fred hutchinson cancer research center
untitled h2

| 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.
fred hutchinson cancer research center
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 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. |                                                                                                                                            |
| Study Design                        | -                                                                                                                                                                                                                                                                                                                 | Safety as measured by CTCAE v5.0.                                                                                                          |
| -                                   | Overall Response Rate (PR + CR, best response for each  subject) by RECIST v1.1.                                                                                                                                                                                                                                  |                                                                                                                                            |
| Primary 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                                                                                                                                                                                                                                                                                |                                                                                                                                            |
| Secondary Endpoints 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            | 22, with possible expansion up to 34 (6 up to 18 in Phase 1,                                                                                                                                                                                                                                                      |                                                                                                                                            |
| subjects                            | additional 16 in Phase 2)                                                                                                                                                                                                                                                                                         |                                                                                                                                            |
| Estimated duration of trial         | 2 years                                                                                                                                                                                                                                                                                                           |                                                                                                                                            |
| Duration of Participation           | 1-2 year (estimated)                                                                                                                                                                                                                                                                                              |                                                                                                                                            |
fred hutchinson cancer research center
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                     | Case Report Forms                                                                                                                                                        |                          |
| CT                      | 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                      | Progressive Disease                                                                                                                                                      |                          |
| PD-1                    | 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                     | Soft Tissue Sarcoma                                                                                                                                                      |                          |
| T4                      | Free thyroxine                                                                                                                                                           |                          |
| 04FEB2020               | Page 3 of 59                                                                                                                                                             | Version 8.0, Amendment 7 |  
| TSH   | Thyroid-Stimulating Hormone   |
|-------|-------------------------------|
| Treg  | Regulatory T cell             |
| ULN   | Upper limit of normal         |  
| Table of Contents                            |                                                  |                          |
|----------------------------------------------|--------------------------------------------------|--------------------------|
| 1.0                                          | GENERAL INFORMATION                              |                          |
| Protocol Title                               |                                                  |                          |
| 1.1                                          |                                                  |                          |
| 1.2                                          | Sponsor-Investigator Information                 |                          |
| 2.0                                          | BACKGROUND AND RATIONAL                          |                          |
| Introduction to "L-type" sarcomas            |                                                  |                          |
| 2.1                                          |                                                  |                          |
| 2.2                                          | P Programming with Discovery Data                |                          |
| Clinical Data Using Avelumab in Solid Tumors |                                                  |                          |
| 2.3                                          |                                                  |                          |
| 2.4                                          | STUDY AGENT                                      |                          |
| 2.5                                          | Dose Rationale .                                 |                          |
| 2.6                                          | Trabectedin - Commercially Sourced .             |                          |
| 2.7                                          | Risks/Benefits                                   |                          |
| STUDY OBJECTIVES                             |                                                  |                          |
| 3.0                                          | 3.1                                              | STUDY ODJECTIVES         |
| 3.1.1                                        | Primary Objectives .                             |                          |
| 3.1.2                                        | Primary Endpoints                                |                          |
| Secondary Objectives                         |                                                  |                          |
| 3.1.3                                        |                                                  |                          |
| 3.1.4                                        | Secondary Endpoints                              |                          |
| 4.0                                          | TRIAL OVERVIEW                                   |                          |
| 4.1                                          | STUDY DESIGN                                     |                          |
| 4.1.1                                        | I II I                                           |                          |
| 4.1.2                                        | Definition of dose limiting toxicity (DLT):      |                          |
| Dosing Administration and Schedule .         |                                                  |                          |
| 4.1.3                                        |                                                  |                          |
| 4.1.4                                        | Assessment of Response and duration of therapy . |                          |
| 4.2                                          | ESTIMATED ACCRUAL                                |                          |
| 5.0                                          | SUBJECT ELIGIBLITY .                             |                          |
| 5.1                                          | Inclusion criteria:                              |                          |
| Exclusion criteria:                          |                                                  |                          |
| 5.2                                          |                                                  |                          |
| 6.0                                          | SUBJECT REGISTRATION                             |                          |
| TREATMENT PLAN                               |                                                  |                          |
| 7.0                                          | T Treatment Plan .                               |                          |
| 7.1                                          |                                                  |                          |
| 7.2                                          | Administration of agents .                       |                          |
| D Drug Product Information                   |                                                  |                          |
| 7.3                                          |                                                  |                          |
| 7.4                                          | Schedule of Treatment Visits .                   |                          |
| 8.0                                          | SUBJECT EVALUATION                               |                          |
| Screening Evaluations                        |                                                  |                          |
| 8.1                                          |                                                  |                          |
| 8.2                                          | ON-Study Clinical Evaluations                    |                          |
| End of Treatment (EOT) Procedures            |                                                  |                          |
| 8.3                                          |                                                  |                          |
| 8.4                                          | Short Term Follow-Up / 30 Day Safety Assessment  |                          |
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| 8.5                                                                                                                                                                            | Long Term Follow-Up / 90 Day Safety Assessment .                                                                                                                          |                          |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------|
| Long-Term Follow-Up for Survival .                                                                                                                                             |                                                                                                                                                                           |                          |
| 8.6                                                                                                                                                                            |                                                                                                                                                                           |                          |
| 8.7                                                                                                                                                                            | lmaging Assessments                                                                                                                                                       |                          |
| 8.8                                                                                                                                                                            | Analyte Listing                                                                                                                                                           |                          |
| Correlative Studies                                                                                                                                                            |                                                                                                                                                                           |                          |
| 8.9                                                                                                                                                                            |                                                                                                                                                                           |                          |
| 8.9.1                                                                                                                                                                          | T THE PROPOSITION                                                                                                                                                         |                          |
