trabectedin 
28-34. Results from these studies have established the optimal regimen of administration to be a 1.5 mg/m2 infusion over 24 hours 
every 3 weeks 35. Notably, Taamma and colleagues performed a Phase I trial of trabectedin in 52 subjects with treatment refractory 
tumors that recommended the current optimal dosing schedule of 1.5 mg/m2 for a 24-hour continuous infusion 31. The most 
prevalent dose limiting toxicities in the study were hematological in nature. At the recommended dose, severe neutropenia was 
reported in 33% of cycles, severe thrombocytopenia in 10% of cycles and reversible, but severe, elevations in transaminase levels 
in 38% of cycles.  
Combination therapies of trabectedin with other chemotherapeutic agents including gemcitabine, doxorubicin, doxil, 
and cisplatin have also been assessed in Phase I trials 36-41. The most promising results from these studies in sarcoma subjects 
have been from the trials administering trabectedin in combination with doxorubicin. One of the trials showed a response rate 
(RR) of 18% and stable disease in 56% of soft tissue sarcoma subjects (n=29) 40. None have seen significant safety concerns. 
Based on these studies, the US, standard starting dose is 1.5mg/m2 – this is noted in the trabectedin package insert, 
however around the world standard dosing varies. In Japan, the standard starting dose is 1.2 mg/m2 as this was the MTD they 
found on a phase I trial they performed.19 The DLTs observed on the Japanese phase I at the 1.5 mg/m2 dosing were LFT 
abnormalities. 
 
Phase II Trials  
 
Two Phase II trials in 2004 provided the initial analysis of trabectedin in soft tissue sarcomas. The first of these studies 
was run on 54 pretreated soft tissue sarcoma subjects, and reported a low response rate of 4%, but a high disease control rate at 
6 months of 24% 42. Trabectedin was administered at a dose of 1.5 mg/m2, over 24 hours every 3 weeks. Approximately half of 


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the subjects in the study eventually developed grade 3/4 AST and ALT levels. Another common adverse event was fatigue, being 
grade 3/4 in 15% of subjects. In this trial, 4 subjects (7.4%) discontinued trabectedin due to adverse events. In addition, there 
were two treatment-related deaths, both were subjects who developed acute renal failure.  
The second Phase II trial, published in 2004, again reported a low response rate of 8% and a one year overall survival rate 
of 53% in 36 previously treated sarcoma subjects 43. This study also utilized the same dosing schedule of trabectedin (1.5 mg/m2, 
over 24 hours every 3 weeks). The toxicity profile of the drug was similar to previous trials with subjects experiencing elevations 
in transaminases, fatigue and hematological toxicity. Growth factors such as, G-CSF, can be administered to help prevent 
hematological toxicity, however a recent retrospective study showed that G-CSF administration has only been used in about 10% 
of Phase II trials of trabectedin in solid tumors 44. 
Early promising results in these Phase II studies led the European Organization for the Research and Treatment of Cancer 
(EORTC) to initiate a Phase II trial of trabectedin in 104 subjects treated in the second and third-line setting 45. This trial also 
reported a low response rate of 8%. The 6-month PFS was 29% and the median overall survival (OS) was reported as 9.2 months. 
Subsequently, a further Phase II trial in 36 subjects was run to evaluate the activity of trabectedin in the first-line setting. The 
overall response rate was reported as 17%, and the 1-year PFS and OS rates were 21% and 72%, respectively 46. This study also 
importantly concluded that trabectedin has similar ranges of objective responses and overall survival rates in the first-line setting 
to the two most active drugs in soft tissue sarcomas: doxorubicin and ifosfamide. 
Demetri and colleagues performed a Phase II trial randomizing 270 subjects with leiomyosarcoma and liposarcoma to 
receive either 1.5mg/m2 of trabectedin over 24 hours every 3 weeks, or 0.58 mg/m2 over 3 hours every week for 3 out of 4 weeks 
47. Subjects were required to have experienced documented disease progression while on doxorubicin and ifosfamide prior to 
trial entry. The 24-hour infusion schedule showed a significantly longer median time to progression (TTP) (3.7 vs. 2.3 months) and 
PFS at 6 months (3.3 vs. 2.3 months) as compared to the 3-hour infusion schedule. No significant difference in overall survival was 
observed between the two arms of the trial, however, there was a strong trend favoring the 24-hour infusion schedule (13.9 
months vs. 11.8 months). Trabectedin was generally well tolerated in this study, with the most frequently reported grade 3/4 
adverse events being neutropenia and elevated transaminases. Febrile neutropenia occurred in 1% of subjects, and the majority 
of adverse events were mild to moderate. There was also no documentation of cumulative toxicities. Another Phase II trial 
recommended the use of trabectedin as a neoadjuvant therapy for subjects with advanced myxoid liposarcoma 48. 
The results of these Phase II trials led to licensing approval of trabectedin by the European Union for advanced soft tissue 
sarcoma in 2007, and the drug is now approved in over 70 countries. 
 
Phase III and FDA Approval 
 
The Phase III trial of trabectedin vs. dacarbazine resulted in FDA approval of trabectedin based on a PFS improvement of 2.7 
months over single agent dacarbazine17.  FDA approved trabectedin under the trade name Yondelis® on October 23, 2015 for the 
treatment of LMS and Liposarcoma.  
 
2.7 Risks/Benefits 
 
Trabectedin as a single agent represents a clear advance in the standard of care for subjects with leiomyosarcoma however with 
PFS in the 3-5 months range and the OS on the trial used for the approval of trabectedin was 12.4 months, there is clearly a 
desperate need for improved treatments. Given that immunomodulation clearly occurs as a result of trabectedin, including the 
elimination of TAM in LMS, there is the potential for synergy with a highly active checkpoint inhibitor such as avelumab. 
 
 
3.0 
STUDY OBJECTIVES 
 
3.1 Study Objectives 
 
3.1.1 Primary Objectives 
• 
To assess the safety and tolerability of the combination of trabectedin and avelumab in subjects with advanced 
leiomyosarcoma and liposarcoma 
• 
To assess the objective response rate of advanced L-type sarcoma subjects receiving the combination regimen of 
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3.1.2 Primary Endpoints 
• 
Safety as measured by CTCAE v5.0. 
• 
Overall Response Rate (PR + CR, best response for each subject) by RECIST v1.1. 
 
3.1.3 
Secondary Objectives 
• 
To further explore the clinical activity and safety profile of avelumab and trabectedin as a combination therapy 
3.1.4 Secondary Endpoints 
• 
Adverse event profile (based on National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE] 
v5.0) for all subjects 
• 
Time to response 
• 
Duration of response 
• 
Progression-free survival (PFS) at 12 weeks, based on RECIST 1.1 
• 
Clinical benefit rate (CR+PR+SD) at 12 weeks, based on RECIST 1.1 
• 
Median overall survival (OS) at 12 months 
 
 


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4.0 
TRIAL OVERVIEW 
 
4.1 Study Design 
4.1.1 
Introduction  
This is a Phase I/II, non-randomized, open-label, interventional study of avelumab combined with trabectedin for subjects with 
advanced L-type sarcoma.  
The Phase I stage will evaluate trabectedin (1.5 mg/m2) combined with avelumab (800 mg flat dose). Dose reduction for the 
trabectedin therapy is permitted after the first cycle. Events which would required  a dose reduction of trabectedin are outlined 
in Section 10, however additional dose reductions may be made at the discretion of the treating clinician down to a lowest possible 
dose of 1 mg/m2. There will be no dose escalation or re-escalation of trabectedin. 
4.1.2 
Definition of dose limiting toxicity (DLT):  
During the phase I portion of the protocol, a DLT will be defined as any grade 3 or higher adverse events, at least possibly-related 
to protocol therapy, which occur during the first 6 weeks of treatment, with the following specifications and limitations: 
• 
Lab abnormalities that have no clinical sequalae (e.g. febrile neutropenia from low ANC, bleeding from 
thrombocytopenias etc.) and resolve to grade 1 or better within 7 days will not be considered a DLT. 
• 
Any elevation in total bilirubin > 2x institutional ULN will be considered a DLT. 
• 
Any elevation in AST and ALT over 8x institutional ULN will be considered a DLT. 
• 
ANC <500/μL lasting 5 days or more will be considered a DLT. 
• 
Platelets < 25,000/ μL  (grade 4 toxicity) lasting 5 days or more will be considered a DLT. 
• 
Hemoglobin < 7.0 lasting 5 days or more will be considered a DLT. 
Additionally, should any grade 5 toxicity (death) occur that is at least possibly-related to treatment (e.g. not easily 
otherwise explained; for example: a car accident), this will be considered a DLT. In the event of any grade 5 toxicity, enrollment 
will immediately be put on hold and a data safety monitoring board (DSMB) meeting will be requested immediately.  
All clinically significant grade 3 or higher toxicities will be recorded and presented to the DSMB at scheduled meetings. 
Expected toxicities are those outlined in Section 10. The DSMB will be specifically instructed to consider whether there are 
increased frequency of known toxicities and to make recommendations accordingly if appropriate. Section 10 summarizes criteria 
for required dose adjustments. 
Enrollment during the first cohort of the Phase 1 portion of the trial will be staggered. The first subject must have received 
their second dose of both avelumab and trabectedin prior to treatment of the second subject, and the second subject must have 
received their second dose of both avelumab and trabectedin prior to treating the third subject. In cases where the first subject’s 
second doses of avelumab and/or trabectedin is delayed beyond week 4, either due to trabectedin toxicity or DLT, or is withdrawn 
or discontinued from the study, the second subject will be allowed to enroll and start therapy. However, the second subject must 
complete their second dose of trabectedin and avelumab prior to the start of the third subject. 
Should 2 or more DLTs be observed in the first 6 subjects, the starting trabectedin dose will be reduced to 1 mg/m2 and 
the Phase 1 will expand to enroll an additional 6 subjects at the new starting dose. Should two or more  DLTs be observed in the 
6 subjects enrolled at 1 mg/m2  the study will go on hold and a DSMB will meet to discuss if there are modifications that could 
allow the protocol to safely be re-opened. If <2 DLTs are observed in the 6 subjects on the 1.0 mg/m2 cohort, enrollment will 
expand to a third cohort, enrolling an additional 6 subjects at 1.2 mg/m2 of trabectedin. If 2 or more DLTs are observed at 1.2 
mg/m2, then 1.0mg/m2 will be determined to be the recommended Phase 2 dose (RP2D). The highest dose with <2 DLTs will be 
selected for Phase 2 dosing. If one of the first six subjects does not complete the DLT period for a reason unrelated to toxicity (for 
example withdrawal of consent or tumor progression) that subject may be replaced. 
In Phase 2, the study will go on hold and a DSMB meeting will be triggered if more than 30% of subjects have unexpected, 
probably related SAE’s grade 3 or higher that do not resolve to grade 2 within 2 weeks.  
 
 


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In any subsequent Phase 1 cohorts (1.0 mg/m2 dosing and 1.2 mg/m2 dosing of trabectedin) subjects may be treated 
concurrently without delay. Prior to beginning Phase 2, each subject on the phase 1 portion must have received their second dose 
of both avelumab and trabectedin or completed their treatment (e.g. come off study for symptomatic progression).  
 
4.1.3 
Dosing Administration and Schedule 
A treatment schedule is provided in Appendix C. Avelumab will be administered via IV infusion over 60  minutes (+/- 10 
minutes). Trabectedin is given as an outpatient 24-hour infusion by pump. During week 1, subjects will receive both drugs: 
avelumab followed by the standard 24-hour infusion of trabectedin. Following avelumab infusions, subjects must be observed for 
60 minutes ± 10 minutes (Cycle 1) or 30 minutes ± 5 minutes (Cycle 2+) post-infusion, prior to beginning trabectedin, for potential 
infusion-related reactions.  
Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses 
(Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward.  After Cycle 2 of trabectedin, dosing may 
extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin 
beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator.  
It should be noted that trabectedin has significant single agent toxicity. Treatment schedule and evaluation of toxicity 
are discussed in Section 7.0. 
 
4.1.4 
Assessment of Response and duration of therapy 
Subjects will have their first post-treatment scan during week 12 and every 12 weeks after that. Additional scans may be 
ordered at the discretion of the treating physician, if clinically indicated. If any non-protocol scans are collected, a RECIST 1.1 read 
should be obtained. Response assessment will be based on RECIST 1.1. Subjects who are demonstrating CR must be treated for 
at least 12 weeks after CR was confirmed (2nd scan with CR). Subjects confirmed to have a CR who have been taken off treatment 
will continue to be followed on study and monitored radiographically every 12 weeks for up to 2 years. Upon relapse they may be 
re-treated with trabectedin and avelumab.  
It is possible that a subject may become surgically resectable during the course of treatment. Subjects who are rendered 
no evidence of disease via a surgical intervention after successful combination therapy should be treated just as if they had a CR 
in response to the medication. These subjects will receive an additional 12 weeks of protocol therapy post-surgery, and will be 
followed on study and monitored radiographically every 12 weeks for up to 2 years. Upon relapse, they may be re-treated with 
trabectedin and avelumab. 
Subjects with an unconfirmed or equivocal progression of disease may continue trial treatment until progression is 
confirmed by repeat CT/MRI, 6 weeks later. Subjects may continue protocol therapy until a confirmation scan is obtained, or until 
symptomatic progression or clinical decline. Subjects may only continue to receive study treatment while waiting for confirmation 
of PD if the following criteria are met: 
 
• 
No significant decline in ECOG performance status in the opinion of the treating investigator 
• 
Absence of rapid progression of disease in the opinion of the treating investigator  
• 
Absence of progressive tumor at critical anatomical sites (e.g. cord compression) requiring urgent alternative 
medical intervention 
4.2 Estimated Accrual 
• 
Phase 1: 6 subjects, may expand up to 18 
• 
Phase 2: 16 subjects 
A minimum of 22, and up to a possible total of 34 subjects are anticipated to receive treatment.   
 


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5.0 
SUBJECT ELIGIBLITY 
5.1 Inclusion criteria: 
1. Subjects, ≥ 18 years old, must have a histologically confirmed diagnosis of advanced (metastatic or unresectable) soft 
tissue sarcoma with one of the following subtypes:  
a. Leiomyosarcoma 
b. Liposarcoma 
2. Subject must be clinically indicated to receive trabectedin therapy as part of routine care. Subjects may be first line, or 
have received any number of prior systemic therapies. 
3. Subjects must have adequate organ function and blood chemistry and blood count parameters as defined below. 
Transfusion is permitted as clinically indicated. 
a. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) mg/dL 
b. AST ≤2.5 x ULN and ALT ≤2.5x ULN 
c. 
Alkaline Phosphatase < 2.5x ULN 
d. Serum creatinine ≤1.5 x ULN  
e. Calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula may be included) 
f. 
Creatinine phosphokinase (CPK) ≤2.5 × ULN 
g. 
Absolute neutrophil count (ANC) ≥1.5 × 109/L; 
h. Platelet count ≥100,000/mm3 (100 × 109/L); 
i. 
Hemoglobin ≥9 g/dL 
4. Subjects must demonstrate a left ventricle ejection fraction (LVEF) of > 45% by ECHO or MUGA.  
5. Male or non-pregnant and non-breast feeding female: 
a. Females of child-bearing potential must agree to use highly effective contraception without interruption 
from initiation of therapy and while on study medication and have a negative serum pregnancy test (β -
hCG) result at screening and agree to ongoing pregnancy testing during the course of the study, and at the 
end of study treatment. A highly effective method of contraception is defined as one that results in a low 
failure rate (that is, <1% per year), when used consistently and correctly, such as implants, injectables, 
combined oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, or a 
vasectomized partner (Appendix C).  
b. Male subjects must practice abstinence or agree to use a condom during sexual contact with a pregnant 
female or a female of childbearing potential while participating in the study (Appendix C). 
6. All ongoing toxicities related to prior therapies must be resolved to Grade 1 or better (except alopecia). 
7. Subjects must have an ECOG performance status ≤ 1 or Karnofsky performance scale ≥ 70 (see Appendix A and B). 
8. Subjects must have one or more measureable lesions, as determined by RECIST v1.1 assessed by CT or MRI. 
9. Subjects must have a life expectancy of ≥ 6 months, as determined by the treating physician. 
10. Ability to understand and sign informed consent document. 
11. Willingness and ability to comply with the scheduled visits, laboratory tests, and other study procedures. 
 
5.2 Exclusion criteria: 
Subjects are not eligible for the trial if they fulfill any of the following exclusion criteria: 
1. Known active, uncontrolled, or symptomatic central nervous system (CNS) metastases. A subject with controlled and 
asymptomatic CNS metastases may participate in this study. As such, the subject must have completed any prior 
treatment for CNS metastases ≥ 28 days (including radiotherapy and/or surgery) prior to the start of treatment in this 
study and should not be receiving chronic corticosteroid therapy in excess of 10 mg daily prednisone (or equivalent) for 
CNS metastases. Subjects with known CNS metastases must be confirmed radiographically stable by at least one 
imaging study, at least 28 days from last treatment. 
 
