A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma (JAVELIN Bladder Medley)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of avelumab in combination with other anti-tumor agents as a maintenance treatment in participants with bladder cancer.

Official Title
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A Phase II, Multicenter, Randomized, Open Label, Parallel-Arm, Umbrella Study of Avelumab (MSB0010718C) in Combination With Other AntiTumor Agents as a Maintenance Treatment in Participants With Locally Advanced or Metastatic Urothelial Carcinoma Whose Disease Did Not Progress With First Line Platinum-Containing Chemotherapy (JAVELIN Bladder Medley)

Conditions
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Locally Advanced or Metastatic Urothelial Carcinoma

Intervention / Treatment
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* Drug: Avelumab
* Drug: Sacituzumab Govitecan
* Drug: M6223
* Drug: NKTR-255


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology Participants has documented Stage IIIA/IIIB with N1-N3, or Stage IV disease (per American Joint Committee on Cancer/International Union for Cancer Control Tumor Node Metastasis system, 8th edition) at the start of first line chemotherapy. The last dose of first line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study Estimated life expectancy of at least 3 months Participants without progressive disease as per RECIST v1.1 guidelines following completion of 4 to 6 cycles of 1L chemotherapy. Eligibility based on this criterion will be determined by Investigator review of pre chemotherapy and post chemotherapy radiological assessments (CT/MRI scans). Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 Adequate hematological, hepatic, and renal function as defined in the protocol Other protocol defined inclusion criteria could apply Exclusion Criteria: Participants with prior immunotherapy with Interleukin-2 (IL-2), IL-15, interferon alfa (IFN-α), or an anti programmed death receptor-1 (PD-1), anti programmed death-ligand 1 (PD-L1), anti PD-L2, anti CD137, or cytotoxic T cell lymphocyte-4 (CTLA-4) antibody (including ipilimumab), anti TROP2, anti-T-cell-immuno-receptor with Ig and ITM domains (anti-TIGIT) any other antibody or drug specifically targeting T cell costimulation or immune checkpoint pathways, agents targeting Nectin-4, or any of the investigational drugs used in combination with avelumab. Participants with active infection 48 hours before randomization requiring systemic therapy Participants with known prior or suspected hypersensitivity to study drugs or any component in their formulations Participants with prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization Participants with vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines) administered >= 2 weeks prior first dose of study treatment. All severe acute respiratory syndrome coronavirus (SARS-CoV-2) vaccines approved or authorized by local Health Authorities are allowed Other protocol defined exclusion criteria could apply

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Avelumab<br> | Drug: Avelumab<br>* Participants will receive avelumab intravenous infusion at a dose of 800 milligrams (mg) once every 2 weeks (Q2W) until unacceptable toxicity, withdraw consent or initiation of a new treatment.<br>* Other names: MSB0010718C;|
| Experimental: Group B: Avelumab + Sacituzumab Govitecan<br> | Drug: Avelumab<br>* Participants will receive avelumab intravenous infusion at a dose of 800 milligrams (mg) once every 2 weeks (Q2W) until unacceptable toxicity, withdraw consent or initiation of a new treatment.<br>* Other names: MSB0010718C;Drug: Sacituzumab Govitecan<br>* Participants will receive sacituzumab govitecan intravenous infusion at dose of 10 milligrams per kilogram (mg/kg) of body weight once a week (Q1W) on Day 1 and 8 of 21-day treatment cycles, in combination with avelumab 800 mg Q2W, until unacceptable toxicity, withdraw consent or initiation of a new treatment.<br>* Other names: GS-0132;|
| Experimental: Group C: Avelumab + M6223<br> | Drug: Avelumab<br>* Participants will receive avelumab intravenous infusion at a dose of 800 milligrams (mg) once every 2 weeks (Q2W) until unacceptable toxicity, withdraw consent or initiation of a new treatment.<br>* Other names: MSB0010718C;Drug: M6223<br>* Participants will receive M6223 (anti-T cell-immuno-receptor with Ig and ITM domains [anti-TIGIT]) intravenous infusion at dose of 1600 mg Q2W in combination with avelumab 800 mg Q2W, until unacceptable toxicity, withdraw consent or initiation of a new treatment.<br>|
| Experimental: Group D: Avelumab + NKTR-255<br> | Drug: Avelumab<br>* Participants will receive avelumab intravenous infusion at a dose of 800 milligrams (mg) once every 2 weeks (Q2W) until unacceptable toxicity, withdraw consent or initiation of a new treatment.<br>* Other names: MSB0010718C;Drug: NKTR-255<br>* Participants will receive NKTR-255 intravenous infusion at a dose of 3 micrograms per kilogram body weight (mcg/kg) once every 4 weeks (Q4W) in combination with avelumab 800 mg Q2W, until unacceptable toxicity, withdraw consent or initiation of a new treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator |  | Time from randomization of study drug until first documentation of progressive disease (PD) or death, assessed approximately up to 51 months | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events, and AEs of Special Interest (AESIs) as per Qualitative Toxicity Scale [National Cancer Institute-Common Terminology Criteria for Adverse Events 5.0] |  | From Randomization up to the last safety follow-up visit at approximately up to 51 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | Time from randomization of study drug until death, assessed approximately up to 51 months | 
| Objective Response (OR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator |  | Time from randomization of study drug up to 51 months | 
| Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator |  | Time from first documented objective response to PD or death due to any cause, assessed approximately up to 51 months | 
| Pharmacokinetic Serum Concentration of Avelumab, M6223, Sacituzumab govitecan and NKTR255 |  | Pre-dose up to safety follow up, assessed approximately up to maximum 51 months | 
| Number of Participants with Positive Anti-Drug Antibody (ADA) of Avelumab, M6223, Sacituzumab govitecan and NKTR-255 |  | Baseline up to 51 months | 
| Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Disease Related Symptoms-Physical Subscale (DRS-P) Scores |  | Baseline, Week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Avelumab, Avelumab in combination, Bladder cancer, M6223 (anti-TIGIT antibody), PD-L1, Sacituzumab govitecan (Trop-2 antibody drug conjugate), NKTR-255 (IL-15 agonist)