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

• Sponsor: Pfizer (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02603432
• Collaborator: (none)
• Enrollment: 700
• Locations: 369
• Arms: 2
• Anticipated Duration (Months): 83.2
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Urothelial Cancer	Biological: Avelumab; Other: Best Supportive Care; Biological: Following the planned interim analysis for this study: Avelumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 700 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 25, 2016
• Actual Primary Completion Date: Oct 21, 2019
• Anticipated Study Completion Date: Mar 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A Avelumab plus Best Supportive Care (BSC)	Biological: Avelumab; 1 hour intravenous infusion every 2 weeks (Q2W) in 4 week cycles; Other: Best Supportive Care; 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.
Other: Arm B 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; 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.; Biological: Following the planned interim analysis for this study: Avelumab; 1 hour intravenous infusion every 2 weeks (Q2W) in 4 week cycles

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [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)]

   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.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) [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)]

   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.

2. Progression-Free Survival (PFS) as Assessed by Investigator [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)]

   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.

3. Percentage of Participants With Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) [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)]

   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.

4. Percentage of Participants With Objective Response as Assessed by Investigator [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)]

   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.

5. Time to Tumor Response (TTR) as Assessed by Blinded Independent Central Review (BICR) [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)]

   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.

6. Time to Tumor Response (TTR) as Assessed by Investigator [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)]

   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.

7. Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR) [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)]

   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.

8. Duration of Response (DOR) as Assessed by Investigator [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)]

   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.

9. Percentage of Participants With Disease Control (DC) as Assessed by Blinded Independent Central Review (BICR) [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)]

   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.

10. Percentage of Participants With Disease Control (DC) as Assessed by Investigator [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)]

    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.

11. Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [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]

    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.

12. 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 [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]

    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]).

13. 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 [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)]

    Vital signs included blood pressure and pulse rate. Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP).

14. 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 [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)]

    Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized.

15. Maximum Plasma Concentration (Cmax) of Avelumab [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]

    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.

16. Predose Plasma Concentration (Ctrough) of Avelumab [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]

    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.

17. Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status [From randomization up to the 30-Day Follow-up visit (maximum duration of up to 41 months at the time of the analysis)]

    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.

18. Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab [From randomization up to the 30-Day Follow-up visit (maximum duration of up to 41 months at the time of the analysis)]

    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.

19. Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status [Up to approximately 60 months]

20. Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) [Up to 41 months at the time of the analysis]

    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.

21. Number of Participants With Cluster of Differentiation 8 (CD8) T Lymphocytes (Cytotoxic T Lymphocytes) [Up to approximately 60 months]

22. 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 [Baseline, 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.

23. 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 [From randomization up to the 90-Day Follow-up Visit (maximum duration of up to 41 months at the time of the analysis)]

    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.

24. Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 [Baseline, Day 1 of 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.

25. Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 [Baseline, Day 1 of 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anschutz Cancer Center Pavilion Pharmacy	Aurora	Colorado	United States	80045
2	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
3	University of Colorado Denver, CTO (CTRC)	Aurora	Colorado	United States	80045
4	University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)	Aurora	Colorado	United States	80045
5	University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)	Aurora	Colorado	United States	80045
6	Smilow Cancer Hospital at Yale New Haven	New Haven	Connecticut	United States	06510
7	Smilow Cancer Hospital at Yale-New Haven	New Haven	Connecticut	United States	06510
8	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
9	University of Minnesota Medical Center	Minneapolis	Minnesota	United States	55455
10	University of Minnesota	Minneapolis	Minnesota	United States	55455
11	Cleveland Clinic Taussing Cancer Center	Cleveland	Ohio	United States	44106
12	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
13	Inova Schar Cancer Institute Infusion Pharmacy	Fairfax	Virginia	United States	22031
14	Inova Schar Cancer Institute	Fairfax	Virginia	United States	22031
15	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109-1023
16	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
17	University of Washington Medical Center	Seattle	Washington	United States	98195
18	Centro de Investigacion Pergamino S.A.	Pergamino	Buenos Aires	Argentina	B2700CPM
19	Fundación CENIT para la Investigación en Neurociencias	Caba		Argentina	C1125ABD
20	GP Diagnostico SRL	La Rioja		Argentina	5300
21	Hospital Regional Dr. Enrique Vera Barros	La Rioja		Argentina	5300
22	Instituto del Diagnostico	La Rioja		Argentina	5300
23	Centro Oncologico Riojano Integral (Cori)	La Rioja		Argentina	F5300COE
24	Chris O'Brien Lifehouse	Camperdown	New South Wales	Australia	2050
25	Concord Hospital	Concord	New South Wales	Australia	2139
26	Dubbo Base Hospital	Dubbo	New South Wales	Australia	2830
27	Ramsay Pharmacy	Kogarah	New South Wales	Australia	2217
28	St George Private Hospital	Kogarah	New South Wales	Australia	2217
29	Epic Pharmacy	Lismore	New South Wales	Australia	2480
30	North Coast Radiology St Vincents	Lismore	New South Wales	Australia	2480
31	Northern Rivers Pathology Service	Lismore	New South Wales	Australia	2480
32	St Vincent's Pathology Lismore	Lismore	New South Wales	Australia	2480
33	Macquarie University Hospital Pharmacy	Macquarie University	New South Wales	Australia	2109
34	Macquarie University	Macquarie University	New South Wales	Australia	2109
35	The Murwillumbah Hospital	Murwillubah	New South Wales	Australia	2484
36	The Tweed Hospital Pharmacy Department	Tweed Heads	New South Wales	Australia	2485
37	The Tweed Hospital	Tweed Heads	New South Wales	Australia	2485
38	Icon Cancer Care Wesley	Auchenflower	Queensland	Australia	4066
39	River City Pharmacy	Auchenflower	Queensland	Australia	4066
40	Oncology Pharmacy	Birtinya	Queensland	Australia	4575
41	Sunshine Coast University Hospital	Birtinya	Queensland	Australia	4575
42	Icon Cancer Care Chermside	Chermside	Queensland	Australia	4032
43	The Townsville Hospital	Douglas	Queensland	Australia	4814
44	Slade Health	Geebung	Queensland	Australia	4034