 


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2. Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 2 
weeks of enrollment. 
3. Prior organ transplantation, including allogeneic stem-cell transplantation. 
4. Prior treatment with trabectedin. 
5. Significant acute or severe chronic infections including, among others: 
• 
Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS) 
• 
Known active infection with Hepatitis B or Hepatitis C. 
6. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: 
a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive 
treatment are eligible 
b. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for 
the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day 
c. 
Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, 
introocular, or inhalation) are acceptable 
7. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v 5.0), any history of 
anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) 
8. Pregnant or lactating females. 
9. Known, active alcohol or drug abuse. 
10. All other significant diseases (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of 
the Investigator, might impair the subject’s tolerance of trial treatment. 
11. Any vaccination within 4 weeks of the first dose of avelumab, with the following exceptions: 
a. Administration of inactivated vaccines, including inactivated flu vaccines, are allowable. However, they should not 
be given within 2 weeks prior to starting study treatment.  
12. Clinically significant cardiovascular disease including cerebral vascular accident/stroke (<6 months prior to enrollment), 
myocardial infarction (<6 months prior to enrollment), congestive heart failure with NYHA class II or greater or serious 
cardiac arrhythmia requiring medication. 
13. Severe (requiring active treatment) acute or chronic medical conditions including: colitis, inflammatory bowel disease, 
pneumonitis, or pulmonary fibrosis. 
14. Recent (within the past year) or active suicidal ideation or behavior. 
 
 
6.0 
SUBJECT REGISTRATION 
 
Each subject who enters into the screening period for the study receives a unique subject identification number before any study-
related procedures are performed. The subject identification number will be assigned. This number will be used to identify the 
subject throughout the clinical study and must be used on all study documentation related to that subject.  
 
The subject identification number must remain constant throughout the entire clinical study; it must not be changed after initial 
assignment, including if a subject is rescreened.  
 
A subject is considered enrolled when the investigator decides that the subject has met all eligibility criteria. The investigator is 
to document this decision and date, in the subject’s medical record and in/on the electronic case report form (eCRF). 
7.0 
TREATMENT PLAN 
 
7.1 Treatment Plan  
Trabectedin is given every three or four weeks (Cycle 1 and Cycle 2 Q3W, and then Q4W for Cycle 3+) and avelumab is given every 
two weeks. During week 1, subjects will receive avelumab followed by a 24 hour infusion of trabectedin afterwards. Trabectedin 
should be administered on a Q3W schedule for Cycle 1 and Cycle 2. Starting at Cycle 3, trabectedin will be administered on a Q4W 
schedule, to coincide with avelumab dosing. For toxicity management after Cycle 2, trabectedin administration may delay to Q5W, 
as clinically indicated for toxicity management only.  Delays of trabectedin beyond 5 weeks may be allowed but require written 


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approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be 
administered first.  
 
Avelumab is administered as a 60 minute IV infusion at a flat dose of 800 mg, diluted with either a 0.9% or 0.45% saline solution. 
In order to mitifate infusion-related reactions, subjects should be premdicated with an antihistamine and paracetamol (e.g., 25-
50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent)) within 30-60 minutes prior to the 
first four (4) doses of avelumab. Premedication may be discontinued for Cycle 5 and beyond of avelumab, at the investigator’s 
discretion. If any infusion-related reaction occurs, the premedication should immediately be reinstated for all cycles of avelumab. 
 
For Cycle 1, avelumab will be given first over 60 minutes (+/- 10 minutes), followed by a 60 minute observation period (+/- 10 
minutes). For Cycle 2 and beyond, the post-avelumab observation period will be 30 minutes (+/- 5 minutes). Following completion 
of the avelumab infusion and observation period, the trabectedin pump will be connected and started. Trabectedin should start 
within 3 hours (+15 minutes) after the end of the avelumab infusion, but not prior to the end of the observation period post-
avelumab dose. Subjects will return to clinic 24 hours later to have the pump disconnected.  
 
Trabectedin is administered by a pump which is callibrated to provide the full, correct dose and rate regardless of whether the 
pump is actually disconnected at 24 hours or after 24 hours. Every attempt should be made to disconnect the trabectedin as close 
to 24 hours after starting the infusion as possible, however delays in disconnection will not constitute a protocol deviation. 
Avelumab infusion will occur over 1 hour, with a +/- 10 minute window. 
 
Trabectedin is a moderately emetogenic chemotherapy and anti-emetics should be given according to standard of care. 
 
Dexamethasone 20 mg IV is recommended as per the trabectedin package insert and should be given 20-30 minutes before 
trabectedin. Dexamethasone premedication should not be administered until after the 60 minute observation period in Cycle 1, 
and not until the avelumab infusion has been completed for Cycle 2+ on days where both avelumab and trabectedin are to be 
administered. Alterations to the dexamethasone are strongly discouraged as dexamethone does not only function as an anti-
emetic, it also may prevent serious toxicities of trabectedin including liver toxicity. Alterations could be considered for extenuating 
circumstances with Sponsor-Investigator approval. Outside of this pre-medication recommended in the trabectedin package 
insert, corticosteroids use is discouraged when not absolutely necessary and is not allowed for the treatment of trabectedin 
associated nausea and vomiting unless the subject has tried and failed to control their nausea with 2 prior anti-emetic regimens.   
 
7.2 Administration of agents 
 
Drug 
Dose/ 
Potency 
Dose Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Avelumab 
800 mg flat 
dose 
Q2 Weeks 
60 minute (+/- 
10 min) IV 
infusion 
Every 2 weeks, 
regardless of 
trabectedin 
dosing 
Experimental 
Trabectedin 
1.5 mg/m2,  
1.2 mg/m2, or 
1.0 mg/m2 
 
Q3 Weeks  
(Cycle 1 and 2) 
 
Q4 Weeks  
(Cycle 3+) 
24 hour IV 
infusion 
Day 1 of each 
cycle*  
Standard  
*Cycles may be adjusted to q5 weeks, or greater with Sponsor-Investigator approval. No schedule adjustments are permitted until 
after Cycle 2 of trabectedin is administered. 
 
7.3 Drug Product Information 
Avelumab will be provided by EMD Serono. The active pharmaceutical ingredient in avelumab drug product is a fully human 
antibody (calculated molecular weight of 143832 Dalton) of the immunoglobulin G (IgG) 1 isotype that specifically targets and 
blocks PD-L1, the ligand for PD-1. Avelumab drug product is a sterile, clear, and colorless concentrate for solution intended for 
intravenous (IV) infusion. The drug is presented at a concentration of 20 mg/mL in single-use glass vial containing 200 mg of 


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avelumab.  Avelumab drug product must be stored at 2°C to 8°C until use, and it must not be frozen. Vigorous shaking of avelumab 
product must be avoided. Avelumab drug product must be diluted with 0.9% saline solution; alternatively a 0.45% saline solution 
can be used if needed. It is recommended that the diluted avelumab solution is used immediately. 
A pharmacy manual will contain details regarding administration and preparation of avelumab.  
Trabectedin will be stored, prepared, and administered per institutional and FDA-approved product labeling guidelines. 
Trabectedin will be obtained commercially as this is an FDA approved product. 
 
7.4 Schedule of Treatment Visits 
Avelumab will be administered every two weeks starting at Week 1. Dosing may be delayed in response to certain toxicities, as 
described under Section 10.  
 
Trabectedin will be given every three weeks for Cycle 1 (Week 1) and Cycle 2 (Week 4), and then will be given every 4 weeks 
(Week 7, Week 11,…). For toxicity management after Cycle 2 (Week 4) Day 1, trabectedin administration may delay to Q5W, as 
clinically indicated for toxicity management.  Delays of trabectedin beyond 5 weeks may be allowed but require written approval 
from the Sponsor-Investigator. 
 
Administration of either study drug may vary ±3 days from planned date.  
 
The administration of study drugs during the first 12 weeks (first response assessment timepoint), assuming no dose delays or 
modifications due to toxicity, is shown below.  
 
The study calendar will be managed in Weeks, with each dose of each drug being noted by a Cycle. For example, assuming there 
are no deviations from the planned schedule events, Week 1 will have Cycle 1 of avelumab and trabectedin. Week 3 will have 
Cycle 2 of avelumab, Week 4 will have Cycle 2 of trabectedin, Week 5 will have Cycle 3 of avelumab, Week 7 will have Cycle 4 of 
avelumab and Cycle 3 of trabectedin, etc. This may change based on dose delays or modifications. Weeks should be counted 
sequentially regardless of what number the dose of each agent is. 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
Drug 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12* 
Avelumab 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
Trabectedin 
● 
 
 
● 
 
 
● 
 
 
 
● 
 
*Response assessment. 
 
8.0 
SUBJECT EVALUATION 
 
8.1 Screening Evaluations 
This study will be conducted at the Fred Hutchinson Cancer Research Center, Seattle, USA. Each subject who enters into the 
screening period for the study receives a unique subject identification number before any study-related procedures are 
performed. The subject identification number will be assigned. This number will be used to identify the subject throughout the 
clincal study and must be used on all study documentation related to that subject.  
 
The subject identification number must remain constant throughout the entire clinical study; it must not be changed after initial 
assignment, including if a subject is rescreened.  
 
Before subjects may be entered into the study, the site must obtain written IRB/IEC approval for the protocol, informed consent 
form, and all other subject information and/or recruitment material, if applicable. A signed and dated Institutional review Board 
(IRB) approved informed consent form (latest approved version) must be obtained from each subject prior to performing any 
study-specific procedures. All subjects or legally authorized representatives must personally sign and date the consent form 


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before commencement of study-specific procedures. Adverse events are to be collected for a subject once they have signed 
informed consent through 90 days after the End of Treatment visit.  
 
Screening evaluations will be performed for all subjects to determine eligibility. These evaluations must be obtained ≤ 28 days 
prior to C1D1. Efforts should be made to complete screening procedures as close to initiation of protocol therapy as possible. 
Standard of care evaluations done prior to signing of consent may be used if they fall within the specified window prior to starting 
treatment. 
 
A subject is considered enrolled when the investigator decides that the subject has met all eligibility criteria and upon completion 
of an eligibility review packet. The investigator is to document this decision and date, in the subject’s medical record and/or in/on 
the electronic case report form (eCRF). Subjects should initiate treatment within 7 days of being enrolled to the study, and within 
the 14 day screening window from time of informed consent.   
 
The following procedures are to be completed during the screening period, after signed informed consent has been obtained, 
designated in the Schedule of Assessments found in Appendix C. 
 
• 
Informed Consent 
• 
Demographics and Medical History 
• 
Complete Physical Exam and ECOG performance status evaluation 
• 
Vitals Signs, including height and weight 
• 
Electrocardiogram (ECG) (Phase 1 Portion Only) 
• 
Serum Pregnancy Test – For Women of Childbearing Potential only (WCBP) 
• 
Hematology:  
o 
White blood cell (WBC) count with differential, absolute neutrophil count (ANC), red blood cell (RBC) count, 
hemoglobin, hematocrit, platelet count, PT/PTT, and INR 
• 
Clinical chemistry and liver function:  
o 
Sodium, chloride, potassium, glucose, blood urea nitrogen (BUN), creatinine, calcium, AST, ALT, total bilirubin, 
alkaline phosphatase, lactic acid dehydrogenase, total protein, albumin, amylase, lipase 
• 
Creatine Kinase (CK) 
• 
Thyroid panel:  
o 
Total T3, Free T4, and thyroid stimulating hormone.  
• 
Urinalysis:  
o 
Protein, glucose, blood, leukocytes, nitrites, urobilinogen, bilirubin, pH, specific gravity, and ketones. 
• 
Tumor imaging, by CT or MRI 
• 
Echocardiogram or MUGA 
• 
Archival Tissue Collection (if available, this does not have to be obtained prior to C1D1) 
8.2 On-Study Clinical Evaluations 
 
A subject is considered on treatment on study day 1 when protocol defined therapy is first administered. Day 1 Avelumab is to 
be administered after all other protocol-specified pre-dose assessments have been performed during each visit that is required. 
Subjects will continue therapy until the completion of planned course of treatment, disease progression, or unacceptable AEs. 
Subjects should be instructed to immediately inform the treating investigator of an AEs. Clinical evaluations take place according 
to the Study Calendar (Appendix C).  
 
Subjects on the Phase I portion of the trial should be evaluated as described below every week for the first 6 weeks and then on 
all weeks the subject is receiving treatment. Subjects on the Phase II portion of the study are evaluated as described below on 
weeks that they have treatment, prior to treatment. Every effort should be made to keep the schedule within ± 3 days from the 
exact date the subject should be scheduled. 
 


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The study calendar will be managed in Weeks, with each dose of each drug being noted by a Cycle. For example, assuming there 
are no deviations from the planned schedule events, Week 1 will have Cycle 1 of avelumab and trabectedin. Week 3 will have 
Cycle 2 of avelumab, Week 4 will have Cycle 2 of trabectedin, Week 5 will have Cycle 3 of avelumab, Week 7 will have Cycle 4 of 
avelumab and Cycle 3 of trabectedin, etc. This may change based on dose delays or modifications. Weeks should be counted 
sequentially regardless of what number the dose of each agent is. 
 
The following assessments will be performed on each treatment visit, unless otherwise specified: 
 
• 
Tumor and Symptom-Directed Physical Exam and ECOG performance status evaluation 
• 
Vitals Signs, including weight 
• 
Urine or Serum Pregnancy Test – For Women of Childbearing Potential only (Only on days where avelumab is given as 
treatment, either alone or in combination with trabectedin. Screening pregnancy test must be serum pregnancy.) 
• 
Hematology:  
o 
White blood cell (WBC) count with differential, absolute neutrophil count (ANC), red blood cell (RBC) count, 
hemoglobin, hematocrit, platelet count 
• 
Clinical chemistry and liver function:  
o 
Sodium, chloride, potassium, glucose, blood urea nitrogen (BUN), creatinine, calcium, AST, ALT, total bilirubin, 
alkaline phosphatase, lactic acid dehydrogenase, total protein, albumin 
• 
Creatine Kinase (to be drawn on days of trabectedin infusion and as clinically indicated) 
o 
If trabectedin dosing schedule is modified to every 5 weeks or more at the discretion of the investigator, then 
the creatine kinase draw will be modified to follow the same schedule. 
• 
Thyroid panel:  
o 
Total T3, Free T4, and thyroid stimulating hormone (on weeks 1, 7, and every 6 weeks thereafter on a treatment 
day [+/- 7 days], and at discontinuation) 
• 
Correlative Studies Blood Collection (See Section 19.3 for schedule) 
• 
Tumor imaging (every 12 weeks).  
o 
Subjects will have their first post-treatment scan during week 12 and every 12 weeks after that. Additional 
imaging may be ordered if clinically indicated. All routine care scans ordered for clinical indication should be 
reviewed via RECIST 1.1.  
• 
Echocardiogram or MUGA (Week 6, then every 12 weeks while receiving trabectedin, beginning with week 18) 
• 
Adverse Event and Concomitant Medication collection and review 
• 
Correlative Studies Blood Collection  
8.3 End of Treatment (EOT) Procedures 
Procedures to be performed during the EOT Visit are listed in the Appendix. Briefly, these include: 
 
• 
Directed Physical Exam and ECOG performance status evaluation 
• 
Vitals Signs, including weight 
• 
Electrocardiogram (ECG) (Phase 1 Portion) 
• 
Pregnancy Test – For Women of Childbearing Potential only (WCBP) 
o 
Either serum or urine pregnancy tests are sufficient 
• 
Hematology:  
o 
white blood cell (WBC) count with differential, absolute neutrophil count (ANC), red blood cell (RBC) count, 
hemoglobin, hematocrit, platelet count 
• 
Clinical chemistry and liver function:  
o 
sodium, chloride, potassium, glucose, blood urea nitrogen (BUN), creatinine, calcium, AST, ALT, total bilirubin, 
alkaline phosphatase, lactic acid dehydrogenase, total protein, albumin 
• 
Creatine Kinase 


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• 
Thyroid panel:  
o 
Total T3, Free T4, and thyroid stimulating hormone  
• 
Tumor imaging (if not done within 4 weeks of last study visit)  
• 
Adverse event and concomitant medication collection and review 
• 
Correlative studies blood collection 
8.4 Short Term Follow-Up / 30 Day Safety Assessment 
The 30 Day Safety Assessment Visit is a safety follow-up visit that is to be performed 30 days after the End of Treatment Visit Date 
(+/- 7) days). All efforts should be made to conduct this visit. If it is not possible to conduct the 30 Day Safety Assessment Visit, 
documentation of efforts to complete the visit should be provided. 
The following procedures will be completed at the 30 Day Visit as designated in the Schedule of Assessments: 
• 
Physical examination and ECOG performance status evaluation  
• 
Vital signs, including weight 
• 
Electrocardiogram (ECG) (Phase 1 Portion) 
• 
Pregnancy Test – For Women of Childbearing Potential only (WCBP) 
 
Either serum or urine pregnancy tests are sufficient 
• 
Hematology: 
 
white blood cell (WBC) count with differential, absolute neutrophil count (ANC), red blood cell (RBC) count, 
hemoglobin, hematocrit, platelet count 
• 
Clinical chemistry and liver function: 
 
sodium, chloride, potassium, glucose, blood urea nitrogen (BUN), creatinine, calcium, AST, ALT, total bilirubin, 
alkaline phosphatase, lactic acid dehydrogenase, total protein, albumin 
• 
Creatine Kinase 
• 
Thyroid panel: 
 
Total T3, Free T4, and thyroid stimulating hormone 
• 
Adverse Event and Concomitant Medication collection and review 
• 
Survival status/post-study anticancer therapy status 
8.5 Long Term Follow-Up / 90 Day Safety Assessment 
AEs will be monitored and recorded in the subject’s medical chart and research shadow chart from the time of first exposure to 
the investigational product avelumab, through 90 days (+/- 7 days) following last dose of a study drug.  AEs with an onset date 
prior to the first exposure to an investigational product will not be followed, except in the case of clinically significant worsening 
of the AE during the specified AE monitoring time frame. Given the potential risk for delayed immune-related toxicities, safety 
follow-up must be performed up to 90 days after the last dose of avelumab administration. The extended safety follow-up 
beyond 30 days after last avelumab administration may be performed either via a site visit or via a telephone call with 
subsequent site visit requested in case any concerns noted during the telephone call. 
 