| Research Blood Specimens .                                                                                                                                                     |                                                                                                                                                                           |                          |
| 8.9.2                                                                                                                                                                          |                                                                                                                                                                           |                          |
| 9.0                                                                                                                                                                            | SAFETY                                                                                                                                                                    |                          |
| 9.1                                                                                                                                                                            | Adverse Event                                                                                                                                                             |                          |
| 9.2                                                                                                                                                                            | Serious Adverse Event                                                                                                                                                     |                          |
| 9.3                                                                                                                                                                            | Unexpected Adverse Event                                                                                                                                                  |                          |
| 9.4                                                                                                                                                                            | Monitoring and Recordings Adverse Events .                                                                                                                                |                          |
| 9.5                                                                                                                                                                            | Grading Adverse Event Severity                                                                                                                                            |                          |
| A A STATE AND IN THE P                                                                                                                                                         |                                                                                                                                                                           |                          |
| 9.6                                                                                                                                                                            |                                                                                                                                                                           |                          |
| 9.7                                                                                                                                                                            | Adverse Event Recording Period                                                                                                                                            |                          |
| Extended safety follow-up                                                                                                                                                      |                                                                                                                                                                           |                          |
| 9.7.1                                                                                                                                                                          |                                                                                                                                                                           |                          |
| 9.8                                                                                                                                                                            | Adverse Event Reporting Requirements .                                                                                                                                    |                          |
| Reporting to Product Manufacturer (EMD Serono)                                                                                                                                 |                                                                                                                                                                           |                          |
| 9.8.1                                                                                                                                                                          |                                                                                                                                                                           |                          |
| 9.8.2                                                                                                                                                                          | SE/ONSET DATE Reporting to IRB                                                                                                                                            |                          |
| FDA Reporting Requirements .                                                                                                                                                   |                                                                                                                                                                           |                          |
| 9.8.3                                                                                                                                                                          |                                                                                                                                                                           |                          |
| 10.0                                                                                                                                                                           | MMANAGEMENT OF TOXICITY AND COMPLICATIONS                                                                                                                                 |                          |
| Adverse Drug Reactions (ADRs) Related to Avelumab                                                                                                                              |                                                                                                                                                                           |                          |
| 10.1                                                                                                                                                                           |                                                                                                                                                                           |                          |
| 10.2                                                                                                                                                                           | Avelumab-Specific Adverse Events or Adverse Drug Reactions ....................................................................................31                         |                          |
| 10.2.1                                                                                                                                                                         | Symptoms of Infusion-Related Reactions                                                                                                                                    |                          |
| 10.2.2                                                                                                                                                                         | MManagement of Infusion-Related Reactions                                                                                                                                 |                          |
| Toxicity of Trabectedin ....................................................................................................................................................41 |                                                                                                                                                                           |                          |
| 10.3                                                                                                                                                                           |                                                                                                                                                                           |                          |
| 10.4                                                                                                                                                                           | Dose Modification of Trabectedin ......................................................................................................................................41 |                          |
| SUBJECT DISCONTINUATION OF ACTIVE TREATMENT .................................................................................................................41                |                                                                                                                                                                           |                          |
| 1.0                                                                                                                                                                            |                                                                                                                                                                           |                          |
| 12.0                                                                                                                                                                           | CONCOMITANT MEDICATIONS                                                                                                                                                   |                          |
| 12.1                                                                                                                                                                           | Pre-Medication Treatment with Trabectedin and Avelumab ..........................................................................................42                       |                          |
| CYP3A4 Inhibitors and Inducers with Trabectedin ...........................................................................................................42                  |                                                                                                                                                                           |                          |
| 12.2                                                                                                                                                                           |                                                                                                                                                                           |                          |
| 13.0                                                                                                                                                                           | CONTRACEPTION                                                                                                                                                             |                          |
| DATA AND SAFETY MONITORING PLAN                                                                                                                                                |                                                                                                                                                                           |                          |
| 14.0                                                                                                                                                                           |                                                                                                                                                                           |                          |
| 15.0                                                                                                                                                                           | DATA MANAGEMENT/CONFIDENTIALITY                                                                                                                                           |                          |
| 15.1                                                                                                                                                                           | DATA QUALITY ASSURANCE                                                                                                                                                    |                          |
