Avelumab and Trabectedin in Treating Patients With Liposarcoma or Leiomyosarcoma That is Metastatic or Cannot Be Removed by Surgery

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

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the safety and tolerability of the combination of trabectedin and avelumab in subjects with advanced leiomyosarcoma and liposarcoma. II. To assess the objective response rate of advanced L-type sarcoma patients receiving the combination regimen of avelumab and trabectedin. SECONDARY OBJECTIVE: I. To further explore the clinical activity and safety profile of avelumab and trabectedin as a combination therapy. OUTLINE: Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression. After completion of study treatment, patients are followed up at 30 and 90 days, then every 12 weeks for 2 years.

Official Title
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A Phase I/II Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma

Conditions
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Metastatic Leiomyosarcoma, Metastatic Liposarcoma, Unresectable Leiomyosarcoma, Unresectable Liposarcoma

Intervention / Treatment
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* Drug: Avelumab
* Drug: Trabectedin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have a histologically confirmed diagnosis of advanced (metastatic or unresectable) soft tissue sarcoma with one of the following subtypes: Leiomyosarcoma Liposarcoma 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 Total bilirubin level =< 1.5 x the upper limit of normal (ULN) mg/dL Aspartate aminotransferase (AST) =< 2.5 x ULN and alanine aminotransferase (ALT) =< 2.5 x ULN Alkaline phosphatase < 2.5 x ULN Serum creatinine =< 1.5 x ULN Calculated creatinine clearance >= 30 mL/min using the Cockcroft-Gault formula may be included Creatinine phosphokinase (CPK) =< 2.5 x ULN Absolute neutrophil count (ANC) >= 1.5 x 10^9/L Platelet count >= 100,000/mm^3 (100 x 10^9/L) Hemoglobin >= 9 g/dL Subject must demonstrate a left ventricular ejection fraction (LVEF) > 45% by echocardiography (ECHO) or multigated acquisition scan (MUGA) Male or non-pregnant and non-breast feeding female: 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 (beta - human chorionic gonadotropin [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 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 All ongoing toxicities related to prior therapies must be resolved to grade 1 or better (except alopecia) Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 1 or Karnofsky performance scale >= 70 Subjects must have one or more measurable lesions, as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 assessed by computed tomography (CT) or magnetic resonance imaging (MRI) Subjects must have a life expectancy of >= 6 months, as determined by the treating physician Ability to understand and sign informed consent document Willingness and ability to comply with the scheduled visits, laboratory tests, and other study procedures Exclusion Criteria: 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 Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 2 weeks of enrollment Prior organ transplantation, including allogeneic stem cell transplantation Prior treatment with trabectedin Significant acute or 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 Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible 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 Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, introocular, or inhalation) are acceptable Known severe hypersensitivity reactions to monoclonal antibodies (grade >= 3 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) Pregnant or lactating females Known, active alcohol or drug abuse 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 Any vaccination within 4 weeks of the first dose of avelumab, with the following exceptions: * Administration of inactivated vaccines, including inactivated flu vaccines, are allowable; however, they should not be given within 2 weeks prior to starting study treatment 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 New York Heart Association (NYHA) class II or greater or serious cardiac arrhythmia requiring medication Severe (requiring active treatment) acute or chronic medical conditions including: colitis, inflammatory bowel disease, pneumonitis, or pulmonary fibrosis Recent (within the past year) or active suicidal ideation or behavior

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Subjects were enrolled into Phase 1, first into 1.5 mg/m^2 trabectedin dose, then 1.0 mg/m^2 trabectedin, then 1.2 mg/m^2 trabectedin. Once the recommended Phase 2 dose was selected at 1.0 mg/m^2 trabectedin, all subsequent subjects were enrolled into Phase 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 (1.5 mg/m^2 trabectedin + avelumab)<br>Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression. | Drug: Avelumab<br>* Given IV<br>* Other names: MSB0010718C;Drug: Trabectedin<br>* Given IV<br>* Other names: Yondelis;|
| Experimental: Phase 1 (1.0 mg/m^2 trabectedin + avelumab)<br>Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression. | Drug: Avelumab<br>* Given IV<br>* Other names: MSB0010718C;Drug: Trabectedin<br>* Given IV<br>* Other names: Yondelis;|
| Experimental: Phase 1 (1.2 mg/m^2 trabectedin + avelumab)<br>Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression. | Drug: Avelumab<br>* Given IV<br>* Other names: MSB0010718C;Drug: Trabectedin<br>* Given IV<br>* Other names: Yondelis;|
| Experimental: Phase 2 (1.0 mg/m^2 trabectedin + avelumab)<br>Avelumab will be administered every 2 weeks. Trabectedin will be administered every 3 weeks for the first two doses (Week 1 and Week 4), and then every four weeks (Week 7, Week 11,…) moving forward. After Cycle 2 of trabectedin, dosing may extend to every 5 weeks at investigator discretion, for management of trabectedin-associated toxicity only. Delays of trabectedin beyond 5 weeks may be allowed but require written approval from the Sponsor-Investigator. On days where both drugs are scheduled to be administered, avelumab will be administered first. This will continue until unacceptable toxicity or confirmed disease progression. | Drug: Avelumab<br>* Given IV<br>* Other names: MSB0010718C;Drug: Trabectedin<br>* Given IV<br>* Other names: Yondelis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. | up to 2 years 7 months total | 
| Overall Response Rate (ORR) | Rate of Partial Response (PR) + Complete Response (CR), which is the best response for each subject determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for target lesions and assessed by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan. Partial response is defined as a decrease in 30% or more in the sum of the longest diameter of target lesions, and complete response is defined as disappearance of all evaluable disease. No subjects had a complete response on this study so the ORR represents subjects who had a partial response only. | Up to 2 years 7 months total | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Response | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Time to response is defined as the amount of time from when the subject first received study treatment (Cycle 1, Day 1) to when they achieved a partial response on trial. With such small numbers, this data is not necessarily representative of what a larger study would report. | Up to 2 years 7 months total | 
| Duration of Response | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Duration of response is defined as the amount of time a subject responded to study treatment with either a partial response or complete response until the date of last follow-up (if response ongoing at data cutoff) or the date until they progressed on study. | Up to 2 years 7 months total | 
| Progression-free Survival (PFS) | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, appearance of new lesions while on study, or clear growth of a non-target lesion. | At 12 weeks | 
| Complete Response Rate (CR) | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response is defined as disappearance of all evaluable disease. | At 12 weeks | 
| Partial Response Rate (PR) | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Partial response is defined as a decrease in 30% or more in the sum of the longest diameter of target lesions. | At 12 weeks | 
| Stable Disease (SD) | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Stable Disease is defined as neither sufficient shrinkage to qualify for a Partial Response (PR) nor sufficient increase to qualify for Progressive Disease (PD). | At 12 weeks | 
| Clinical Benefit Rate | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Clinical Benefit Rate is defined as the percentage of subjects who achieved a Complete Response (CR) + Partial Response (PR) + Stable Disease (SD). | At 12 weeks | 
| Median Overall Survival (OS) | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Up to 2 years post End of Treatment, for a total of 3 years | 
| Adverse Event Profile - All Treatment-Related Grade 3-5 Adverse Events | Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Up to 2 years 7 months total |