8.6 Long-Term Follow-Up for Survival 
Disease status and any subsequent anticancer therapy information status will continue to be monitored. Subjects will be 
followed for survival status via chart review or telephone contact every 12 weeks (+/- 2 weeks) from baseline for up to 2 years, 
or until disease recurrence, death, withdrawal of consent, or the study closes – whichever is earliest. Subjects will then be 
followed every 6 months (+/- 3 months) for survival status, until death or the study closes. Subjects who have a CR and 
discontinue therapy (section 4.1.4) should continue to return to clinic for assessment and scans every 12 weeks for two years. 
Extended follow-up will be performed as mentioned in Section 9.7.1 


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8.7 Imaging Assessments 
Disease status will be assessed by CT or MRI scan of the chest, abdomen, and pelvis (CAP), in addition to any additional known 
disease sites (per institutional guidelines); image preparation and evaluation will follow the specifications provided in the RECIST 
version 1.1. The same modality (CT or MRI) must be used at screening and throughout the study. For subjects with stable disease 
or better per RECIST v1.1 criteria, scans will continue to be performed while receiving study treatment. Scans will follow this 
schedule even if a subject has a dosing delay that causes the beginning of a treatment cycle to be delayed. 
CT/MRI scans to be performed at the following frequency: 
• 
≤28 days prior to C1D1 
• 
Followed by every 12 weeks (± 1 week) from baseline, regardless of missed or delayed doses, until disease 
progression, withdrawal of consent, end of study, completion of protocol participation, or death – whichever occurs 
first.  
An unscheduled scan for suspected disease recurrence/progression may be performed at any time at investigator discretion. 
RECIST reads via RECIST 1.1 should be performed on any imaging obtained for suspected disease recurrence/progression during 
the course of the trial. 
8.8 .Analyte Listing 
Table 1 - Analyte Listing 
Chemistry 
Hematology 
 
Urinalysis 
Other Labs 
Sodium 
WBC 
 
Specific gravity Pregnancy test 
Potassium 
RBC 
 
pH 
PT/INR 
Bicarbonate 
Hemoglobin 
 
Blood 
PTT 
Chloride 
Hematocrit 
 
Protein 
Amylase 
Total protein 
MCV 
 
Glucose 
Lipase 
Albumin 
MCH 
 
Ketones 
Creatinine Kinase (CK) 
Calcium 
MCHC 
 
Microscopic 
 
Glucose 
RDW 
 
 
 
BUN 
Platelets 
 
 
 
Creatinine 
Differential: 
 
 
 
Total bilirubin 
-Neutrophils 
 
 
 
Alkaline phosphatase -Lymphocytes 
 
 
 
AST (SGOT) 
-Monocytes 
 
 
 
ALT (SGPT) 
-Eosinophils 
 
 
 
Lactate 
Dehydrogenase 
-Basophils 
 
 
 
 
8.9 Correlative Studies 
8.9.1 Tumor Specimens 
Subjects with paraffin embedded tumor available should have 10 slides collected for immunohistochemical staining with PD-1, 
PD-L1, and immune infiltrates. When possible, up to 2 additional curls, 1 mm thick should be obtained for nanostring analysis and 
TCR sequencing. This archival tissue does not need to be collected prior to initiating therapy on Week 1.  
 


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8.9.2 Research Blood Specimens 
Research blood will be processed and frozen by the Digel Lab. This will include 30 mL for PBMC (green top or any heparinized 
tube) and 10 mL for serum in red top. 
 
A schedule for collection of research labs is included in Appendix C. 
 
 
9.0 
SAFETY 
Monitoring for both acute and chronic toxicities will be evaluated at all study related visits and will be assessed by the Sponsor-
Investigator. Toxicity information will be recorded and periodically reported to the the DSMB and EMD Serono. The Investigator 
will follow the guidelines below for treatment for toxicity. If a subject experiences toxicity, lab value abnormality, or other 
adverse event that is not described below, it will be up to the discretion of the treating Investigator if they want to delay study 
treatment and duration. 
All adverse events and toxicity will be evaluated using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0 as described in Section 9.5.  
 
9.1 Adverse Event  
 
According to ICH guidelines for Good Clinical Practice; 21 CFR 312.32, IND Safety Reports; and ICH E2A, Definitions and Standards 
for Expedited Reporting, an adverse event is defined as follows: 
 
An adverse event is any untoward medical occurrence in a clinical investigation subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
 
Abnormal laboratory values for laboratory parameters specified in the study should not be recorded as an adverse event unless 
an intervention is required (repeat testing to confirm the abnormality is not considered intervention), the laboratory abnormality 
results in a serious adverse event or the adverse event results in study termination or interruption/discontinuation of study 
treatment. 
 
Medical conditions present at screening (i.e., before the study treatment is administered) should be captured as baseline in the 
subject’s research shadow chart. Medical conditions present at baseline that worsen in intensity or frequency during the 
treatment or post-treatment periods should be reported and recorded as adverse events. 
  
9.2 Serious Adverse Event  
An adverse event should be classified as an SAE if it meets one of the following criteria: 
 
Fatal 
Adverse event results in death. 
Life threatening:  
The adverse events placed the subject at immediate risk of death. This 
classification did not apply to an adverse event that hypothetically might 
cause death if it were more severe.  
Hospitalization:  
It required or prolonged inpatient hospitalization. Hospitalizations for 
elective medical or surgical procedures or treatments planned before 
enrollment in the treatment plan or routine check-ups are not SAEs by this 
criterion. Admission to a palliative unit or hospice care facility is not 
considered to be a hospitalization.  
Disabling/incapacitating  
Resulted in a substantial and permanent disruption of the subject’s ability to 
carry out normal life functions.  
Congenital anomaly or birth 
An adverse outcome in a child or fetus of a subject exposed to the molecule 


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defect:  
or treatment plan regimen before conception or during pregnancy.  
Medically significant:  
The adverse event did not meet any of the above criteria, but could have 
jeopardized the subject and might have required medical or surgical 
intervention to prevent one of the outcomes listed above.  
 
Classification of an event as serious or non-serious determines the reporting procedures to be followed.  
 
9.3 Unexpected Adverse Event 
An unexpected adverse event is defined as an event that has a nature or severity, or frequency that is not consistent with the 
applicable investigator brochure, or the prior medical condition of the subject or other treatment given to the subject.  
“Unexpected,” as used in this definition, refers to an adverse drug experience that has not been previously observed and reported 
in preclinical or clinical studies rather than an experience that has not been anticipated based on the pharmacological properties 
of the study drug. 
 
9.4 Monitoring and Recordings Adverse Events 
All AEs will be assessed by the investigator or qualified designee and recorded in the subject’s research shadow chart. The 
investigator should attempt to establish a diagnosis of the event on the basis of signs, symptoms and/or other clinical information. 
In such cases, the diagnosis should be documented as the adverse event and/or serious adverse event and not described as the 
individual signs or symptoms. The following information should be recorded: 
• 
Description of the adverse event using concise medical terminology 
• 
Description as to whether or not the adverse event is serious, noting all criteria that apply  
• 
The start date (date of adverse event onset) 
• 
The stop date (date of adverse event resolution) 
• 
The severity (grade) of the adverse event  
• 
A description of the potential relatedness of the adverse event to study drug, a study procedure, or other causality  
• 
The action taken due to the adverse event 
• 
The outcome of the adverse event 
 
9.5 Grading Adverse Event Severity 
All AEs will be graded in severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. If a 
CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life-threatening), or Grade 5 (fatal) to describe the maximum intensity of the adverse event.  
 
9.6 Attribution of an Adverse Event 
Association or relatedness to the study agent will be assessed by the investigator as follows: 
• 
Definite: The event follows a reasonable temporal sequence from exposure to the investigational agent, has been 
previously described in association with the investigational agent, and cannot reasonably be attributed to other factors 
such as the subject’s clinical state, other therapeutic interventions or concomitant medications; AND the event 
disappears or improves with withdrawal of the investigational agent and/or re-appears on re-exposure (e.g., in the 
event of an infusion reaction). 
• 
Probable: The event follows a reasonable temporal sequence from exposure to the investigational agent and has been 
previously been described in association with the investigational agent OR cannot reasonably be attributed to other 
factors such as the subject’s clinical state, other therapeutic interventions or concomitant medications. 
• 
Possible: The event follows a reasonable temporal sequence from exposure to the investigational agent, but could be 
attributable to other factors such as the subject’s clinical state, other therapeutic interventions or concomitant 
medications. 
• 
Unlikely: Toxicity is doubtfully related to the investigational agent(s).  The event may be attributable to other factors 
such as the subject’s clinical state, other therapeutic interventions or concomitant medications. 
• 
Unrelated: The event is clearly related to other factors such as the subject’s clinical state, other therapeutic 
interventions or concomitant medications. 
 


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For general AE assessment, an AE is considered related if it is assessed as definitely or probably related; unrelated if it is assessed 
as possibly, unlikely related or unrelated.  
 
9.7 Adverse Event Recording Period 
AEs will be monitored and recorded in the subject’s medical chart and research shadow chart from the time of first exposure to 
the investigational product avelumab, through 90 days following last dose of a study drug.  AEs with an onset date prior to the 
first exposure to an investigational product will not be followed, except in the case of clinically significant worsening of the AE 
during the specified AE monitoring time frame.  
9.7.1 
Extended safety follow-up 
• 
Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed up to 90 days after 
the last dose of avelumab administration. 
• 
The extended safety follow-up beyond 30 days after last avelumab administration may be performed either via a site 
visit or via a telephone call with subsequent site visit requested in case any concerns noted during the telephone call. 
 
9.8 Adverse Event Reporting Requirements  
9.8.1 Reporting to Product Manufacturer (EMD Serono) 
The following reportable events must be submitted to EMD Serono within 2 business days or 3 calendar days (whichever comes 
first) using the applicable safety report form provided. 
• 
Serious Adverse Events 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event) 
• 
Occupational exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy’s Law cases): These events are considered important medical events and should 
be reported as SAEs. 
 
Contact information for submission of reportable events to EMD Serono: 
 
Fax: +49 6151 72 6914 
OR 
E-mail:  ICSR_CT_GPS@merckgroup.com 
 
 
Specifying: 
• 
PROTOCOL Number 
• 
SUBJECT Number 
• 
SITE Number/Sponsor-Investigator Name 
9.8.2 SAE/ONSET DATE Reporting to IRB 
The investigator or designee must report events to the FHCRC IRB in accordance with the policies of the IRB. 
9.8.3 
FDA Reporting Requirements 
The Sponsor-Investigator assumes responsibility for IND safety reporting to the FDA, in accordance with regulations 
under 21 CFR 312.32. 
 
Each SAE report will be evaluated by the Sponsor-Investigator to assess the seriousness of the event, the expectedness 
of the event, and the relationship to participation in the study. For regulatory reporting purposes, the Sponsor-Investigator will 
determine expectedness relating to avelumab and trabectedin using safety information specified in the avelumab investigator 
brochure and trabectedin FDA-approved package insert. An event will be classified as related if the Sponsor-Investigator 
determines that the event may be related to the study drug. 
 
For determination of IND safety reporting, AE attribution will be assessed according to the suspected adverse reaction 
definition described in 21 CRF 312.32 as an AE for which there is a reasonable possibility that the drug caused the adverse event 


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where “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the AE. Suspected 
adverse reactions that are serious, related, and unexpected will be reported to the FDA as an IND safety report, in accordance 
with regulations under 21 CFR 312.32. 
 
The Sponsor-Investigator will provide written notification of safety report to the FHCRC IRB per IRB policies.  
 
All SAEs must be reported to EMD Serono from the time of study drug administration through completion of the study. 
SAEs that occur after the study-specific informed consent is signed but prior to the first dose of the investigational agent will be 
collected only if they are considered by the investigator to be causally related to the study required procedures.  Probably related 
SAE will be reported to EMD Serono within 2 business days or 3 calendar days (whichever comes first) of investigator becoming 
aware. 
 
 


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10.0 
MANAGEMENT OF TOXICITY AND COMPLICATIONS 
 
10.1 Adverse Drug Reactions (ADRs) Related to Avelumab 
Adverse Drug Reactions Requiring Avelumab Discontinuation or Modifications 
The following ADR/AEs require permanent treatment discontinuation of avelumab if they are not expected toxicities of 
trabectedin and their management is not specifically outlined below: 
Any Grade 4 ADR/AEs require treatment discontinuation with avelumab except for single laboratory values out of normal range 
that are unlikely related to study treatment as assessed by the Investigator, do not have any clinical correlate, and resolve or 
return to baseline within 7 days with adequate medical management 
Any Grade 3 ADR/AEs require treatment discontinuation with avelumab except for any of the following:  
• Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical management 
• Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves to Grade ≤ 1  
• Laboratory values out of normal range that may be related to trabectedin.  
• Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or suspected tumor 
• Change in ECOG PS to ≥ 3 that does not resolve to ≤ 2 within 14 days (infusions should not be given on the following cycle, if 
the ECOG PS is ≥ 3 on the day of study drug administration). Subjects may continue on study with ECOG PS ≤ 2. 
Any Grade 2 ADR/AE should be managed as follows: 
• If a Grade 2 ADR/AE resolves to Grade ≤ 1 by the last day of the current week, treatment may continue. 
• If a Grade 2 ADR/AE does not resolve to Grade ≤ 1 by the last day of the current week, infusions should not be given on the 
following week.  If at the end of the following week the event has not resolved to Grade 1, the subject should permanently 
discontinue treatment with a avelumab ADR/AE (except for hormone insufficiencies, that can be managed by replacement 
therapy; for these hormone insufficiencies, up to 2 subsequent doses may be omitted). 
 
10.2 Avelumab-Specific Adverse Events or Adverse Drug Reactions 
10.2.1 Symptoms of Infusion-Related Reactions 
 
Symptoms of infusion-related reactions include: 
• 
Fever 
• 
Chills 
• 
Rigors 
• 
Dyspnoea, wheezing 
• 
Diaphoresis 
• 
Headache 
10.2.2 Management of Infusion-Related Reactions  
 


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10.2.2.1 
Table 1:  Treatment Modification for Symptoms of Infusion-Related Reactions 
NCI-CTCAE Grade  
Treatment Modification for Study Drug 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the avelumab infusion rate by 50% and monitor closely 
for any worsening. 
The total infusion time for study drug should not exceed 
120 minutes. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 h. 
Temporarily discontinue avelumab infusion. 
Resume infusion at 50% of previous rate once infusion-related 
reaction has resolved or decreased to at least Grade 1 in severity, 
and monitor closely for any worsening. 
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (for example, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
Stop the avelumab infusion immediately and disconnect infusion 
tubing from the subject. 
Subjects have to be withdrawn immediately from avelumab 
treatment and must not receive any further avelumab treatment. 
 
If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it must remain decreased for the 
next scheduled infusion.  If no infusion reaction is observed in the next scheduled infusion, the infusion rate may be returned to 
baseline at the subsequent infusions based on treating investigator’s medical judgment. If hypersensitivity reaction occurs, the 
subject must be treated according to the best available medical practice. 
 