45	Icon Cancer Care South Brisbane	South Brisbane	Queensland	Australia	4101
46	Icon Cancer Care	South Brisbane	Queensland	Australia	4101
47	Icon Cancer Care Southport	Southport	Queensland	Australia	4215
48	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
49	SA Pharmacy, Level 3 Pharmacy	Bedford Park	South Australia	Australia	5042
50	Adelaide Cancer Centre	Kurralta Park	South Australia	Australia	5037
51	Ashford Cancer Centre Research	Kurralta park	South Australia	Australia	5037
52	Cancer Care SA Pty Ltd	Kurralta Park	South Australia	Australia	5037
53	Icon Cancer Care SA trading as Icon Pharmacy Adelaide	Kurralta Park	South Australia	Australia	5037
54	The Queen Elizabeth Hospital	Woodville South	South Australia	Australia	5011
55	BHS Diagnostic Services	Ballarat	Victoria	Australia	3350
56	Lake Imaging	Ballarat	Victoria	Australia	3350
57	Ballarat Oncology & Haematology Services	Ballarat	Victoria	Australia	3355
58	Box Hill Hospital	Box Hill	Victoria	Australia	3128
59	Eastern Health Clinical School	Box Hill	Victoria	Australia	3128
60	Monash Medical Centre	Clayton	Victoria	Australia	3168
61	Monash Cancer Centre	East Bentleigh	Victoria	Australia	3165
62	Moorabbin Radiology	East Bentleigh	Victoria	Australia	3165
63	Ballarat Day Procedure Centre	Wendouree	Victoria	Australia	3355
64	Ballarat Oncology & Haematology Services	Wendouree	Victoria	Australia	3355
65	Nova Pharmacy	Wendouree	Victoria	Australia	3355
66	Fiona Stanley Hospital	Murdoch	Western Australia	Australia	6150
67	St John of God Murdoch Hospital	Murdoch	Western Australia	Australia	6150
68	Slade Health	Mount Waverley		Australia	3149
69	Macquarie Heart	New South Wales		Australia	2109
70	AZ Klina - Apotheek	Brasschaat		Belgium	2930
71	AZ Klina	Brasschaat		Belgium	2930
72	Hôpital Erasme	Brussels		Belgium	1070
73	Hôpital Erasme	Bruxelles		Belgium	1070
74	UZ Gent	Gent		Belgium	9000
75	UZ Gent	Ghent		Belgium	9000
76	AZ Groeninge	Kortrijk		Belgium	8500
77	CHU de Liège	Liège		Belgium	4000
78	GZA Sint-Augustinus	Wilrijk		Belgium	2610
79	Hospital da Bahia	Salvador	BA	Brazil	41820-011
80	CENOB Centro de Oncologia da Bahia S/S Ltda. / Oncovida	Salvador	BA	Brazil	41820-021
81	Hospital Mãe de Deus/Aesc	Porto Alegre	RIO Grande DO SUL	Brazil	90110-270
82	Instituto Nacional de Câncer - INCA	Rio de Janeiro	RJ	Brazil	20230-130
83	Associação Hospital de Caridade Ijuí / Hospital de Caridade de Ijuí	Ijuí	RS	Brazil	98700-000
84	Associação Educadora São Carlos - AESC / Hospital Mãe de Deus	Porto Alegre	RS	Brazil	90110-000
85	Associação Educadora São Carlos - AESC / Hospital Mãe de Deus - Ambulatório Quimioterapia	Porto Alegre	RS	Brazil	90110-270
86	Associação Educadora São Carlos - AESC / Hospital Mãe de Deus - Centro de Abastecimento Farmaceu	Porto Alegre	RS	Brazil	90110-270
87	Associação Educadora São Carlos - AESC / Hospital Mãe de Deus - Farmácia Oncológica	Porto Alegre	RS	Brazil	90110-270
88	Associação Educadora São Carlos - AESC / Hospital Mãe de Deus	Porto Alegre	RS	Brazil	90110-270
89	Uniao Brasileira de Educacao e Assistencia / Hospital Sao Lucas da PUCRS	Porto Alegre	RS	Brazil	90610-000
90	Fundação FPio XII Barretos	Barretos	SP	Brazil	14784-400
91	Fundação Pio XII Barretos	Barretos	SP	Brazil	14784-400
92	Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto	Sao Jose do Rio Preto	SP	Brazil	15090-000
