A Study Of Avelumab In Patients With Locally Advanced Or Metastatic Urothelial Cancer (JAVELIN Bladder 100)

Study Overview
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Brief Summary
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The main purpose of this study is to compare maintenance treatment with avelumab plus best supportive care (BSC) with BSC alone, to determine if avelumab has an effect on survival in patients with locally advanced or metastatic urothelial cancer that did not worsen during or following completion of first-line chemotherapy.

Official Title
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A PHASE 3, MULTICENTER, MULTINATIONAL, RANDOMIZED, OPEN-LABEL, PARALLEL-ARM STUDY OF AVELUMAB (MSB0010718C) PLUS BEST SUPPORTIVE CARE VERSUS BEST SUPPORTIVE CARE ALONE AS A MAINTENANCE TREATMENT IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL CANCER WHOSE DISEASE DID NOT PROGRESS AFTER COMPLETION OF FIRST-LINE PLATINUM-CONTAINING CHEMOTHERAPY

Conditions
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Urothelial Cancer

Intervention / Treatment
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* Biological: Avelumab
* Other: Best Supportive Care
* Biological: Following the planned interim analysis for this study: Avelumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium Stage IV disease at the start of first-line chemotherapy Measurable disease (per RECIST v1.1) prior to the start of first-line chemotherapy Prior first-line chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin No evidence of progressive disease following completion of first-line chemotherapy (i.e., ongoing CR, PR, or SD per RECIST v1.1 guidelines ) Exclusion Criteria: Prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA 4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways Persisting toxicity related to prior therapy (Grade >1 NCI CTCAE v4.0); however, alopecia, sensory neuropathy (Grade 2 or less), or other (Grade 2 or less) adverse events not constituting a safety risk based on the investigator's judgement are acceptable. Patients with known symptomatic central nervous system (CNS) metastases requiring steroids Diagnosis of any other malignancy within 5 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast or of the cervix, low grade prostate cancer on surveillance without any plans for treatment intervention, or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms.