10.2.2.2 
Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the subject must be treated according to the best available medical practice. Subjects should 
be instructed to report any delayed reactions to the Investigator immediately. 
For prophylaxis of flu-like symptoms, 25 mg of indomethacin or comparable nonsteroidal anti-inflammatory drug (NSAID) dose 
(for example, ibuprofen 600 mg, naproxen sodium 500 mg) may be administered 2 hours before and 8 hours after the start of 
each dose of avelumab IV infusion, as indicated per standard institutional practice.  Alternative treatments for fever (for example, 
acetaminophen) may be given to subjects at the discretion of the Investigator. 
10.2.2.3 
Tumor Lysis Syndrome 
In addition, avelumab can induce antibody-dependent cell-mediated cytotoxicity and can therefore theoretically cause tumor lysis 
syndrome.  Should this occur, subjects should be treated per standard of care and the management algorithm listed in the 
appendix (Howard 2011). Because tumor lysis is almost never seen in soft tissue sarcoma subjects with the exception of several 
case reports, all subjects should be treated as having a low risk for tumor lysis syndrome.  
10.2.2.4 
Immune-Related Adverse Events 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (irAEs) may occur.  Treatment of irAEs is mainly 
dependent upon severity (NCI-CTCAE grade): 
Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent monitoring 
Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
Grade 3 to 4:  treat with high dose corticosteroids 


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Table 2   Management of Immune-mediated Adverse Reactions: Guidance in this table is relevant to toxicities probably related to Avelumab. For toxicity attributed 
to trabectedin, treat according to the protocol or standard of care if treatment is not otherwise specified. 
Gastrointestinal irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day over Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g. loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening immediately 
If worsens: Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day over Baseline; 
IV fluids indicated < 24 hours; not interfering 
with ADL 
Colitis: abdominal pain; blood in stool  
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤ 1: Resume avelumab therapy 
 
If  persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per day over 
Baseline; incontinence; IV fluids ≥ 24 h; 
interfering with ADL 
Colitis (Grade 3):  severe abdominal pain, 
medical intervention indicated, peritoneal 
signs 
Grade 4: life-threatening, perforation 
Withhold avelumab for Grade 3. Permanently 
discontinue avelumab for Grade 4 or recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day prednisone IV or equivalent 
Add prophylactic antibiotics for opportunistic infections.  
Consider lower endoscopy. 
If improves: Continue steroids until Grade ≤ 1, then taper 
over at least 1 month; resume avelumab therapy 
following steroids taper (for initial Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs after 
improvement: Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab should not be used in 
cases of perforation or sepsis.  
 
 


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Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 to 2  
Covering ≤ 30% body surface area  
Continue avelumab therapy Symptomatic therapy (for 
example, antihistamines, topical steroids)  
If persists > 1 to 2 weeks or recurs: Withhold avelumab 
therapy. Consider skin biopsy. Consider 0.5-1.0 
mg/kg/day prednisone or equivalent. Once improving, 
taper steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic infections, and 
resume avelumab therapy following steroids taper. 
 
If worsens: Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body surface area;  
Grade 4: Life threatening consequences  
Withhold avelumab for Grade 3.Permanently discontinue 
for Grade 4 or recurrent Grade 3.  
 
Consider skin biopsy, Dermatology consult, 1.0 to 2.0 
mg/kg/day prednisone  or equivalent. Add prophylactic 
antibiotics for opportunistic infections.  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume avelumab 
therapy following steroids taper (for initial Grade 3). 
 
 


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Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes only  
Consider withholding avelumab therapy. Monitor for 
symptoms every 2 to 3 days. Consider Pulmonary and 
Infectious Disease consults. 
Re-assess at least every 3 weeks 
 
If worsens: Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold avelumab therapy. Pulmonary and Infectious 
Disease consults. Monitor symptoms daily; consider 
hospitalization. 1.0 to 2.0 mg/kg/day prednisone  or 
equivalent. Add prophylactic antibiotics for opportunistic 
infections. Consider bronchoscopy, lung biopsy . 
Re-assess every 1 to 3 days.  
If improves: When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month, and then resume 
avelumab  therapy following steroids taper. 
 
If not improving after 2 weeks or worsening or for 
recurrent Grade 2: Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue avelumab therapy. Hospitalize. 
Pulmonary and Infectious Disease consults. 1.0 to 2.0 
mg/kg/day  prednisone or equivalent. Add prophylactic 
antibiotics for opportunistic infections. Consider 
bronchoscopy, lung biopsy. 
 
If improves to Grade ≤ 1: Taper steroids over at least 1 
month  
 
If not improving after 48 hours or worsening:  Add 
additional immunosuppression (for example, infliximab, 
cyclophosphamide, IV immunoglobulin, or 
mycophenolate mofetil)  
 
 


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Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Grade 1 AST or ALT > ULN to 3.0 x ULN and/or 
Total bilirubin > ULN to 1.5 x ULN  
Continue avelumab therapy. 
Continue liver function monitoring  
If worsens: Treat as Grade 2 or 3 to 4.  
Grade 2  
AST or ALT > 3.0 to ≤ 5 x ULN and / or total 
bilirubin > 1.5 to ≤ 3 x ULN (this is common for 
trabectedin) 
Withhold avelumab therapy. Increase frequency of monitoring 
to every 3 days. 
If returns to Grade ≤ 1 or Baseline: Resume 
routine monitoring; resume avelumab therapy. 
 
If elevation persists > 5 to 7 days or worsens: 
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and / or total bilirubin > 
3 x ULN  
 
Permanently discontinue avelumab therapy. Increase frequency 
of monitoring to every 1 to 2 days. 1.0 to 2.0 mg/kg/day 
prednisone or equivalent. Add prophylactic antibiotics for 
opportunistic infections. Consult gastroenterologist/ 
hepatologist. Consider obtaining MRI/CT scan of liver and liver 
biopsy if clinically warranted. 
If returns to Grade ≤ 1 or baseline: Taper steroids 
over at least 1 month  
 
If does not improve in > 3 to 5 days, worsens or 
rebounds:  Add mycophenolate mofetil 1 gram (g) 
twice daily. If no response within an additional 3 to 
5 days, consider other immunosuppressants per 
local guidelines. 
 
 


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Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-up 
Grade 1 or Grade 2 endocrinopathies 
(hypothyroidism, hyperthyroidism, adrenal 
insufficiency, type I diabetes mellitus) 
Continue avelumab therapy. Endocrinology consult if needed. 
 
Start thyroid hormone replacement therapy (for hypothyroidism), 
anti-thyroid treatment (for hyperthyroidism), corticosteroids (for adrenal 
insufficiency) or insulin (for Type I diabetes mellitus) as appropriate.   
 
Rule-out secondary endocrinopathies (i.e. hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 
Grade 3 or Grade 4 endocrinopathies 
(hypothyroidism, hyperthyroidism, adrenal 
insufficiency, type I diabetes mellitus) 
Withhold avelumab therapy. Consider hospitalization. 
Endocrinology consult.  
 
Start thyroid hormone replacement therapy (for hypothyroidism), 
anti-thyroid treatment (for hyperthyroidism), corticosteroids (for adrenal 
insufficiency) or insulin (for type I diabetes mellitus) as appropriate.   
 
Rule-out secondary endocrinopathies (i.e. hypopituitarism / hypophysitis) 
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤ 1 (with or without hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.  
Hypopituitarism/Hypophysitis (secondary 
endocrinopathies) 
If secondary thyroid and/or adrenal insufficiency is confirmed (i.e. 
subnormal serum FT4 with inappropriately low TSH and/or low serum 
cortisol with inappropriately low ACTH) : 
Refer to endocrinologist for dynamic testing as indicated and 
measurement of other hormones (FSH, LH, GH/IGF-1, PRL, testosterone in 
men, estrogens in women). Hormone replacement/suppressive therapy 
as appropriate. Perform pituitary MRI and visual field examination as 
indicated.  
 
If hypophysitis confirmed: 
Continue avelumab if mild symptoms with normal MRI. Repeat the MRI in 
1 month. Withhold avelumab if moderate, severe or life-threatening 
symptoms of hypophysitis and/or abnormal MRI. Consider hospitalization. 
Initiate corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) 
followed by corticosteroids taper during at least 1 month. Add 
prophylactic antibiotics for opportunistic infections. 
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 1 
(with or without hormone replacement). 
 
In addition, for hypophysitis with 
abnormal MRI, resume avelumab only 
once shrinkage of the pituitary gland on 
MRI/CT scan is documented.  
 
Continue hormone 
replacement/suppression therapy as 
appropriate. 
 
 


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Renal irAEs 
Grade of Creatinine Increased (NCI-CTCAE v4) Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x ULN 
Continue avelumab therapy. 
Continue renal function monitoring. 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x ULN 
 
 
 
Withhold avelumab therapy. Increase frequency of  
monitoring to every 3 days. 1.0 to 2.0 mg/kg/day 
prednisone or equivalent. Add prophylactic antibiotics for 
opportunistic infections. Consider renal biopsy. 
If returns to  Grade ≤1 or baseline: 
Taper steroids over at least 1 month, and resume 
avelumab therapy following steroids taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
Permanently discontinue avelumab therapy. Monitor 
creatinine daily. 1.0 to 2.0 mg/kg/day prednisone or 
equivalent. Add prophylactic antibiotics for opportunistic 
infections. Consider renal biopsy. Nephrology consult. 
If returns to Grade ≤1 or baseline: 
Taper steroids over at least 1 month. 
 
 


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Cardiac irAEs 
Myocarditis 
Management 
Follow-up 
New onset of cardiac signs or symptoms and / 
or new laboratory cardiac biomarker 
elevations (e.g. troponin, CK-MB, BNP) or 
cardiac imaging abnormalities suggestive of 
myocarditis.  
Withhold avelumab therapy. Hospitalize. In the presence 
of life threatening cardiac decompensation, consider 
transfer to a facility experienced in advanced heart 
failure and arrhythmia management. Cardiology consult 
to establish etiology and rule-out immune-mediated 
myocarditis.  Guideline based supportive treatment as 
per cardiology consult.* 
 
Consider myocardial biopsy if recommended per 
cardiology consult. 
If symptoms improve and immune-mediated etiology is 
ruled out, re-start avelumab therapy. 
 
If symptoms do not improve/worsen, viral myocarditis is 
excluded, and immune-mediated etiology is suspected or 
confirmed following cardiology consult, manage as 
immune-mediated myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue avelumab. Guideline based 
supportive treatment as appropriate as per cardiology 
consult.* 1.0 to 2.0 mg/kg/day prednisone or equivalent. 
Add prophylactic antibiotics for opportunistic infections. 
Once improving, taper steroids over at least 1 month. 
 
If no improvement or worsening, consider additional 
immunosuppressants (e.g. azathioprine, cyclosporine A). 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
 
 


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Other irAEs (not described above) 
Grade of other irAEs  
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs or symptoms 
suggestive of a potential irAE 
Withhold avelumab therapy pending clinical investigation. If irAE is ruled out, manage as appropriate according to the 
diagnosis and consider re-starting avelumab therapy 
If irAE is confirmed, treat as Grade 2 or 3 irAE. 
Grade 2 irAE  or first occurrence of Grade 3 
irAE 
Withhold avelumab therapy. 1.0 to 2.0 mg/kg/day 
prednisone  or equivalent. Add prophylactic antibiotics for 
opportunistic infections. Specialty consult as appropriate. 
If improves to Grade ≤ 1 or baseline: Taper steroids over 
at least 1 month and resume avelumab therapy following 
steroids taper. 
Recurrence of same Grade 3 irAEs 
Permanently discontinue avelumab therapy. Up to 2.0 
mg/kg/day prednisone  or equivalent. Add prophylactic 
antibiotics for opportunistic infections. Specialty consult as 
appropriate. 
If improves to Grade ≤ 1 or baseline: Taper steroids over at
least 1 month. 
Grade 4  
 
Permanently discontinue avelumab therapy. Up to 2.0 
mg/kg/day prednisone  or equivalent and/or other 
immunosuppressant as needed. Add prophylactic 
antibiotics for opportunistic infections. Specialty consult. 
If improves to Grade ≤ 1 or baseline: Taper steroids over 
at least 1 month 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks for reasons other than hormonal 
replacement for adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE lasting 12 weeks 
or longer 
Permanently discontinue avelumab therapy. Specialty 
consult. 
 
**Grade 2 hepatic toxicity is common with trabectedin and grade 3 can happen occasionally. While it is necessary to include these treatment guidelines for safety, 
in reality it is more likely that hepatic toxicity will be related to trabectedin. 


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10.3 Toxicity of Trabectedin 
 
Trabectedin is given as standard of care and does have notable toxicities.  The following are to be considered expected toxicities 
of trabectedin: 
 
• 
Leukopenia (with neutropenia as the predominant component)  
• 
Malaise 
• 
Infection/sepsis 
• 
Transaminase Elevation 
• 
CK elevation 
• 
Bilirubin or Alkaline phosphatase elevation 
• 
Fatigue 
• 
Nausea/vomiting 
• 
Renal toxicity 
Rhabdomyolysis is an unusual but well-described toxicity of trabectedin. If rhabdomyolysis is observed in a single case, this should 
not be considered a DLT but if multiple cases are seen, this must be reviewed by the DSMB.  
 
10.4 Dose Modification of Trabectedin 
 
Trabectedin is to be started at 1.5 mg/m2. After the first week, the dose may be reduced if clinically indicated for toxicity 
management. Dose reductions will be noted in the subject’s clinical record or research shadow chart.  
 
 
As per standard practice, the subjects first dose reduction will be to 1.2 mg/m2 and the second dose reduction will be to 
1 mg/m2. Dose reductions beyond 1 mg/m2 are not permitted. If a subject is unable to tolerate a dose of 1mg/m2, they must come 
off study. Trabectedin may be spaced out initially to 4 weeks and then to 5 weeks, as needed for toxicity management. If, in the 
opinion of the treating investigator, trabectedin needs to be spaced out greater than 5 weeks, Sponsor-Investigator approval is 
required.  
 
 
Trabectedin dose reduction is required for the following adverse reactions: 
• 
ANC < 1000/μL with fever and infection 
• 
ANC <500/μL lasting > 5 days 
• 
Platelets < 25,000/ μL 
• 
Grade 3 or higher nausea and vomiting that persists despite a full anti-emetic regimen 
• 
Grade 3 transaminitis not recovering to <2.5 x ULN or subject’s baseline by 3 weeks post infusion  
• 
Grade 3 Alk Phos Elevation not recovering to <2.5 x ULN or subject’s baseline by 3 weeks  post-infusion 
• 
Total Bilirubin > 2.5 x ULN (direct bilirubin can be used if there is suspicion for Gilbert’s syndrome) 
• 
CK > 2.5 x ULN 
• 
EF <45% 
Subjects receiving the 1mg/m2 dose of trabectedin with liver involvement from their cancer or baseline liver dysfunction, who 
are otherwise tolerating treatment well and appear to be benefiting from treatment on the study, may continue at the 
1mg/m2 after recovery from their liver dysfunction to grade 2, with Sponsor-Investigator approval. 
 
11.0 
SUBJECT DISCONTINUATION OF ACTIVE TREATMENT 
Subjects may be removed from this study at any time at their discretion. Subjects may also be removed from this protocol if 
they develop any untoward side effects from the study medications.  
If a subject withdraws consent to participate in the study or aspects of the study, attempts should be made to obtain permission 
to record survival data up to the protocol-described end of the subject follow-up period. Documentation in the medical record 


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or source should state that the subject is withdrawing from the study and what, if any, selected data the subject will permit the 
investigator to obtain. 
An explanation for discontinuing treatment is recorded for each subject discontinuing treatment In the subject’s medical record 
or research shadow chart. The Sponsor-Investigator must be notified immediately if a subject discontinues treatment. All 
subjects, irrespective of treatment status, will continue to be followed for survival. Treatment in this study must be discontinued 
for any of the following reasons: 
 
• 
if the Sponsor-Investigator decides to stop the study; 
• 
at Investigator’s discretion; 
• 
at the subject’s request; 
• 
if the subject enrolls in a trial of another investigational agent; 
• 
Grade 4 or life-threatening toxicity (See Section 9, Adverse Events) attributable to study agent, unless otherwise 
addressed; 
• 
progression; 
• 
pregnancy. 
 
A subject that enters hospice care will be considered withdrawn from the study. Adverse events will no longer be monitored or 
recorded. If the subject experiences a serious adverse event related to study treatment prior to withdrawal, this event will be 
followed to resolution or recovered with sequelae. Subjects and their families will no longer be contacted, however survival status 
may be obtained via electronic medical record or public database. 
 
12.0 
CONCOMITANT MEDICATIONS 
All medications taken at the start of the study will be documented/recorded in in the subject’s medical record or research 
shadow chart.  
12.1 Pre-Medication Treatment with Trabectedin and Avelumab 
Pre-medication: Subjects will receive avelumab by IV infusion following pretreatment with H1 blockers and acetaminophen once 
every 2 weeks. Premedication with an antihistamine and with paracetamol (acetaminophen) (for example, 25-50 mg 
diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent) 30 to 60 minutes prior to the first four (4) 
doses of avelumab. Premedication may be discontinued for Cycle 5 and beyond of avelumab, at the investigator’s discretion.  This 
regimen may be modified based on local treatment standards and guidelines as appropriate provided it does not include systemic 
corticosteroids. 
Likewise, trabectedin is a moderately emetogenic chemotherapy and anti-emetics should be given according to standard of care 
including 20 mg dexamethasone IV given at 20-30 minutes before trabectedin. Alterations to the dexamethasone route of 
administration may be allowed with Sponsor-Investigator approval. Outside of this pre-medication recommended in the 
trabectedin package insert, corticosteroids use is discouraged when not absolutely necessary and is not allowed for the treatment 
of trabectedin associated nausea and vomiting unless the subject has tried and failed to control their nausea with 2 prior anti-
emetic regimens. Additional information regarding premedication and administration schedule is noted in Section 7.0. 
12.2 CYP3A4 Inhibitors and Inducers with Trabectedin 
 
It is notable that trabectedin is metabolized through CYP3A4. All inhibitors or inducers of cytochrome CYP3A4 (see below) should 
be noted prior to study entry.  
 