93	Fundacao Faculdade de Medicina / Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP	Brazil	01246-000
94	Hospital Alemao Oswaldo Cruz	Sao Paulo	SP	Brazil	01323-903
95	Hospital das Clinicas da Faculdade de Medicina da USP - HCFMUSP	Sao Paulo	SP	Brazil	05403-900
96	Centro Integrado de Pesquisa Clinica - CIP	São José do Rio Preto	SP	Brazil	15090-000
97	Sociedade Beneficente de Senhoras Hospital Sírio Libanês	São Paulo	SP	Brazil	01308-050
98	Hospital Israelita Albert Einstein - SP	São Paulo	SP	Brazil	05652-900
99	Sociedade Beneficente de Senhoras Hospital Sírio Libanês/ Instituo Sirio Libanes de Ensino e Pesqu	São Paulo		Brazil	01308-060
100	William Osler Health System	Brampton	Ontario	Canada	L6R 3J7
101	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
102	CHUM - Centre Hospitalier de l'Universite de Montreal	Montréal	Quebec	Canada	H2X 3E4
103	Fakultni nemocnice u sv. Anny v Brne	Brno	Ceska Republika	Czechia	656 91
104	Fakultni nemocnice Brno	Brno		Czechia	625 00
105	Fakultni nemocnice u sv. Anny v Brne	Brno		Czechia	656 91
106	Fakultni nemocnice u sv.Anny v Brne	Brno		Czechia	656 91
107	Nemocnice Horovice, NH Hospital a.s.	Horovice		Czechia	268 31
108	Nemocnice Horovice	Horovice		Czechia	268 31
109	Aalborg Universitetshospital Syd	Aalborg		Denmark	9000
110	Aalborg Universitetshospital	Aalborg		Denmark	9000
111	Sygehusapoteket Aalborg	Aalborg		Denmark	9000
112	Aarhus Universitetshospital	Aarhus C		Denmark	8000
113	Aarhus Universitetshospital	Aarhus N		Denmark	8200
114	CT-Klinikken A/S	Aarhus N		Denmark	8200
115	Rigshospitalet, Onkologisk Klinik, afsnit 5073	Copenhagen OE		Denmark	2100
116	Herlev Hospital	Herlev		Denmark	2730
117	Herlev og Gentofte Hospital	Herlev		Denmark	2730
118	Klinik for Klinisk Fysiologi,Nuklearmedicin og PET	København Ø		Denmark	2100
119	Rigshospitalet	København Ø		Denmark	2100
120	Odense Universitetshospital	Odense C		Denmark	5000
121	Odense Universitetshospital	Odense		Denmark	5000
122	Groupe hospitalier Pitie Saleptriere	Paris	Cedex 13	France	75651
123	Institut de cancérologie de l'Ouest - Site Paul Papin	Angers Cedex 02		France	49055
124	Institut de cancérologie de l'Ouest - Site Paul Papin	Angers		France	49100
125	Centre d'Oncologie et de Radiothérapie du Pays-Basque	Bayonne		France	64100
126	Clinique CAPIO Belharra	Bayonne		France	64100
127	Hôpital Jean Minjoz	BESANCON cedex		France	25030
128	CHU Besançon	Besançon		France	25030
129	Hôpital Henri Mondor	CRÉTEIL Cedex		France	94010
130	Hôpital Privé Toulon-Hyères - Clinique Sainte Marguerite	Hyères		France	83400
131	Clinique Victor Hugo	Le Mans		France	72015
132	Centre Oscar Lambret	Lille cedex		France	59020
133	Centre Oscar Lambret	Lille		France	59000
134	Centre Leon Berard	Lyon cedex 8		France	69373
135	Centre Léon Berard	LYON cedex 8		France	69373
136	Hopital La Conception	Marseille cedex 5		France	13285
137	Institut Paoli Calmettes	Marseille Cedex 9		France	13273
138	Institut Paoli Calmettes	Marseille		France	13009
139	Hopital de La Timone	Marseille		France	13385 cedex 05
140	Hopital de La Timone	Marseille		France	13385
141	CHU Nimes - Institut de Cancerologie du Gard	Nimes Cedex 9		France	30029
142	CHU Nimes	Nimes Cedex 9		France	30029
143	CHU Nimes - Hopital Caremeau	Nimes		France	30000