| DATA Documents .                                                                                                                                                               |                                                                                                                                                                           |                          |
| 15.2                                                                                                                                                                           |                                                                                                                                                                           |                          |
| 15.3                                                                                                                                                                           | DATA MANAGEMENT                                                                                                                                                           |                          |
| 15.4                                                                                                                                                                           | Investigator Responsibilities for Data Collection                                                                                                                         |                          |
| 16.0                                                                                                                                                                           | STATISTICAL CONSIDERATIONS                                                                                                                                                |                          |
| 16.1                                                                                                                                                                           | S STUDY DESIGN                                                                                                                                                            |                          |
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| 16.2                                                                                                                                                                    | Phase I Design .                                                                                                                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 16.3                                                                                                                                                                    | Phase II Design                                                                                                                                                           |
| DATA AND SAFETY MONITORING BOARD (DSMB) .............................................................................................................................45 |                                                                                                                                                                           |
| 16.4                                                                                                                                                                    |                                                                                                                                                                           |
| 16.5                                                                                                                                                                    | Additional Efficacy Hypotheses                                                                                                                                            |
| Ethnic and Gender Distribution Chart..............................................................................................................................46    |                                                                                                                                                                           |
| 16.6                                                                                                                                                                    |                                                                                                                                                                           |
| 17.0                                                                                                                                                                    | INVESTIGATOR OBLIGATIONS .                                                                                                                                                |
| 18.0                                                                                                                                                                    | ADMINISTRATIVE AND REGULATORY CONSIDERATIONS                                                                                                                              |
| 18.1                                                                                                                                                                    | Study Site Training ...................................................................................................................................................46 |
| 18.2                                                                                                                                                                    | D Documentation                                                                                                                                                           |
| DATA COLLECTION                                                                                                                                                         |                                                                                                                                                                           |
| 18.3                                                                                                                                                                    |                                                                                                                                                                           |
| 18.4                                                                                                                                                                    | Protocol Interpretation and Compliance ..............................................................................................................................47   |
| Study Monitoring and Data Collection                                                                                                                                    |                                                                                                                                                                           |
| 18.5                                                                                                                                                                    |                                                                                                                                                                           |
| 18.6                                                                                                                                                                    | D Disclosure of Data/Publication                                                                                                                                          |
| 18.7                                                                                                                                                                    | E E HICAL CONSIDERATIONS                                                                                                                                                  |
| Informed Consent .                                                                                                                                                      |                                                                                                                                                                           |
| 18.8                                                                                                                                                                    |                                                                                                                                                                           |
| 18.9                                                                                                                                                                    | Institutional Review Board/Ethics Committee                                                                                                                               |
| SUBJECT Privacy                                                                                                                                                         |                                                                                                                                                                           |
| 18.10                                                                                                                                                                   |                                                                                                                                                                           |
| 19.0                                                                                                                                                                    | APPENDICES .                                                                                                                                                              |
| 19.1                                                                                                                                                                    | APPENDIX A: ECOG Performance Status Scale                                                                                                                                 |
| APPENDIX B: Karnofsky Performance Status Scale .                                                                                                                        |                                                                                                                                                                           |
| 19.2                                                                                                                                                                    |                                                                                                                                                                           |
| 19.3                                                                                                                                                                    | APPENDIX C: Study Calendar .                                                                                                                                              |
| 19.4                                                                                                                                                                    | APPENDIX D: Assessment and Initial Management of Tumor Lysis Syndrome                                                                                                     |
| 19.5                                                                                                                                                                    | APPENDIX E: Women and Men of Childbearing Potential Definitions and Methods of Contraception ..................55                                                         |
| 19.5.1                                                                                                                                                                  | DEFINITIONS                                                                                                                                                               |
| 19.5.2                                                                                                                                                                  | Contraception Guidance for Females of Childbearing Potential .                                                                                                            |
| Contraception Guidance for Males of Childbearing Potential .                                                                                                            |                                                                                                                                                                           |
| 19.5.3                                                                                                                                                                  |                                                                                                                                                                           |
| 19.6                                                                                                                                                                    | APPENDIX F: References .                                                                                                                                                  |
fred hutchinson cancer research center
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
fred hutchinson cancer research center
2.0 background and rationale 2.1