Inhibitors of CYP3A4 include but are not limited to: 
• 
aprepitant 
• 
clarithromycin 
• 
clotrimazole  


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• 
diltiazem 
• 
erythromycin  
• 
fluconazole 
• 
grapefruit juice  
• 
indinavir 
• 
itraconazole  
• 
ketoconazole 
• 
nefazodone  
• 
nelfinavir 
• 
ritonavir  
• 
saquinavir 
• 
telithromycin  
• 
troleandomycin 
• 
verapamil 
Inducers of CYP3A4 include but are not limited to: 
• 
barbiturates  
• 
phenytoin 
• 
carbamazepine  
• 
rifabutin 
• 
rifampin  
• 
St. John’s Wort 
Should a subject start on any of these drugs, dose modifications of trabectedin may be considered in consultation with the 
pharmacy and at the discretion of the subjects treating physician.  
 
Inactivated vaccines, including inactivated flu vaccines, are allowed on study. All other vaccinations that include live-virus 
components are prohibited for subjects on while on study. 
 
 
13.0 
CONTRACEPTION 
 
Avelumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if avelumab has transient adverse effects 
on the composition of sperm.   
 
Contraception guidance and definitions are provided in Appendix E. 
 
14.0 
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 


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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. 
 
15.0 
DATA MANAGEMENT/CONFIDENTIALITY 
 
The investigator will ensure that data collected conform to all established guidelines. Each subject is assigned a unique subject 
number to protect subject confidentiality. Subjects will not be referred to by this number, by name, or by any other individual 
identifier in any publication or external presentation. The licensed medical records department, affiliated with the institution 
where the subject receives medical care, maintains all original inpatient and outpatient chart documents. 
 
Subject research files are stored in a secure place (or database). Access is restricted to authorized personnel. 
15.1 Data Quality Assurance 
Accurate and reliable data collection will be ensured by verification and crosscheck of the eCRFs against the investigator’s 
records by the study monitor (source document verification) and by the maintenance of a drug–dispensing log by the 
investigator. 
15.2 Data Documents 
The investigator must ensure that the records and documents pertaining to the conduct of the study and the distribution of the 
investigational product are complete, accurate, filed, and retained. Examples of source documents include: hospital records; 
clinic and office charts; laboratory notes; memoranda; checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; microfiche; x-ray film and reports; and 
records kept at the pharmacy; and the laboratories, as well as copies of CRFs or CD-ROM. 
15.3 Data Management 
Data will be collected  and entered into the eCRF. These data will be electronically verified through use of programmed edit 
checks specified by the clinical team. Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary. Resolutions to these issues will be reflected in the database. An audit trail within the 
system will track all changes made to the data. 
15.4 Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments and data collection (including subjects 
not receiving protocol-required therapies) as stipulated in the protocol for each subject in the study. For subjects who 
withdraw prior to completion of all protocol-required visits and are unable or unwilling to continue the Schedule of Assessments 
(in Appendix B, the investigator can search publicly available records (where permitted) to ascertain survival status.  
This ensures that the data set(s) produced as an outcome of the study is/are as comprehensive as possible. 
16.0 
STATISTICAL CONSIDERATIONS 
16.1 Study Design  
The first six subjects (may expand up to 18) treated with avelumab combined with trabectedin will constitute the Phase 1 portion 
of the trial. If the combination is safe, the trial will be expanded to treat an additional 16 subjects. If a dose reduction is required 
based on 2 out of 6 subjects in the first phase having DLT, a dose reduction will be made, first to 1.0 mg/m2 and if <2 subjects have 
DLTs at that dose, re-escalated to 1.2 mg/m2. An additional 16 Phase 2 subjects will accrue using the highest dose tolerated with 
<2 DLTs.  
 
A data and safety monitoring board will review any dose limiting toxicities that should arise on the Phase I portion of the trial. The 
DSMB will also review any DLTs in the extension portion of the trial at meetings described in the DSMB Charter. Should more than 
30% of subjects have DLTs, accrual will halt until the DSMB can meet to advise on whether the trial may resume, with or without 
modification. Subjects on the Phase I portion of the study will also be included in the efficacy analysis. 


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16.2 Phase I Design 
The primary objective of the Phase I component of this study is to evaluate the safety of avelumab given in combination with 
trabectedin among subjects with advanced L-type sarcomas.  The phase I component of this study will treat 6 subjects (modified 
3+3 design) to demonstrate safety of the combination.  Dose-limiting toxicities will be defined as unexpected, probably-related 
toxicities of grade 3 or higher. 
 
The study design is as follows: 
 
6 subjects will be treated initially. 
 
• 
If 2 or more subjects experience a DLT at any point during the Phase 1 portion, a new cohort will be added, enrolling 
an additional 6 subjects at a reduced dose of 1 mg/m2 trabectedin. 
• 
Should 2 or more of these next 6 subjects at the reduced dose have a DLT, stop and convene DSMB meeting to 
recommend changes to the protocol.  
• 
If at any time in the study (including those above) 30% of subjects have a DLT, have a DSMB meeting to review 
specific toxicities. We will re-calculate the percent of subjects who have had a DLT each time there is a new DLT. 
If <2 subjects have DLTs on the 1 mg/m2 dose level, another Phase I cohort of 6 subjects implemented, re-escalating to 1.2 mg/m2 
dosing of trabectedin. If <2 DLTs are seen there, that will be the recommended Phase II dose. If 2 or greater DLTs are seen there, 
the Phase 2 will move forward at the 1.0 mg/m2 dose level, after discussion with the DSMB. 
 
Safety analysis will continue through the entire trial, if at any point during the trial 30% of subjects experience a DLT, the trial 
should halt and convene a meeting of the DSMB. 
 
A total of up to 18 subjects may enroll on Phase 1, and an additional 16 on Phase 2.  
 
16.3 Phase II Design 
The primary objective of the Phase II portion is to compare the objective response rate (ORR) with historical rates for single agent 
trabectedin. Subjects from the Phase I portion of the trial who are treated at the dose ultimately used in the expansion will be 
included in the efficacy analysis. Our null hypothesis estimates the overall response rate of single agent trabectedin at 9.9%. We 
believe an increase in the response rate to 35% would be highly compelling. A total subject number of 22 gives us an 85% power 
to detect this increased response rate assuming a two-sided alpha of 0.05. 6 or more subjects with responses would suggest 
clinical activity of this regimen over single agent trabectedin. 
 
16.4 Data and Safety Monitoring Board (DSMB) 
A DSMB will make recommendations to the Sponsor-Investigator should significant toxicity be observed. The DSMB will 
meet if 2 of the first 6 subjects have a DLT or at any point after that if more than 30% of subjects have a DLT at the 1.5, 1.2 or 1 
mg/m2 dose. The DSMB will otherwise meet every 6 months while the study is actively enrolling and has active subjects on trial. 
If the trial is closed to enrollment and all subjects on study are in follow-up, the DSMB will meet once a year. 
 
16.5 Additional Efficacy Hypotheses 
The study is not powered to detect specific hypotheses with regards to correlative endpoints, rather this data and analysis 
will help better identify subjects 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 subject plots. Peripheral blood will be analyzed to examine the 
impact of T cell subpopulations and investigational work using formalin fixed tumor samples for immunohistochemistry and 
molecular analysis; this work will be exploratory. 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 


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characterize the pattern of change over time. Kaplan-Meier methodology and Cox Proportional Hazards models will be used to 
evaluate time to event endpoints. 
 
16.6 Ethnic and Gender Distribution Chart 
 
Projected Target Accrual 
 
TARGETED / PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex / Gender 
Females 
Males 
Total 
Hispanic or Latino 
4 
4 
8 
Not Hispanic or Latino 
13 
13 
26 
Ethnic Category Total of All Subjects* 
17 
17 
34 
Racial Categories 
 
American Indian / Alaska Native 
1 
1 
2 
Asian 
3 
3 
6 
Native Hawaiian or Other Pacific Islander 
1 
1 
2 
Black or African American 
2 
2 
4 
White 
8 
8 
16 
More Than One Race 
2 
2 
4 
Racial Categories: Total of All Subjects* 
17 
17 
34 
 
 
17.0 
INVESTIGATOR OBLIGATIONS 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the site and is responsible for personally overseeing 
the evaluation of all study subjects. The Sponsor-Investigator must assure that all study site personnel, including sub-Investigators 
and other study staff members, adhere to the study protocol and to all applicable regulations and guidelines regarding clinical 
trials both during and after study  completion. 
 
All subjects are informed of the nature of the program, its possible hazards, and their right to withdraw at any time, and each 
subject signs a form indicating their consent to participate prior to receiving any study-related procedures. 
 
  
18.0 
ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
 
18.1 Study Site Training 
The Sponsor-Investigator is responsible for ensuring that all staff involved in the study are well acquainted with the protocol, 
study procedures, record keeping and administrative requirements, AE reporting, Good Clinical Practice guidelines, CRF/eCRF 
completion guidelines, monitoring requirements, and the ability of the site to satisfactorily complete the protocol. Additional 
documents with instructions for study compliance and CRF/eCRF completion will be provided. 
18.2 Documentation 
The documentation of clinical data must be stored by the Sponsor-Investigator according to legal requirements. The Sponsor-
Investigator and study staff has responsibility for maintaining a comprehensive and centralized filing system containing all study-
related documentation. These files must be suitable for inspection by the Sponsor-Investigator, the FDA, and/or other applicable 
regulatory agencies/competent authorities at any time, and should consist of the following elements: subject files (complete 
medical records, laboratory data, supporting source documentation, and the Informed Consent); study files (the protocol with all 


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amendments, copies of all pre-study documentation, and all correspondence between the Competent Authorities, IRB/EC, site, 
and Sponsor-Investigator); and drug accountability files, containing a complete account of the receipt and disposition of the study 
drug. 
 
18.3 Data Collection 
Electronic case report forms must be completed and submitted for each subject enrolled in the study. Any changes or corrections 
made to the CRF/eCRF must be subsequently reviewed and signed by the Sponsor-Investigator. All data fields in the CRF/eCRF 
must be completed to avoid queries. 
 
18.4 Protocol Interpretation and Compliance 
The procedures defined in the protocol are carefully reviewed by the Sponsor-Investigator and his/her staff prior to the time of 
study initiation to ensure accurate representation and implementation. Protocol amendments, if any, are reviewed and 
implemented promptly following IRB/EC approval. The Sponsor-Investigator is responsible for submitting protocol amendments 
to the FDA as described in 21 CFR § 312.30 (Protocol Amendments) and other regulatory agencies according to national, state 
or local requirements. The Sponsor-Investigator, or its designee, is always available to answer protocol- or subject-related 
questions. 
 
18.5 Study Monitoring and Data Collection 
A study monitor may be used to ensure adherence to the protocol, applicable FDA regulations and/or other regulatory agencies 
national, state or local requirements, and the maintenance of adequate and accurate clinical records. Electronic case report forms 
are reviewed to ensure that key safety and efficacy data are collected and recorded as specified by the protocol, using the REDcap 
database platform. The monitor will be permitted to access subject medical records, laboratory data and other source 
documentation as needed to appropriately monitor the trial. Please reference Section 15 for additional information regarding 
data management and confidentiality. 
 
18.6 Disclosure of Data/Publication 
Individual subject medical information obtained as a result of this study is considered confidential and disclosure to third parties 
other than those noted below is prohibited. Such medical information may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated as a result of this study are to be available 
for inspection on request by the FDA or other regulatory agencies, the Sponsor-Investigator and by the IRB/EC. Public presentation 
of data in any form will be thoroughly de-identified to ensure confidentiality.  
 
18.7 Ethical Considerations 
The Investigator agrees to conduct this study in accordance with applicable United States FDA clinical trial regulations and 
guidelines, applicable United States FDA clinical trial regulations and guidelines, the ICH (E6) GCP guidelines, the European Union 
Directive 2001/20/EC for clinical trials conducted in the European Union, the IRB/EC and local legal requirements and with the 
Declaration of Helsinki (1989). The Investigator will conduct all aspects of this study in accordance with all national, state, and 
local laws of the applicable regulatory agencies. 
 
18.8 Informed Consent 
The Sponsor-Investigator assumes the responsibility of obtaining written Informed Consent from each subject or the subject’s 
legally authorized representative before any study-specific procedures are performed. 
 
Subjects meeting the criteria set forth in the protocol will be offered the opportunity to participate in the study. To avoid 
introduction of bias, the Investigator must exercise no selectivity with regard to offering eligible subjects the opportunity to 
participate in the study. Subjects or legal guardians of all candidate subjects will receive a comprehensive explanation of the 
proposed treatment, including the nature of the therapy, alternative therapies available, any known previously experienced 
adverse reactions, the investigational status of the study drug, their right to withdraw consent at any time, and other factors that 
are part of obtaining a proper Informed Consent. Subjects will be given the opportunity to ask questions concerning the study, 
and adequate time to consider their decision to or not to participate. 
 
Informed Consent will be documented by the use of a written Consent Form that includes all the elements required by FDA 
regulations and ICH guidelines. The form is to be signed and dated by the subject or subject's legally authorized representative 
and by the person who administers the consent process. A copy of the signed form will be given to the person who signed it, the 


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original signed Consent Form will be filed with the subject’s medical and/or research records, and copy maintained with the 
subject’s study records. The date of the Informed Consent must be recorded in the source documents. 
 
If an amendment to the protocol changes the subject participation schedule in scope or activity, or increases the potential risk to 
the subject, the Informed Consent Form must be amended. Any amended Informed Consent must be approved by the IRB/EC 
prior to use. The revised Informed Consent Form must be used to obtain re-consent from any subjects currently enrolled in the 
study if the subject is affected by the amendment, and must be used to document consent from any new subjects enrolled after 
the approval date of the amendment. 
 
18.9 Institutional Review Board/Ethics Committee 
The Sponsor-Investigator will assure that an appropriately constituted IRB/EC that complies with the requirements of 21 CFR 
Section 56 or written assurance of compliance with ICH (E6) guidelines will be responsible for the initial and continuing review 
and approval of the clinical study. Before initiation of the study, the Sponsor-Investigator or designee will forward copies of the 
protocol and Consent Form to be used for the study to the IRB/EC for its review and approval.  
 
The Sponsor-Investigator or designee will also assure that all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others will be reported promptly to the IRB/EC, and that no changes will be made to the 
protocol without prior IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects. 
 
The Sponsor-Investigator or designee must notify the IRB of SAEs occurring at the site and of safety reports (e.g., IND Safety 
Reports) received from EMD Serono, in accordance with the IRB’s policies. 
 
The Investigator or designee will be responsible for submitting periodic progress reports to the IRB at intervals appropriate to the 
degree of subject risk involved in the study, but not less than once per year and at the completion or termination of the study. 
 
18.10 
Subject Privacy 
 
The Sponsor-Investigator affirms and will uphold the principle of the subject's right to privacy. The Sponsor-Investigator shall 
comply with applicable national and local privacy laws. 
 
 


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19.0 
APPENDICES 
19.1 APPENDIX A: ECOG Performance Status Scale 
 
ECOG Performance Status Scale 
 
GRADE 
SCALE 
0 
Fully active, able to carry out all pre-disease performance without restriction 
1 
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 
Ambulatory and capable of all self-care but unable to carry out work activities. Up and about more than 50% of waking 
hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
 


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19.2  APPENDIX B: Karnofsky Performance Status Scale 
 
KARNOFSKY PERFORMANCE STATUS SCALE 
 
General 
Index 
Specific Criteria 
Able to carry on normal activity; no special care 
needed 
100 
Normal, no complaints, no evidence of disease 
 
90 
Able to carry on normal activity, minor signs or 
symptoms of disease 
 
80 
Normal activity with effort, some signs or 
symptoms of disease 
Unable to work, able to live at home and care for 
most personal needs, varying amount of 
assistance needed 
70 
Care for self, unable to carry on normal activity 
or to do work 
 
60 
Requires occasional assistance from others 
but able to care for most needs 
 
50 
Requires considerable assistance from others 
and frequent medical care 
Unable to care for self, requires institutional or 
hospital care or equivalent; disease may be 
rapidly progressing 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled, hospitalization indicated, 
death not imminent 
 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary 
 
10 
Moribund 
 
0 
Dead 
 
 


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19.3  APPENDIX C: Study Calendar 
 
Study Flow Chart (for phase I portion) 
Please note phase I and phase II schedules differ in that subjects on the phase I portion are required to be evaluated weekly up to week 7. Subjects on the phase II portion of 
the study and subjects on the phase I portion following week 7 are not required to be evaluated during weeks when they are not receiving therapy.  
 