144	Groupe Hospitalier Pitié Salpêtrière	PARIS cedex 13		France	75651
145	Groupe Hospitalier Pitié Salpêtrière	Paris		France	75013
146	Centre Eugene Marquis	Rennes Cedex		France	35042
147	Centre Henri Becquerel	Rouen Cedex 1		France	76038
148	CHU de Rouen - Hôpital Charles Nicolle	Rouen		France	76031
149	CHU de Rouen	Rouen		France	76031
150	Institut de Cancérologie de l'Ouest - Centre René Gauducheau	Saint Herblain Cedex		France	44805
151	Centre de Radiothérapie - Clinique Sainte Anne	Strasbourg		France	67000
152	Clinique Sainte Anne	Strasbourg		France	67000
153	Hopital Foch	Suresnes		France	92151
154	Institut Gustave Roussy	Villejuif cedex		France	94805
155	Institut Gustave Roussy	Villejuif		France	94805
156	Medical Center of Athens	Marousi	Athens	Greece	15125
157	Metropolitan General Hospital	Athens	PC	Greece	11562
158	Sotiria General Chest Disease Hospital	Athens		Greece	11527
159	Alexandra General Hospital, Oncology Department	Athens		Greece	11528
160	University General Hospital of Patras, Division of Oncology	Patra		Greece	26504
161	EUROMEDICA General Clinic of Thessaloniki	Thessaloniki		Greece	546 45
162	Department of Clinical Oncology	Hong Kong		Hong Kong
163	Kaposvári Egyetem Egészségügyi Centrum	Kaposvár		Hungary	7400
164	Somogy Megyei Kaposi Mór Oktató Kórház	Kaposvár		Hungary	7400
165	Dr Ram Manohar Lohia (RML) Hospital & PGI MER	New Delhi	Delhi	India	110001
166	CIMS Cancer, Care Institute of Medical Sciences, CIMS Hospital	Ahmedabad	Gujarat	India	380060
167	Sahyadri Super Speciality Hospital	Pune	Maharashtra	India	411004
168	Apollo Hospitals	Hyderabad	Telangana	India	500096
169	Medica Superspecialty hospital	Kolkata	WEST Bengal	India	700099
170	Rajiv Gandhi Cancer Institute And Research Centre	Delhi		India	110085
171	Hadassah University Hospital	Kiryat Hadassah	Jerusalem	Israel	91120
172	The Chaim Sheba Medical Center	Tel-Hashomer	Ramat - GAN	Israel	5265601
173	Assaf Harofe MC	Beer Yaakov		Israel	70300
174	Rambam Health Care Campus	Haifa		Israel	31096
175	The Chaim Sheba Medical Center	Ramat - Gan		Israel	5265601
176	Farmacia Ospedaliera	Candiolo	(torino)	Italy	10060
177	AOU Ospedali Riuniti di Ancona	Torrette	Ancona	Italy	60126
178	U.O. Anatomia Patologica	Forli	Forli-cesena	Italy	47121
179	U.O. Radiologia	Forli	Forli-cesena	Italy	47121
180	U.O.S. Medicina Nucleare	Forli	Forli-cesena	Italy	47121
181	Farmacia Oncologica	Meldola	Forli-cesena	Italy	47014
182	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	Forli-cesena	Italy	47014
183	U.O.C. Farmacia	Genova	Genoa	Italy	16132
184	IRCCS Ospedale Policlinico San Martino	Genova	Liguria	Italy	16132
185	Farmacia Studi Clinici	Rozzano	Milan	Italy	20089
186	Istituto Clinico Humanitas	Rozzano	Milan	Italy	20089
187	AUSL della Romagna - RAVENNA, Presidio Ospedaliero di Faenza	Faenza	Ravenna	Italy	48018
188	Presidio Ospedaliero di Lugo	Lugo	Ravenna	Italy	48022
189	Fondazione del Piemonte per l'Oncologia - IRCCS Candiolo	Candiolo	Torino	Italy	10060
190	Farmacia Ospedaliera	Arezzo		Italy	52100
191	Presidio Ospedaliero San Donato	Arezzo		Italy	52100
192	Centro di Riferimento Oncologico - IRCCS	Aviano (PN)		Italy	33081
193	S.O.C. di Farmacia	Aviano (PN)		Italy	33081
194	Azienda Ospedaliero-Universitaria Policlinico S.Orsola Malpighi	Bologna		Italy	40138
195	U.O. Farmacia Clinica - IDS	Bologna		Italy	40138