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: Arm A<br>Avelumab plus Best Supportive Care (BSC) | Biological: Avelumab<br>* 1 hour intravenous infusion every 2 weeks (Q2W) in 4 week cycles<br>Other: Best Supportive Care<br>* BSC will be administered as deemed appropriate by the treating physician, and could include treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including palliative radiotherapy), etc. BSC does not include any active anti-tumor therapy, however local radiotherapy of isolated lesions with palliative intent is acceptable.<br>|
| Other: Arm B<br>Best Supportive Care (BSC) alone Following the planned interim analysis for this study, eligible patients in Arm B whose cancer has not worsened and are still in the watch and wait part of the study will be given the option to receive Avelumab plus BSC. Prior to this, Arm B patients received BSC alone. All patients who choose not to receive Avelumab will be discontinued. | Other: Best Supportive Care<br>* BSC will be administered as deemed appropriate by the treating physician, and could include treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including palliative radiotherapy), etc. BSC does not include any active anti-tumor therapy, however local radiotherapy of isolated lesions with palliative intent is acceptable.<br>Biological: Following the planned interim analysis for this study: Avelumab<br>* 1 hour intravenous infusion every 2 weeks (Q2W) in 4 week cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. | From randomization to discontinuation from the study, death or date of censoring, whichever occurred first (maximum duration of up to 41 months at the time of final analysis) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Score at Day 1 of Cycle 6 | NCCN-FACT FBlSI-18 is an 18-item participant completed questionnaire, designed to assess impact of cancer therapy on urothelial cancer-related symptoms and quality of life based on numerical point scoring of symptoms/concerns. It included four subscales: Disease related symptoms- physical subscale with 9 items, disease related symptoms- emotional subscale with 2 items, treatment side effects subscale with 5 items and general function/well-being subscale with 2 items. Participants rated their level of symptoms for each item using 5-point scale ranging from 0=not at all to 4=very much. Items that were negatively framed, and the scores were reversed for analysis so that higher scores= good quality of life. Overall score: total of 18 items, ranging from 0=severely symptomatic to 72=asymptomatic. Higher scores= better functioning or lower symptom burden. | Baseline, Day 1 of Cycle 6 | 
| Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status | ADA against avelumab in serum samples was determined and reported separately for ADA never positive and ADA ever positive participants. Participants were considered ADA ever-positive if they had at least one positive ADA result at any time point during study and were otherwise considered negative. Data for this outcome measure was not planned to be collected and analyzed for reporting arm Best Supportive Care, since, avelumab was not administered in this arm. | From randomization up to the 30-Day Follow-up visit (maximum duration of up to 41 months at the time of the analysis) | 
| Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab | Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum of ADA titer (60, 180, 540, 1620, 4860, 14580, and 43740) are reported. | From randomization up to the 30-Day Follow-up visit (maximum duration of up to 41 months at the time of the analysis) | 
| Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status |  | Up to approximately 60 months | 
| Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | PD-L1 assessment was performed using immunohistochemistry on pre-treatment tumor tissue samples. Participants were classified as having PD-L1 -positive status if at least one of the following three criteria were met: at least 25% of tumor cells stained for PD-L1, at least 25% of immune cells stained for PD-L1 if more than 1% of the tumor area contained immune cells, or 100% of immune cells stained for PD-L1 if no more than 1% of the tumor area contained immune cells. | Up to 41 months at the time of the analysis | 
| Number of Participants With Cluster of Differentiation 8 (CD8) T Lymphocytes (Cytotoxic T Lymphocytes) |  | Up to approximately 60 months | 
| Predose Plasma Concentration (Ctrough) of Avelumab | The LLQ of avelumab was 0.20 mcg/mL. Data for this outcome measure was not collected for reporting group Best Supportive Care, since avelumab was not administered in this arm. | Pre-dose (0 hour) on Day 1 of Cycle 1, 2, 3, 5, 7, 9, 11, 13 and Day 15 of Cycle 1, 2, 3 | 
| Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) | BICR assessed PFS: Duration from randomization until disease progression (PD) or death. PD as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was defined for target disease as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier. PFS data was censored on date of last adequate tumor assessment for participants with no event (PD or death), who started new anti-cancer therapy prior to an event or with an event after 2 or more missing tumor assessments. | From randomization to date of progression of disease, discontinuation from the study, death or date of censoring, whichever occurred first (maximum duration of up to 41 months at the time of the analysis) | 
| Progression-Free Survival (PFS) as Assessed by Investigator | Investigator assessed PFS: Duration from randomization to first documentation of PD or death, whichever occurred first. PD as per RECIST version 1.1 was defined for target disease as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier. PFS data was censored on date of last adequate tumor assessment for participants with no event (PD or death), who started a new anti-cancer therapy prior to an event or with an event after 2 or more missing tumor assessments. | From randomization to date of progression of disease, discontinuation from the study, death or date of censoring, whichever occurred first (maximum duration of up to 41 months at the time of the analysis) | 
| Percentage of Participants With Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) | BICR assessed objective response according to RECIST version 1.1, was defined as participants with confirmed best overall response of complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. | From randomization to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (maximum duration of up to 41 months at the time of the analysis) | 
| Percentage of Participants With Objective Response as Assessed by Investigator | Investigator assessed objective response according to RECIST version 1.1, was defined as participants with confirmed best overall response of CR or PR. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. A CR also required normalization of tumor marker levels and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. | From randomization to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (maximum duration of up to 41 months at the time of the analysis) | 
| Time to Tumor Response (TTR) as Assessed by Blinded Independent Central Review (BICR) | TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR), which was confirmed subsequently. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. | From the date of randomization to the first documentation of objective response (CR or PR) (maximum duration of up to 41 months at the time of the analysis) | 
| Time to Tumor Response (TTR) as Assessed by Investigator | TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. A CR also required normalization of tumor marker levels and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. | From the date of randomization to the first documentation of objective response (CR or PR) (maximum duration of up to 41 months at the time of the analysis) | 
| Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR) | BICR assessed DOR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR: complete disappearance of all target and non-target lesions, with exception of nodal disease sustained for 4 weeks. Any pathological lymph nodes reduced in short axis to <10 mm. PR: at least 30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD for target disease: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study and relative increase of 20%, sum also demonstrated absolute increase of at least 5 mm. PD for non-target disease: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. | First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (maximum duration of up to 41 months at the time of the analysis) | 
| Duration of Response (DOR) as Assessed by Investigator | Investigator assessed DOR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR: complete disappearance of all target and non-target lesions, with exception of nodal disease sustained for 4 weeks. Additionally, normalization of tumor marker levels and any pathological lymph nodes reduced in short axis to <10 mm. PR: at least 30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD for target disease: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study and relative increase of 20%, sum also demonstrated absolute increase of at least 5 mm. PD for non-target disease: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD. | First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (maximum duration of up to 41 months at the time of the analysis) | 
| Percentage of Participants With Disease Control (DC) as Assessed by Blinded Independent Central Review (BICR) | Disease Control (DC) was defined as a best overall response of CR, PR, non-CR/non-PD or stable disease (SD) as assessed by BICR. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. | From randomization to PD, death or start of new anti-cancer therapy (maximum duration of up to 41 months at the time of the analysis) | 
| Percentage of Participants With Disease Control (DC) as Assessed by Investigator | DC was defined as a best overall response of CR, PR, non-CR/non-PD or SD as assessed by Investigator. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Additionally, normalization of tumor marker levels and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. | From randomization to PD, death or start of new anti-cancer therapy (maximum duration of up to 41 months at the time of the analysis) | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Treatment-emergent AEs are events between first dose of study drug and up to 90 days after last dose of study drug or end of treatment (EOT) visit, that were absent before treatment or that worsened relative to pretreatment state. | For Avelumab + Best Supportive Care (BSC)'' group: Day 1 up to 90 days after last dose of study drug; for Best Supportive Care'' group: Day 1 up to 90 days after EOT visit, for a maximum duration of up to 41 months at the time of the analysis | 
| Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Hematology (Anemia G3: hemoglobin<8.0 grams per deciliter [g/dL],<4.9 mmol/L,<80 g/L, transfusion indicated, Grade 4 [G4]: life-threatening consequences, urgent intervention indicated, Grade 5 [G5]: death; platelet count decreased-G3:<50.0 to 25.0*10^9/L, G4: <25.0*10^9/L; lymphocyte count decreased-G3:<0.5-0.2*10^9/L, G4:<0.2*10^9/L; neutrophil count decreased-G3:<1.0 to 0.5*10^9 /L, G4:<0.5*10^9/L). Chemistry (creatinine increased-G3:>3.0 to 6.0*upper limit of normal [ULN], G4:>6.0*ULN; serum amylase increased, lipase increased-G3:>2.0- 5.0*ULN, G4:>5.0*ULN. Aspartate aminotransferase [AST], alanine aminotransferase [ALT]-G3:>5.0 to 20.0*ULN, G4:>20.0*ULN]. Blood bilirubin increased-[G3:>3.0 to 10.0*ULN, G4:>10.0*ULN], Creatine phosphokinase [CPK] increased- [G3:>5.0 to 10.0*ULN, G4:>10.0*ULN], Hyperglycemia-[G3:>250 to 500 mg/dL; >13.9 to 27.8 mmol/L hospitalization indicated, G4:>500 mg/DL; >27.8 mmol/L life-threatening consequences]). | For Avelumab + Best Supportive Care (BSC)'' group: Day 1 up to 90 days after last dose of study drug; for Best Supportive Care'' group: Day 1 up to 90 days after EOT visit, for a maximum duration of up to 41 months at the time of the analysis | 
| Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Vital signs included blood pressure and pulse rate. Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP). | Baseline (D1 of Cycle 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7, EOT visit (maximum duration of up to 41 months at the time of the analysis) | 
| Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit | Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized. | Baseline (D1 of Cycle 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7, EOT visit (maximum duration of up to 41 months at the time of the analysis) | 
| Maximum Plasma Concentration (Cmax) of Avelumab | The LLQ of avelumab was 0.20 mcg/mL. Data for this outcome measure was not collected for reporting group Best Supportive Care, since avelumab was not administered in this arm. | End of avelumab infusion on Day 1 of Cycle 1, 2, 3, 5, 7, 9, 11, 13 and Day 15 of Cycle 1, 2, 3 | 
| Time to Deterioration (TTD) Based on 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 | NCCN-FACT FBlSI-18: an 18-item participant completed questionnaire, designed to assess impact of cancer therapy on urothelial cancer-related symptoms and quality of life based on numerical point scoring of symptoms/concerns. It included four subscales: Disease related symptoms-physical subscale with 9 items,disease related symptoms-emotional subscale with 2 items, treatment side effects subscale with 5 items,general function/well-being subscale with 2 items. Participants rated their level of symptoms for each item using 5-point scale ranging: 0=not at all to 4=very much. For items negatively framed, scores were reversed for analysis so that higher scores= good quality of life. DRS-P score: total 9 items, ranging from 0=severely symptomatic to 36= asymptomatic. Higher scores=better functioning or lower symptom burden. TTD: time from randomization to first time participant's score showed 3 point or greater decrease from baseline in FBlSI-DRS-P subscale for 2 consecutive assessments. | From randomization up to the 90-Day Follow-up Visit (maximum duration of up to 41 months at the time of the analysis) | 
| Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 | The EQ-5D-5L was a 6-item participant-completed questionnaire designed to assess health status in terms of a single utility score. There were 2 components to the EQ-5D-5L, a Health State Profile which had individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which participant rated their overall health status from 0 (worst imaginable) to 100 (best imaginable). Published UK weights was used to create a single summary utility score. Utility scores range from -0.594 to 1, with low scores representing lower health status. | Baseline, Day 1 of Cycle 6 | 
| Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 | The EQ-5D-5L was a 6-item participant-completed questionnaire designed to assess health status in terms of a single utility score. There were 2 components to the EQ-5D-5L, a Health State Profile which had individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which participant rated their overall health status from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state. | Baseline, Day 1 of Cycle 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urologic neoplasms, urothelial carcinoma, PD-L1, programmed cell death protein, maintenance treatment, Bladder cancer