The study calendar will be managed in Weeks, with each dose of each drug being noted by a Cycle. For example, assuming there are no deviations from the planned schedule 
events, Week 1 will have Cycle 1 of avelumab and trabectedin. Week 3 will have Cycle 2 of avelumab, Week 4 will have Cycle 2 of trabectedin, Week 5 will have Cycle 3 of 
avelumab, Week 7 will have Cycle 4 of avelumab and Cycle 3 of trabectedin, etc. This may change based on dose delays or modifications. Weeks should be counted sequentially 
regardless of what number the dose of each agent is. 
 
 


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Treatment Week 
Screening 
1 
213 
3 
4 
5 
613 
7+10 
EOT 
30D 
Post 
EOT 
90 Day 
Post 
EOT12 
LTFU12 
Scheduling Window (Days) 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
± 7 
Q12W 
Drug Administration1 
None 
A+T 
None 
A 
T 
A 
None 
A+T 
None 
None 
None 
 
Echo/MUGA2 
X 
 
 
 
 
 
X2 
 
 
 
 
 
Informed Consent, IC/EC 
Review, Demographnics and 
Med History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and Con-Med Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Post-study anticancer 
therapy status 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination (to 
include vitals, weight, ECOG) 
X 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical 
Examination (to include 
vitals, weight, ECOG) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG (Phase 1 only) 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Pregnancy Test – Serum 
(WCBP Only)3 
X 
X 
 
X 
 
X 
 
X3 
X 
X 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential, Blood 
Chemistry5 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
CK 
X 
X 
 
 
X 
 
 
X6 
X 
X 
 
 
T3, FT4 and TSH7 
X 
 
 
 
 
 
 
X7 
X 
X 
 
 
Tumor Imaging8 
X 
 
 
 
 
 
 
X8 
X8 
 
 
 
Archival Tissue Collection 
(slides)11 
X 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood 
Collection9 
 
X 
 
X 
 
X 
 
X9 
X 
 
 
 
 
 


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1A= Avelumab, T = Trabectedin. Avelumab is administered every 2 weeks. Trabectedin is administered every 3 weeks for Cycle 1 and 2 (Week 1 and Week 4), and every 4 
weeks after that (Week 7, Week 11, Week 15,…). Trabectedin may be given every 5 weeks if required due to toxicity (see section 9). Please reference Section 7 for additional 
details. 
2ECHO or MUGA to be completed at baseline, week 6, and every 12 weeks while on trabectedin, beginning with week 18. 
3Serum pregnancy test to be performed at baseline, and every 2 weeks (or every visit where avelumab is to be administered). Serum pregnancy will also be collected at end 
of treatment and 30 day follow-up visit. Women of childbearing potential only. 
5Amylase and Lipase are only to be collected at baseline. Chemistry and LFT panel should include sodium, chloride, potassium, glucose, blood urea nitrogen (BUN), creatinine, 
calcium, AST, ALT, total bilirubin, alkaline phosphatase, lactic acid dehydrogenase, total protein, and albumin. Reference Table 1 for a full analyte listing. 
6CK to be performed at all visits where trabectedin is administered. If trabectedin dosing schedule is modified at discretion of investigator to q4weeks or q5weeks or more, 
the creatine kinase draw should also be modified to follow that schedule. 
7Thyroid studies should be checked at baseline, week 1, and every 6 weeks (+/- 7 days) (Week 1, Week 7, Week 13…) 
8Can be done up to 28 days prior to Week 1. While on treatment, tumor imaging should be performed every 12 weeks. Subjects will have their first post-treatment scan during 
week 12 and every 12 weeks thereafter at the provider’s discretion. Imaging schedule will continue every 12 weeks regardless of dose delays or schedule modifications. Tumor 
imaging will only be performed at EOT visit if not done within 4 weeks of the study visit. 
9On treatment days, correlative blood should be drawn before study related treatment is administered. Correlative blood will be collected at week 7, and then starting at 
week 12 every 6 weeks on a treatment day (+/- 7 days). (Week 12, Week 18, Week 24…). 
10Additional treatment days where avelumab is administered as a single agent should follow the schedule for Week 3, unless otherwise noted. Additional treatment days 
where trabected is administered and connected/disconnected as a single agent should follow the schedule for Week 4, unless otherwise noted. Additional treatment days 
where both avelumab and trabectedin are administered should follow the schedule for Week 1, unless otherwise indicated.  
11Archival tissue collection does not need to be completed prior to beginning protocol therapy, but every effort should be made to ensure these samples are collected. 
12The extended safety follow-up beyond 30 days after last avelumab administration may be performed either via a site visit or via a telephone call with subsequent site visit 
requested in case any concerns noted during the telephone call. 
13Subjects enrolled to Phase 1 must complete weekly visits through Week 7. Subjects on the Phase II portion of the study and subjects on the Phase I portion after week 7 are 
not required to be evaluated during weeks when they are not receiving any therapy.  


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19.4 
APPENDIX D: Assessment and Initial Management of Tumor Lysis Syndrome  
 
 
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia


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19.5 APPENDIX E: Women and Men of Childbearing Potential Definitions and Methods of Contraception 
19.5.1 Definitions 
 
19.5.1.1 
Woman of Childbearing Potential (WOCBP) 
 
A woman is considered fertile following menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
 
Women in the following categories are not considered WOCBP 
 
• 
Premenarchal 
• 
Premenopausal female with 1 of the following: 
o 
Documented hysterectomy 
o 
Documented bilateral salpingectomy 
o 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s medical records, medical 
examination, or medical history interview. 
• 
Postmenopausal female 
o 
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 years in the absence 
of other biological or physiological causes.  
 
19.5.1.2 
Male of Childbearing Potential (WOCBP) 
 
• 
For this trial, male subjects will be considered to be of non-reproductive potential if they have azospermia (whether due 
to having had a vasectomy or due to an underlying medical condition).   
19.5.2 Contraception Guidance for Females of Childbearing Potential 
 
One of the highly effective methods of contraception listed below is required during study duration and until the end of relevant 
systemic exposure, defined as 3 months after last treatment. Local laws and regulations may require use of alternative and/or 
additional contraception methods. 
 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of < 1% per year when used consistently and correctly.a 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
o 
oral 
o 
intravaginal 
o 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
o 
oral 
o 
injectable 
• 
Sexual abstinence Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in related to the duration of the study and the preferred and usual lifestyle of the 
participant. 
o 
It is not necessary to use any other method of contraception when complete abstinence is elected. 
o 
WOCBP participants who choose complete abstinence must continue to have pregnancy tests as specified in 
study calendar. 
o 
Acceptable alternate methods of highly effective contraception must be discussed in the event that the WOCBP 
participants chooses to forego complete abstinence. 
 
Highly Effective Methods That are User Independent 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of 
Ovulation  


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• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local 
regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
 
Less Than Highly Effective Contraceptive Methods That are User Dependent 
 
Failure rate of > 1% per year when used consistently and correctly. 
• 
Male or female condom with or without spermicide. Male and female condoms cannot be used simultaneously. 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal sponge with spermicide 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
 
Unacceptable Methods of Contraception 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus) 
• 
Spermicide only 
• 
Lactation amenorrhea method (LAM) 
19.5.3 Contraception Guidance for Males of Childbearing Potential 
 
Male participants with female partners of childbearing potential are eligible to participate if they agree to the following during 
the treatment and until the end of relevant systemic exposure. 
 
• 
Inform any and all partner(s) of their participation in a clinical drug study and the need to comply with contraception 
instructions as directed by the investigator. 
 
• 
Male participants are required to use a condom for study duration and until the end of 
relevant systemic exposure defined as 5 months after last systemic dose. 
 
• 
Female partners of males participating in the study to consider use of effective methods of contraception until the end 
of relevant systemic exposure, defined as 5 months after last systemic dose. 
 
• 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile vaginal 
intercourse or use a male condom during each episode of penile penetration during the treatment and until 5 months 
after last systemic dose. 
 
• 
Refrain from donating sperm for the duration of the study treatment and for5 months after last systemic dose. 
 
• 
Male participants may experience testicular side effects, such as reduced sperm production rates, reduced sperm 
concentrations, decreased epidydimal weights, atrophy and degeneration of the testes with aspermia (no sperm 
production), hypospermia (low or reduced sperm production), and cellular changes in the epididymis (a tube within the 
testes that transports sperm).  
 
 
 


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19.6 APPENDIX F: References 
1. 
Allavena P, Signorelli M, Chieppa M, et al. Anti-inflammatory properties of the novel antitumor agent yondelis 
(trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res. 2005;65(7):2964-2971. 
2. 
Germano G, Frapolli R, Simone M, et al. Antitumor and anti-inflammatory effects of trabectedin on human myxoid 
liposarcoma cells. Cancer Res. 2010;70(6):2235-2244. 
3. 
Germano G, Frapolli R, Belgiovine C, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer 
Cell. 2013;23(2):249-262. 
4. 
Bathan AJ, Constantinidou A, Pollack SM, Jones RL. Diagnosis, prognosis, and management of leiomyosarcoma: 
recognition of anatomic variants. Curr Opin Oncol. 2013;25(4):384-389. 
5. 
Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line 
treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and 
Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995;13(7):1537-1545. 
6. 
Gelderblom H, Blay JY, Seddon BM, et al. Brostallicin versus doxorubicin as first-line chemotherapy in patients with 
advanced or metastatic soft tissue sarcoma: An European Organisation for Research and Treatment of Cancer Soft Tissue 
and Bone Sarcoma Group randomised phase II and pharmacogenetic study. Eur J Cancer. 2014;50(2):388-396. 
7. 
Judson IR, Verjeij J, Gelderblom H, Hartman J, Schoffski P, Blay J, Paolo dei Tos A, Marreud S, Litiere S, van der Grraaf W. 
Result of a Randomised phase III trial (EORTC 62012) of single agent doxorubicin versus plus ifosfamide as first line 
chemotherapy for patients with advanced, soft tissue sarcoma: a suvival study by the EORTC Soft Tissue and Bone 
Sarcoma Group. Oral Presentation 2013 Connective Tissue Oncology Society Meeing. 2013. 
8. 
Rajendra R, Jones RL, Pollack SM. Targeted treatment for advanced soft tissue sarcoma: profile of pazopanib. 
OncoTargets and therapy. 2013;6:217-222. 
9. 
van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, 
double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886. 
10. 
Conley AP, Trent J, Zhang W. Recent progress in the genomics of soft tissue sarcomas. Curr Opin Oncol. 2008;20(4):395-
399. 
11. 
Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with 
epithelial cancer. Science. 2014;344(6184):641-645. 
12. 
Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant 
antigens. Nature. 2014;515(7528):577-581. 
13. 
Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49-61. 
14. 
Ganjoo KN, Witten D, Patel M, et al. The prognostic value of tumor-associated macrophages in leiomyosarcoma: a single 
institution study. Am J Clin Oncol. 2011;34(1):82-86. 
15. 
Espinosa I, Beck AH, Lee CH, et al. Coordinate expression of colony-stimulating factor-1 and colony-stimulating factor-1-
related proteins is associated with poor prognosis in gynecological and nongynecological leiomyosarcoma. Am J Pathol. 
2009;174(6):2347-2356. 
16. 
Edris B, Weiskopf K, Volkmer AK, et al. Antibody therapy targeting the CD47 protein is effective in a model of aggressive 
metastatic leiomyosarcoma. Proc Natl Acad Sci U S A. 2012;109(17):6656-6661. 
17. 
Demetri GD, von Mehren M, Jones RL, et al. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma 
or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical 
Trial. J Clin Oncol. 2016;34(8):786-793. 
18. 
Larsen AK, Galmarini CM, D'Incalci M. Unique features of trabectedin mechanism of action. Cancer chemotherapy and 
pharmacology. 2015. 
19. 
Ueda T, Kakunaga S, Ando M, et al. Phase I and pharmacokinetic study of trabectedin, a DNA minor groove binder, 
administered as a 24-h continuous infusion in Japanese patients with soft tissue sarcoma. Invest New Drugs. 
2014;32(4):691-699. 
20. 
Cuevas C, Francesch A. Development of Yondelis[registered sign] (trabectedin, ET-743). A semisynthetic process solves 
the supply problem. Natural Product Reports. 2009;26(3):322-337. 
21. 
Martínez-Serra J, Maffiotte E, Martín J, et al. Yondelis® (ET-743, Trabectedin) sensitizes cancer cell lines to CD95-
mediated cell death: New molecular insight into the mechanism of action. European Journal of Pharmacology. 
2011;658(2–3):57-64. 
22. 
Allavena P, Signorelli M, Chieppa M, et al. Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis 
(Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production. Cancer Research. 2005;65(7):2964-
2971. 
23. 
Germano G, Frapolli R, Belgiovine C, et al. Role of Macrophage Targeting in the Antitumor Activity of Trabectedin. Cancer 
Cell. 2013;23(2):249-262. 


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24. 
Galmarini C, #039, Incalci M, Allavena P. Trabectedin and Plitidepsin: Drugs from the Sea that Strike the Tumor 
Microenvironment. Marine Drugs. 2014;12(2):719-733. 
25. 
D'Incalci M, Badri N, Galmarini CM, Allavena P. Trabectedin, a drug acting on both cancer cells and the tumour 
microenvironment. Br J Cancer. 2014;111(4):646-650. 
26. 
Bonfanti M, La Valle E, Fernandez Sousa Faro JM, et al. Effect of ecteinascidin-743 on the interaction between DNA 
binding proteins and DNA. Anti-Cancer Drug Design. 1999;14(3):179-186. 
27. 
Erba E, Bergamaschi D, Bassano L, et al. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique 
mechanism of action. European Journal of Cancer. 2001;37(1):97-105. 
28. 
Forouzesh B, Hidalgo M, Chu Q, et al. Phase I and Pharmacokinetic Study of Trabectedin as a 1- or 3-hour Infusion Weekly 
in Patients with Advanced Solid Malignancies. Clinical Cancer Research. 2009;15(10):3591-3599. 
29. 
Puchalski T, Ryan D, Garcia-Carbonero R, et al. Pharmacokinetics of ecteinascidin 743 administered as a 24-h continuous 
intravenous infusion to adult patients with soft tissue sarcomas: associations with clinical characteristics, 
pathophysiological variables and toxicity. Cancer Chemother Pharmacol. 2002;50(4):309-319. 
30. 
Ryan DP, Supko JG, Eder JP, et al. Phase I and Pharmacokinetic Study of Ecteinascidin 743 Administered as a 72-Hour 
Continuous Intravenous Infusion in Patients with Solid Malignancies. Clinical Cancer Research. 2001;7(2):231-242. 
31. 
Taamma A, Misset JL, Riofrio M, et al. Phase I and Pharmacokinetic Study of Ecteinascidin-743, a New Marine Compound, 
Administered as a 24-hour Continuous Infusion in Patients With Solid Tumors. Journal of Clinical Oncology. 
2001;19(5):1256-1265. 
32. 
Twelves C, Hoekman K, Bowman A, et al. Phase I and pharmacokinetic study of Yondelis™ (Ecteinascidin-743; ET-743) 
administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours. European Journal of Cancer. 
2003;39(13):1842-1851. 
33. 
van Kesteren C, Cvitkovic E, Taamma A, et al. Pharmacokinetics and Pharmacodynamics of the Novel Marine-derived 
Anticancer Agent Ecteinascidin 743 in a Phase I Dose-finding Study. Clinical Cancer Research. 2000;6(12):4725-4732. 
34. 
Villalona-Calero MA, Eckhardt SG, Weiss G, et al. A Phase I and Pharmacokinetic Study of Ecteinascidin-743 on a Daily × 
5 Schedule in Patients with Solid Malignancies. Clinical Cancer Research. 2002;8(1):75-85. 
35. 
Schöffski P, Dumez H, Wolter P, et al. Clinical impact of trabectedin (ecteinascidin-743) in advanced/metastatic soft tissue 
sarcoma. Expert Opinion on Pharmacotherapy. 2008;9(9):1609-1618. 
36. 
Blay J-Y, von Mehren M, Samuels BL, et al. Phase I Combination Study of Trabectedin and Doxorubicin in Patients with 
Soft-Tissue Sarcoma. Clinical Cancer Research. 2008;14(20):6656-6662. 
37. 
Messersmith W, Jimeno A, Ettinger D, et al. Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with 
advanced solid tumors. Cancer Chemother Pharmacol. 2008;63(1):181-188. 
38. 
Sessa C, Cresta S, Noberasco C, et al. Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid 
tumours. European Journal of Cancer. 2009;45(12):2116-2122. 
39. 
Sessa C, Del Conte G, Christinat A, et al. Phase I clinical and pharmacokinetic study of trabectedin and cisplatin given 
every three weeks in patients with advanced solid tumors. Invest New Drugs. 2013;31(5):1236-1243. 
40. 
Sessa C, Perotti A, Noberasco C, et al. Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in 
advanced soft tissue sarcoma and breast cancer. European Journal of Cancer. 2009;45(7):1153-1161. 
41. 
von Mehren M, Schilder RJ, Cheng JD, et al. A phase I study of the safety and pharmacokinetics of trabectedin in 
combination with pegylated liposomal doxorubicin in patients with advanced malignancies. Annals of Oncology. 
2008;19(10):1802-1809. 
42. 
Yovine A, Riofrio M, Blay JY, et al. Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma 
Patients. Journal of Clinical Oncology. 2004;22(5):890-899. 
43. 
Garcia-Carbonero R, Supko JG, Manola J, et al. Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients With 
Progressive Sarcomas of Soft Tissues Refractory to Chemotherapy. Journal of Clinical Oncology. 2004;22(8):1480-1490. 
44. 
Le Cesne A, Yovine A, Blay J-Y, et al. A retrospective pooled analysis of trabectedin safety in 1,132 patients with solid 
tumors treated in phase II clinical trials. Invest New Drugs. 2012;30(3):1193-1202. 
45. 
Le Cesne A, Blay JY, Judson I, et al. Phase II Study of ET-743 in Advanced Soft Tissue Sarcomas: A European Organisation 
for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group Trial. Journal of Clinical 
Oncology. 2005;23(3):576-584. 
46. 
Garcia-Carbonero R, Supko JG, Maki RG, et al. Ecteinascidin-743 (ET-743) for Chemotherapy-Naive Patients With 
Advanced Soft Tissue Sarcomas: Multicenter Phase II and Pharmacokinetic Study. Journal of Clinical Oncology. 
2005;23(24):5484-5492. 
47. 
Demetri GD, Chawla SP, von Mehren M, et al. Efficacy and Safety of Trabectedin in Patients With Advanced or Metastatic 
Liposarcoma or Leiomyosarcoma After Failure of Prior Anthracyclines and Ifosfamide: Results of a Randomized Phase II 
Study of Two Different Schedules. Journal of Clinical Oncology. 2009;27(25):4188-4196. 