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.
fred hutchinson cancer research center
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 antiCD47 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. 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 PD1 in 84% of these tumors with high levels of expression in 63% of tumors tested. While LMS frequently had high numbers of PDL1 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.
fred hutchinson cancer research center
2.3 clinical data using avelumab

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).
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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 PD1. 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 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 nonlinear 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 nonhuman primates is not deemed predictive for an immune response to avelumab in humans.
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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.  
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.
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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 Page 13
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2.5 dose rationale

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.
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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.
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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.
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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 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.
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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.
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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.
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3.0 study objectives 3.1 study

- 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 avelumab and trabectedin
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3.1.2primary 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
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3.1.4secondary 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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4.1 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.
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4.1.2 definition of dose limiting

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.  
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).
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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**.
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4.1.4 assessment of response and

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
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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

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.
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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.  
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.
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6.0 subject registration

Each subject who enters into the screening period for the study receives a unique subject identification number before any studyrelated 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).
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7.0 treatment plan 7.1 treatment

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 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., 2550 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 postavelumab 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 antiemetic, it also may prevent serioustoxicities 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.  
| Drug                                                                                                                            | Dose/                                 | Dose Frequency                                     | Route of       | Regimen/      |          |
|---------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|----------------------------------------------------|----------------|---------------|----------|
| Potency                                                                                                                         | Administration                        | Treatment  Period                                  | Use            |               |          |
| Avelumab                                                                                                                        | 800 mg flat                           | Q2 Weeks                                           | 60 minute (+/- |               |          |
| dose                                                                                                                            | 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)                           | 24 hour IV     | Day 1 of each | Standard |
| infusion                                                                                                                        | cycle*                                |                                                    |                |               |          |
| Q4 Weeks  (Cycle 3+)                                                                                                            |                                       |                                                    |                |               |          |
| *Cycles may be adjusted to q5 weeks, or greater with Sponsor-Investigator approval. No schedule adjustments are permitted until |                                       |                                                    |                |               |          |  
*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.  
7.2 Administration of agents
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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 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.
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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. |    |    |    |    |    |    |    |    |    |    |    |     |
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8.0 subject evaluation 8.1 screening

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 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)
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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.  
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
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8.3 end of treatment (eot)

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
- 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
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8.4 short term follow-up /

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
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8.5 long term follow-up /

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.
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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 Page 25
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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.
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8.8 .analyte listing table 1

| 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              | -Basophils    |                  |                        |
| Dehydrogenase        |               |                  |                        |
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8.9 correlative studies 8.9.1tumor 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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8.9.2research 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**.
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9.0 safety

Monitoring for both acute and chronic toxicities will be evaluated at all study related visits and will be assessed by the SponsorInvestigator. 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**.
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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.
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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                                                                                                                                                                                                                                                                |  
Page 27  
| 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.
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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.
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9.4 monitoring and recordings adverse

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
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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.
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9.6 attribution of an adverse

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.  
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.
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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.
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9.8 adverse event reporting requirements

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
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9.8.2sae/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 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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10.1 adverse drug reactions (adrs)

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  
| 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.
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10.2.2.2 severe hypersensitivity reactions and

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.
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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.