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48. 
Gronchi A, Bui BN, Bonvalot S, et al. Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized 
myxoid liposarcoma. Annals of Oncology. 2012;23(3):771-776. 
 

ICF_001.pdf: 
Main Consent  
Version 11.0 24 June 2020 
Page 1 of 20  
  
Fred Hutchinson Cancer Research Center 
University of Washington School of Medicine 
 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
A Phase I/II Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and 
Leiomyosarcoma 
 
PROTOCOL NO.:  
 
FH9717 
 
SPONSOR-INVESTIGATOR: 
Seth Pollack, MD 
 
 
 
 
 
1100 Fairview Ave N, D3-100 
 
 
 
 
 
Seattle, Washington 98109 
 
 
 
 
 
United States 
 
FUNDING SOURCE:  
 
EMD Serono 
 
SITE(S): 
 
 
 
Fred Hutchinson Cancer Research Center 
 
 
 
 
 
1100 Fairview Ave N 
 
 
 
 
 
Seattle, Washington 98109 
 
 
 
 
 
 
University of Washington 
 
 
 
 
 
1959 NE Pacific St 
 
 
 
 
 
Seattle, Washington 98195 
 
 
 
 
 
 
Seattle Cancer Care Alliance 
 
 
 
 
 
825 Eastlake Ave E 
 
 
 
 
 
Seattle, Washington 98109 
 
STUDY-RELATED 
PHONE NUMBER(S): 
 
Seth Pollack, MD 
 
 
 
 
 
206-667-6629 
 
 
 
 
 
 
Roxanne Moore, Assistant Director 
 
 
 
 
 
206-606-6425 (Office Hours) 
 
 
 
 
 
romoore@seattlecca.org 
 
 
 
 
 
 
Oncology Fellow On-Call 
 
 
 
 
 
206-598-6190 (24 hours) 
 
Emergency phone:  
• Monday through Friday, 9 am to 5 pm: Seattle Cancer Care Alliance at 206-606-
7400 
• 24 Hours: University of Washington Medical Center paging operator at 206-598-
6190. Ask the operator to page the oncology fellow on-call. 
 
 
IRO REC'D JUL 16 2020


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Page 2 of 20  
Important things to know about this study. 
Your doctors are inviting you to participate in a research study. The purpose of this 
research is to test the safety and efficacy of combining a new drug called avelumab with 
standard trabectedin therapy.   
If you agree to join the study, you will receive avelumab in combination with trabectedin. 
We do not know if avelumab would help trabectedin work better and it could cause 
increased side effects.  
You do not have to join this study. You could choose to receive standard methods to treat 
your sarcoma. We will give you details about the purposes, procedures, risks and possible 
benefits related to this study. We will explain other choices that you have. We will also 
give you any other information that you need in order to make an informed decision 
about joining this study.  
Following is a more complete description of this study. Please read this description 
carefully. Afterwards, you can ask questions that will help you decide whether to join the 
study. If you join this study, we would give you a signed copy of this form to keep for 
future reference.  
We invite you to join this research study. 
We invite you to join this research study because you have Liposarcoma or 
Leiomyosarcoma. About 34 people will join this study. 
Research is not the same as treatment or medical care. The purpose of a research study is 
to answer scientific questions.  
You do not have to be in the study. You are free to say “yes” or “no”, or to drop out after 
joining. If you say “no,” you would have no penalty or loss of benefits. Whatever you 
decide, your regular medical care would not change.  
Why are we doing this study? 
We are doing this study to determine whether a new drug called avelumab can improve 
the activity of standard treatment using trabectedin (Yondelis). We want to know if this 
combination is safe and effective. 
Although thousands of patients have been treated with avelumab either alone or in 
combination with other drugs, it has never before been combined with trabectedin. 
In this study, we want to learn what effects, good or bad, the combination of avelumab 
and trabectedin has on people with liposarcoma and leiomyosarcoma. If you join this 
study, we would give you this combination and watch carefully for any side effects. 


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What research tests, procedures, and treatments are done in this study? 
This study will include a Phase I and Phase II portion. In the Phase I portion, we will 
determine the appropriate dose of trabectedin to be given with avelumab. The Phase II 
portion will use the dose we found in Phase I to treat additional patients. Your physician 
will tell you which phase of the trial you are in.  
Detailed below are the procedures that will be done during your visits for this trial.  
Screening 
Tests will be done during a screening visit at the study clinic to make sure that this study 
is appropriate for you. These tests will be completed within 28 days of the first treatment 
on Week 1. After you review and sign this informed consent form, these tests and 
procedures will be done: 
• Physical exam and vital signs, including height and weight 
• Blood sample collection for 
o Routine safety tests such as a complete blood count, comprehensive 
metabolic panel 
o Thyroid function tests 
o Creatine kinase (CK)/creatinine phosphokinase (CPK) test 
o Pregnancy test if you are a woman who is able to have children 
o Research blood tests – done to understand your immune system and 
sarcoma and how it may respond to the study drugs 
• Urine sample collection for routine safety tests 
• Electrocardiogram – tracing of the electrical activity of your heart (Phase I 
Portion Only) 
• Echocardiogram or multigated acquisition scan (MUGA) to test if your heart 
function is normal. 
• Computed tomography (CT) scans to look at your tumor. You may also have  
magnetic resonance imaging (MRI) if you are unable to have a CT scan or if your 
doctor feels that this test is better to look at your disease.  
• If available, study staff will obtain tissue from a prior surgery or biopsy of your 
tumor for research testing. If this tumor is not available, you may still participate 
in the trial and no additional biopsies are required.  
When these tests and procedures are complete, the study doctor will review all of the 
information and make sure you can take part in the study. If your screening results 
qualify and if you agree to take part in the study, you will then be enrolled onto the study.  
 
 


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On-Study Visits 
In general, the treatment schedule for patients on this trial is based on what you would 
receive if you were getting “standard” treatment. Trabectedin is usually given every 21 
days while single agent avelumab is usually given every 14 days.  
For this trial, you will receive trabectedin every three weeks (21 days, ±3 days) for the 
first six weeks. Avelumab will be given every two weeks (14 days, ±3 days). After the 
first six weeks, trabectedin will be given every 4 weeks to reduce the number of visits 
you need to make to Seattle Cancer Care Alliance. 
Below is a table showing when you will receive the study drugs during the first 12 weeks, 
if you do not need a dose delay or modification: 
 
 
Week  
 
 
 
 
 
 
 
 
 
 
Drug 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12* 
Avelumab 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
Trabectedin 
● 
 
 
● 
 
 
● 
 
 
 
● 
 
*Week 12 is when you will have your first CT or MRI scan for disease assessment. 
The following procedures will be done at each treatment visit, unless otherwise specified: 
• Physical exam and vital signs, including weight 
• Blood sample collection for 
o Routine safety tests such as a complete blood count and comprehensive 
metabolic panel 
o Thyroid function tests 
o CK/CPK test, only on days you receive trabectedin 
o Research blood tests – done to understand your immune system, sarcoma, and 
how your disease may respond to the study drugs. This will be done on 
treatment days until you have your first CT or MRI scan. Then we will collect 
this every 6 weeks on treatment days for the rest of the trial.  
• Urine pregnancy test (or blood test) if you are a woman who is able to have children 
• Echocardiogram or multigated acquisition scan (MUGA) to test if your heart function 
is normal. This will be done on Week 6, then every 12 weeks while you are receiving 
trabectedin. 
• CT or MRI scan – done every 12 weeks while on treatment 
• Study treatment as described in the diagram above 
End of Treatment (EOT) Visit 
If your cancer gets worse, or you choose to stop treatment, you would have three 
additional visits. One will be on the day you end treatment (EOT), a 30-day safety 
follow-up visit, and a 90-day safety follow-up visit . The following procedures will be 


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done at your EOT visit:  
• Physical exam and vital signs, including weight 
• Blood sample collection for: 
o Routine safety tests such as a complete blood count and comprehensive 
metabolic panel 
o Thyroid function tests 
o CK/CPK test 
o Research blood tests 
• Urine pregnancy test (or blood test) if you are a woman who is able to have 
children 
• Electrocardiogram, if you are in the Phase 1 portion of the trial 
• Tumor imaging if not done within the 4 weeks of your last visit 
30-day Safety Follow-up Visit 
The following procedures will be done at your 30-day safety follow-up visit: 
• Physical exam and vital signs, including weight 
• Blood sample collection for: 
o Routine safety tests such as a complete blood count and comprehensive 
metabolic panel 
o Thyroid function tests 
o CK/CPK test 
• Urine pregnancy test (or blood test) if you are a woman who is able to have 
children 
• Electrocardiogram, if you are in the Phase 1 portion of the trial 
We will also ask you if you have started a new anti-cancer treatment.  
90-day Safety Follow-up Visit 
This visit may be done either in-clinic or over the phone to check on how you are doing 
and to make sure you are not experiencing adverse events related to the study treatment. 
If this visit is done over the phone, we may request for you to come into the clinic if any 
concerns are noted.  
Long-Term Follow-up 
Every 12 weeks after your 90-day follow-up visit, we will contact you either by phone or 
review your medical record for up to two years, to check on how you are doing, to 
receive information about your cancer status, and about your current cancer therapy. 
After two years, this follow-up will change to every 6 months.  
 
 


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How long would you stay in this study? 
If you join this study, you would stay in this study until your disease progresses. If your 
disease progresses, we may contact you by phone every 12 weeks to see how you are 
doing until the study closes. 
Doctors could take you out of this study at any time. This would happen if: 
• 
They think it is in your best interest not to continue in the study. 
• 
You not able or willing to follow study procedures. 
• 
The whole study is stopped.  
If you withdraw from the study for any reason, previously collected information would 
remain in the study records and would be included in the analysis of results. This 
information could not be removed from the study records.  
With some immunotherapy drugs, people’s first set of scans after starting treatment show 
their disease getting worse (progressing), but the next scan might show the disease 
getting better. We will tell you if any scan shows that your disease is progressing. If your 
first scan shows progressive disease but you are doing well overall, you may be allowed 
to continue on the study until progression is confirmed on one additional scan. We do not 
know if the next scan would show that your disease is better, worse, or the same. Staying 
on the study would delay your opportunity to try another treatment. As always, you are 
allowed to leave the study at any time or ask your doctor to discuss other treatments that 
may be right for you. 
What are the side effects (risks)? 
In this part of the consent form, we describe the side effects we expect from the tests and 
treatments in this study. The combination of trabectedin and avelumab could cause side 
effects we do not know about yet. We carefully watch everyone in the study for side 
effects.  
If you join this study, we would tell you if we discover new side effects that could affect 
you.  
This form lists side effects of individual drugs. Other side effects could occur when we 
use these drugs together. 
Side effects may be mild or very serious. Medicines could be given to help lessen side 
effects. Many side effects go away soon after you stop taking trabectedin and avelumab. 
In some cases, side effects can last a long time or never go away. There also is a risk of 
death. 
Risks of Trabectedin: 
Trabectedin is an FDA-approved chemotherapy that is part of the standard of care for 
soft-tissue sarcoma. It is likely to make you feel tired and nauseated. We are generally 
able to keep the nausea from getting too bad using drugs to make you feel better.  


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Trabectedin can sometimes weaken your immune system and could make you susceptible 
to life-threatening infections. Because of this, if you have a fever during the weeks 
following your trabectedin infusion, you should seek medical attention immediately. It 
can also lower your blood counts and occasionally people even need a blood transfusion.  
Although very rare, trabectedin can cause heart problems, this is why we require an 
Echocardiogram or MUGA scan prior to study entry.  
There is a very rare, but very serious and potentially fatal, problem that trabectedin can 
cause called rhabdomyolysis. This is a problem of wide-spread muscle breakdown. If you 
have severe generalized muscle pain or feel very ill generally, seek immediate medical 
attention 
Most Common (greater than or equal to 20% of subjects) side effects of trabectedin 
are: 
• 
Fatigue 
• 
Vomiting 
• 
Nausea 
• 
Constipation 
• 
Loss of appetite 
• 
Diarrhea 
• 
Swelling of your hands, ankles, and feet 
• 
Shortness of breath 
• 
Headache 
• 
Back pain and stomach pain 
Less Common (greater than or equal to 5% of subjects) side effects of trabectedin are: 
• 
Decreased red blood cell count (anemia), which may cause you to be tired 
• 
Decreased platelet cell counts (thrombocytopenia), which may make it miore 
likely that you have bleeding 
• 
Changes in liver and kidney function blood tests 
• 
Decreased level of white blood cell counts, which can increase your risk for 
infection 
• 
Increase in creatinine phosphokinase (CPK), an enzyme found in your heart, brain 
and skeletal muscles. High levels usually indicate some type of stress or injury to 
your heart or other muscles. 
Rare But Serious (less than 2% of subjects) side effects at these doses of trabectedin 
are: 
• 
Rhabdomyolysis (explained above) 
• 
Liver failure 


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• 
Severe infection 
• 
Heart muscle problems, including heart failure 
• 
Acute kidney injury or failure 
• 
Small bowel obstruction 
• 
Capillary Leak Syndrome, a condition that causes fluid to leak out of blood 
vessels into different tissues. This can cause swelling, a sudden drop in blood 
pressure, and a drop in a blood protein called albumin. This can be fatal. 
• 
Severe allergic infusion reactions, can be fatal 
• 
Development of a blood cancer such as leukemia or myelodysplastic syndrome 
(MDS), can be fatal 
• 
Damage to tissue or tissue death if trabectedin leaks outside of the IV during 
infusion. 
There have also been rare cases of death related to trabectedin. This includes patients 
who have had multi-organ failure, kidney failure, liver failure, bleeding of the stomach or 
bowel, fluid in the lungs, blood clots in the lungs, and infections with low blood counts 
leading to septic shock (neutropenic sepsis).  
Risks of Avelumab  
Although Avelumab has been tested in prior clinical trials and has an established safety 
record, it is important to note that it is still an investigational therapy that has not yet been 
approved by the FDA. Avelumab is generally well tolerated for a majority of patients but 
it can cause side effects which in some cases can be very serious.  
The likely (>10%) side effects of avelumab are: 
• 
Anemia (low red blood cells) 
• 
Diarrhea 
• 
Constipation 
• 
Nausea  
• 
Vomiting 
• 
Abdominal (stomach) pain 
• 
Fatigue 
• 
Fevers 
• 
Edema (swelling) 
• 
Infusion reactions 
• 
Weight loss  
• 
Decreased appetite 
• 
Back and joint pain 


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• 
Cough 
• 
Shortness of breath 
The less common (1-10%) side effects of avelumab are: 
• 
Problems with the thyroid gland which makes hormones including low thyroid 
function, too much thyroid hormone, inflamed thyroid and autoimmune thyroid 
destruction 
• 
Chills 
• 
Dizziness 
• 
Headaches 
• 
Inflammation of the lungs (pneumonitis) 
• 
Rash or itching 
• 
High blood pressure 
Avelumab can rarely have very serious autoimmune effects which can even be fatal. 
The rare (<1%) side effects of avelumab are: 
• 
Problems with the adrenal gland (adrenal insufficiency)  
• 
Problems with the pituitary gland that makes hormones, which may cause 
headaches, stomachache, double vision, menstrual changes, weakness, skin 
darkening, rapid heartbeat (hypophysitis) 
• 
Inflammation of the uvea in the eye (uveitis) 
• 
Inflammation of the bowels and colon causing severe diarrhea (colitis) 
• 
Liver problems ranging from abnormalities on routine lab tests to autoimmune 
hepatitis and liver failure 
• 
Allergy to the medication including anaphylaxis 
• 
Development of diabetes 
• 
Inflammation of muscles may include weakness, aches, muscle tenderness, 
swelling, and pain (myositis) 
• 
Inflammation of kidneys (nephritis) 
• 
Kidney failure 
• 
Inflammation of the heart which can cause chest pain, abnormal heartbeat, 
shortness of breath, and sudden death (myocarditis or pericarditis)  
• 
Inflammation of the pancreas, which may include pain in the upper abdomen, 
nausea, vomiting, constipation, weight loss, or indigestion (pancreatitis) 
• 
Small bowel obstruction 
• 
Development of Myasthenia Gravis / Myasthenic Syndrome: a weakness and 
rapid fatigue of muscles your body uses for movement. Symptoms may include 


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weakness in the arm and leg muscles, difficulty with speech, swallowing or 
chewing, double vision, or an unsteady walk 
Risks of Combination Therapy  
One of most important reasons for doing this study is to confirm that the combination of 
trabectedin and avelumab is safe. We do not expect to see additional toxicities with the 
combination that are not seen with either drug alone, however this is possible. It is even 
possible those side effects could be serious or life threatening.  
The combination of trabectedin and avelumab could cause side effects we do not know 
about yet. We carefully watch everyone in the study for side effects.  
Side effects may be mild or very serious. Medicines could be given to help lessen side 
effects. Many side effects go away soon after you stop taking trabectedin and avelumab. 
In some cases, side effects can last a long time or never go away. There also is a risk of 
death. 
If you join this study, we would tell you if we discover new side effects that could affect 
you.  
Port Inflammation and Clotting 
Two side effects have been noted in subjects treated with avelumab and trabectedin in 
combination on this study. One is an increased risk of port inflammation and the other is 
clotting in the subject’s ports.  
5 subjects out of the 33 subjects (15.2%) treated on this trial have experienced port 
inflammation or irritation at their port site. You may notice redness or pain at your port 
site. If you experience this, please let the study team or your provider know. Your port 
may need to be replaced if this happens. 
2 subjects out of the 33 subjects (6.1%) treated on this trial have experienced a blood clot 
within or near their port. These clots could require you to have your port removed and 
replaced and could even potentially cause more serious problems. We have made changes 
in the way the drugs are administered that we hope will prevent this problem in the 
future, however this remains a risk. 
Although rates of inflammation and clotting are similar to what has been seen in 
published literature for trabectedin, there was one particularly severe clotting event for a 
subject on this trial that required surgical intervention. It is unclear if the addition of 
avelumab might have contributed in this case.  
Reproductive risks 
Trabectedin and avelumab treatments could cause sterility (unable to have children). For 
this reason, we recommend that males or females who are considering having children in 
the future consider either sperm banking or egg freezing. Discuss this with your doctor. 
The risk of trabectedin and avelumab to an unborn child or nursing infant is unknown. 
Therefore, you cannot join this study if you are pregnant, if you are planning to become 


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pregnant, or if you are breast-feeding. You must agree to not become pregnant while you 
are in this study. 
Women: 
If you are able to have children and are sexually active, two effective methods of birth 
control must be used. This could include the following:  
• Hormonal contraceptive 
o Oral pills 
o Intravaginal, such as the NuvaRing 
o Transdermal, such as a patch 
o Injectable, such as Depo-Provera  
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)  
• Double-barrier method  
o This includes the use of condoms, occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam, cream, gel, film, or suppository.  
Abstinence is an allowed method of birth control. If you are sexually active, you must 
agree to use 2 methods of birth control as explained above. These methods need to be 
discussed with your study doctor before you begin treatment. You will need to use birth 
control while you are on study through 5 months after your last dose. 
If you get pregnant during the study, you must tell your study doctor immediately. You 
will have to stop taking trabectedin and avelumab. Your doctor will advise you about 
your medical care. We may ask you to allow us to follow your pregnancy for information 
about your health and that of your baby. 
Men: 
The effects of fathering a child while you are study treatment are also unknown. Men 
who join this study must also agree to use a condom or other form of effective and 
acceptable birth control while you are on study until at least 5 months after the last dose 
of trabectedin. 
If your partner becomes pregnant while you are receiving treatment, you must tell your 
study doctor immediately. We may ask you to allow us to follow the pregnancy for 
information about your partner’s health and that of your baby. 
No sperm donations should be made from time of your first dose of study treatment until 
5 months after the last dose of study drug. 
Risks of Study Procedures 
Blood draws: When you have your blood drawn you may feel some minor discomfort. 
Possible side effects include pain, redness, bruising or bleeding at the site of the needle 


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puncture. Some people feel lightheaded or faint when their blood is drawn. Rarely blood 
clots or an infection may occur. 
CT Scans: You will be exposed to radiation at a level below the levels considered to 
cause harmful effects. If a contrast dye is used, there is a small risk of an allergic 
reaction. You may experience discomfort related to lying still in an enclosed space for a 
prolonged period of time. 
MRI Scans: A loud banging noise will be produced. Earplugs or headphones will be 
available if needed. If a contrast dye is used, there is a small risk of an allergic reaction. 
You may experience discomfort related to lying still in an enclosed space for a prolonged 
period of time. 
MUGA Scans: During the MUGA scan, a small amount of a radioactive substance or 
tracer (called a radionuclide) is put into your blood. The tracer attaches to your red blood 
cells. The amound of radiation exposure is similar to what you would receive in a CT 
Scan 
Radiation: Some of the tests that you will have in this research study will expose you to 
radiation. Everyone receives a small amount of radiation every day called “background 
radiation”. This radiation is natural and comes from space, air, water, soil, and the food 
you eat. Each year you are exposed to about 3 milliSieverts (mSv) of this background 
radiation. A milliSievert is a unit of radiation dose. For comparison, the estimated 
radiation dose from each of these tests is listed below. The risk to your health from this 
level of radiation exposure is likely zero. 
• 
MUGA scan: 9.4 mSv 
• 
CT scan of the chest: 7 mSv 
• 
CT scan of the abdomen: 8 mSv 
• 
CT scan of the pelvis: 6 mSv 
Non-physical risks 
If you join this study, non-physical risks are: 
• 
You might not be able to work. 
• 
You might have financial expenses caused by transportation to and from the 
doctor’s office 
• 
Results of research studies, including genetic tests, might be released by accident. 
This risk is very low, because we keep personal information private. If these 
results became known, you could have problems with family members or 
insurance. 
What are the benefits? 
We do not know if this study would help you. We are testing the addition of avelumab to 
trabectedin to see its effects on people with sarcoma. You might get better if you receive 
the combination of trabectedin and avelumab but your condition could stay the same or 


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even get worse. We hope the information from this study will help other people with 
sarcoma in the future. 
You have other choices besides this study. 
You do not have to join this study. You are free to say “yes” or “no”. Your regular 
medical care would not change if you decide to say “no”.  
You have other choices for treatment. Each of these choices has risks and benefits. You 
should talk to your doctor or healthcare provider about these choices.  
There may be other FDA-approved treatment choices for your disease that you have not 
received yet. This may include older chemotherapies such as doxorubicin or newer, FDA-
approved drugs such as pazopanib or eribulin. Talk to your doctor about these other 
treatments as they may be good options for you.  
Other choices include: trabectedin alone, another “standard” treatment like 
chemotherapy, another research study, no treatment, comfort care.  
Enrollment in this study may exclude you from other research studies.  
Protecting Privacy as an Individual and the Confidentiality of Personal Information  
If you join this study, some people or organizations might need to look at your medical 
records and research records for quality assurance or data analysis. They include: 
• The researchers involved in the study. 
• EMD Serono (the maker of Avelumab) who is financially supporting the study. 
• Institutional Review Boards (IRB), including the Fred Hutchinson Cancer 
Research Center IRB. An IRB is a group that reviews the study to protect the 
rights and welfare of research participants. 
• 
Fred Hutchinson Cancer Research Center, University of Washington, Seattle 
Children’s, and Seattle Cancer Care Alliance. 
• 
US National Institutes of Health, National Cancer Institute, Office for Human 
Research Protections, Food and Drug Administration, and other regulatory 
agencies as required. 
We will do our best to keep personal information confidential. But we cannot guarantee 
total confidentiality. Personal information may be given out if required by law. For 
example, workplace safety rules may require health workers to contact you about lab 
tests. Or a court may order study information to be disclosed. Such cases are rare. 
We will not use personal information in any reports about this study, such as journal 
articles or presentations at scientific meetings. 
Policies of the University of Washington (UW Medicine) and the Seattle Cancer Care 
Alliance (SCCA) require that certain information about participation in this research 
must be included in permanent medical records.  


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If you join this study but do not already have a medical record at UW Medicine or 
SCCA, we would create a record even if the only connection with UW Medicine or 
SCCA involves this research study.  
The information in the permanent medical record would include: 
• Name of the study. 
• Name of the group or company that is paying for the research. 
• The number the group or company assigned to this study. 
• The name of the researcher. 
• The name of the study coordinator. 
• Contact phone number for the study. 
• Contact email address for the study. 
• Emergency phone number for the study. 
If you join this study, information about research procedures and test results might also 
be put in your medical record. This information would include all scans and standard 
labs drawn as part of the study and may include non-standard research tests as well. 
If you join this study, information about your participation would be made part of your 
permanent medical record. This information would include a copy of this consent form. 
If an insurance company or employer or anyone else were authorized to see the medical 
record, they would see a copy of this consent form. 
How is my genetic information protected? 
A federal law called the Genetic Information Nondiscrimination Act (GINA) helps 
protect genetic information about people who join research studies.  
GINA restricts access to genetic information so that it cannot be used for health insurance 
coverage decisions. GINA prevent health insurance companies or group health plans 
from  
• Asking for genetic information obtained in research studies, or 
• Using genetic information when making decisions regarding your eligibility or 
premiums  
GINA does not help or protect against genetic discrimination by companies that sell life, 
disability or long-term care insurance.  
Would we pay you if you join this study? 
There is no payment for being in this study.  


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Would you have extra costs if you join this study?  
If you join this study, you or your insurance company would have to pay for the costs of 
standard treatment in this study. 
You would not be billed for: 
• 
Avelumab 
• 
Correlative blood tests for research 
• 
Tissue slides and curls from a previous biopsy 
• 
12-lead ECG done at screening and at the discontinuation of treatment 
• 
Urine Pregnancy tests for women of child-bearing potential 
• 
Thyroid tests, including TSH, Free T4, and Total T3 
What if you get sick or hurt after you join this study? 
For a life-threatening problem, call 911 right away or seek help immediately. Contact 
your study doctor when the medical emergency is over or as soon as you can.   
For all other medical problems or illness related to this research, immediately contact one 
of the study coordinators, their numbers are below. They will refer you for treatment. 
You or your health insurance will have to pay for the treatment. There are no funds to pay 
you for a research-related injury, added medical costs, loss of a job, or other costs to you 
or your family. State or national law may give you rights to seek payment for some of 
these expenses. You do not waive any right to seek payment by signing this consent 
form. 
You or your insurer will be billed for treatment of problems or complications that result 
from your condition or from standard clinical care. 
You would not lose any legal right to seek payment for treatment if you sign this form. 
We invite you to donate tissue samples for other research.  
After we do tests on tissue in this study, some tissue may be left over. We invite you to 
donate this leftover tissue for future research. This may include genetic research.  
If you join this study, you would not have to donate tissue for research. You would be 
free to say “yes” or “no”. Regular medical care would not change if you say “no.”  
If you donate tissue, it would be stored in a secure location. If we want to use your tissue 
for other research or share it with other scientists for research, an ethics review 
committee (IRB) would review the request. The IRB would decide if we need to ask you 
for permission to do the research.  
Your donated tissue would be used only for research. This research could be done by for-
profit companies. Researchers would not report their results to you or your doctors. The 


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research results would not be included in medical records. The results would not affect 
your medical care.  
Research with tissue might help develop new products. If these products make money, 
there is no plan to share the money with the participants who donate the tissue.  
If you donate tissue for research, you could withdraw the donation at any time by calling 
Roxanne Moore at 206-606-6425. You would have no penalty for withdrawing the 
donation, and regular medical care would not change. We could not return donated tissue, 
but we might be able to destroy the donated tissue. We could not destroy tissue if it is 
stored or shared without any label saying who donated it. In this case, it could still be 
used for research.  
 
 


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Your rights 
• 
You do not have to join this study. You are free to say “yes” or “no”.  
• 
If you get sick or hurt in this study, you do not lose any of your legal rights to 
seek payment by signing this form. 
• 
During the study, we might learn new information that you need to know. For 
example, some information may affect your health or well-being. Other 
information might make you change your mind about being in this study. If 
we learn these kinds of information, we would tell you. 
• 
If you join this study, you would not have to stay in it. You could stop at any 
time (even before you start). Your regular medical care would not change. 
You would have no penalty for stopping, but it would be better not to join the 
study if you think that you would change your mind later.  
• 
If you decide to drop out, we would want you to tell the study doctor. The 
doctor could tell you about the effects of stopping avelumab and trabectedin. 
You and the doctor could talk about the follow-up care and testing that would 
help the most.  
• 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will 
not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
Your responsibilities 
If you join this study, you would have some responsibilities.  
• 
Follow the schedule of study visits and procedures. 
• 
Take study medications as directed.  
• 
Prevent pregnancy. 
• 
Tell us about side effects.   


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For more information 
If you have questions or concerns about this study, you could talk to your doctor 
anytime. Other people you could talk to are listed below. 
 
If you have questions about: 
 
Call: 
This study (including 
complaints and requests for 
information) 
 
206-667-6629 Dr. Seth Pollack 
206-606-6425 Roxanne Moore (Assistant Director) 
If you get sick or hurt in this 
study 
 
206-667-6629 Dr. Seth Pollack 
Your rights as a research 
participant 
 
206-667-5900 or email irodirector@fredhutch.org 
(Director of Institutional Review Office, Fred 
Hutchinson Cancer Research Center) 
206-543-0098 (Human Subjects Division, 
University of Washington) 
Your bills and health 
insurance coverage 
 
206-606-1113 (Seattle Cancer Care Alliance 
Patient Financial Services) 
 
Emergency phone:  
• Monday through Friday, 9 am to 5 pm: Seattle Cancer Care Alliance at 206-606-
7400 
• 24 Hours: University of Washington Medical Center paging operator at 206-598-
6190. Ask the operator to page the oncology fellow on-call. 
 
Read each question and think about your choice. When you decide on each question, 
please circle YES or NO. 
 
Do you agree to donate your tissue to study cancer? 
(circle one and initial next to choice) 
YES  
NO  
 
 


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Subject’s Statement 
I have read the information in this consent form (or it has been read to me). All my 
questions about the study and my part in it have been answered. I freely consent to take 
part in this research study. If I sign this form I will not lose any of the legal rights that I 
would otherwise have as a subject in a research study. 
CONSENT SIGNATURE: 
 
____________________________________________ 
Subject Name (printed) 
 
 
____________________________________________          ______________________ 
Signature of Subject (18 years and older) 
 
 
   Date 
 
Researcher’s Statement 
I confirm that the research study was thoroughly explained to the subject.  I reviewed the 
consent form with the subject and answered the subject’s questions.  The subject 
appeared to have understood the information and was able to answer the following 
questions correctly: 
 
1. What is the purpose of this study? 
2. If you decide to be in the study, what will you be asked to do? 
3. What is the possible benefit of participating in this study? 
4. What are the possible risks of participating in this study?  
5. If you decide not to participate in this study, what options do you have? 
6. Will participating in this study cost you anything?  If so, what will you have to pay 
for? 
7. Do you have to be in this study? 
8. If you decide to be in the study, can you leave the study when you want to? 
 
 
________________________________________ 
 
Printed Name of Person Conducting the 
 
Informed Consent Discussion 
 
 
________________________________________ 
__________________ 
Signature of Person Conducting the 
Date 
Informed Consent Discussion 
 
 
 
 
FHCRC IRB Approval  
AUG 06 2020 
Document Released Date


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Witness or Interpreter: 
If you served as an interpreter or witness during the consent process, sign below to 
indicate you attest to the accuracy of the presentation to the participant and the apparent 
understanding of the research by the participant. 
 
 
 
 
 
 
Printed Name 
Signature 
Date 
 
 
Copies to: Researcher’s file 
Subject 
Subjects medical record