196	Fondazione IRCCS Istituto Nazionale Dei Tumori	Milan		Italy	20133
197	SC Farmacia	Milan		Italy	20133
198	Instituto Europeo di Oncologia	Milan		Italy	20141
199	Servizio di Farmacia	Milan		Italy	20141
200	Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"	Naples		Italy	80131
201	UOSC Farmacia	Naples		Italy	80131
202	Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS Fondazione Giovanni Pascale	Napoli		Italy	80131
203	S.C. Farmacia Ospedaliera	Napoli		Italy	80131
204	A.O.U. Pisana Ospedale S. Chiara	Pisa		Italy	56126
205	Presidio Ospedaliero di Ravenna	Ravenna		Italy	48121
206	Servizio Farmacia Ospedaliera - Farmacia Oncologica	Ravenna		Italy	48121
207	Azienda Ospedaliera San Camillo Forlanini_Oncologia Medica	Rome		Italy	00152
208	U.O.C. Farmacia	Rome		Italy	00152
209	Azienda Ospedaliera S. Maria di Terni	Terni		Italy	05100
210	S.C. Farmacia Interna	Terni		Italy	05100
211	Nagoya University Hospital	Nagoya	Aichi	Japan	466-8560
212	Hirosaki University School of Medicine & Hospital	Hirosaki	Aomori	Japan	036-8563
213	National Hospital Organization Shikoku Cancer Center	Matsuyama	Ehime	Japan	791-0280
214	Gunma Prefectural Cancer Center	Ota	Gunma	Japan	373-8550
215	National Hospital Organization hokkaido Cancer Center	Sapporo,	Hokkaido	Japan	0030804
216	Hokkaido University Hospital	Sapporo	Hokkaido	Japan	060-8648
217	Kobe City Medical Center General Hospital	Kobe-city	Hyogo	Japan	650-0047
218	Tsukuba Medical Center Hospital	Tsukuba	Ibaraki	Japan	305-8558
219	Iwate Medical University Hospital	Shiwa-gun	Iwate	Japan	028-3695
220	National Hospital Organization Sagamihara National Hospital	Sagamihara	Kanagawa	Japan	252-0392
221	Kanagawa cancer center	Yokohama	Kanagawa	Japan	241-8515
222	Kindai University Hospital	Osakasayama	Osaka	Japan	589-8511
223	Saitama Medical University International Medical Center	Hidaka	Saitama	Japan	350-1298
224	Dokkyo Medical University Saitama Medical Center	Koshigaya	Saitama	Japan	343-8555
225	Hamamatsu University School of Medicine, University Hospital	Hamamatsu	Shizuoka	Japan	431-3192
226	Nihon University Itabashi Hospital	Itabashi-ku	Tokyo	Japan	173-8610
227	The Cancer Institute Hospital of JFCR	Koto-Ku	Tokyo	Japan	135-8550
228	Keio University Hospital	Shinjuku-Ku	Tokyo	Japan	160-8582
229	Yamaguchi University Hospital	Ube	Yamaguchi	Japan	755-8505
230	Chiba Cancer Center	Chiba		Japan	260-8717
231	National Hospital Organization Kyushu Cancer Center	Fukuoka		Japan	811-1395
232	Kyushu University Hospital	Fukuoka		Japan	812-8582
233	Hiroshima City Hiroshima Citizens Hospital	Hiroshima		Japan	730-8518
234	Kagoshima University Hospital	Kagoshima		Japan	890-8520
235	National Hospital Organization Kumamoto Medical Center	Kumamoto		Japan	860-0008
236	Niigata University Medical & Dental Hospital	Niigata		Japan	951-8520
237	Osaka City University Hospital	Osaka		Japan	545-8586
238	Tokushima University Hospital	Tokushima		Japan	770-8503
239	Yamagata University Hospital	Yamagata		Japan	990-9585
240	National Cancer Center - Clinical Trial Pharmacy	Goyang-si	Gyeonggi-do	Korea, Republic of	10408
241	National Cancer Center Urology center for Prostate Cancer	Goyang-si	Gyeonggi-do	Korea, Republic of	10408
242	Seoul National University Bundang Hospital, Clinical Pharmacy	Seongnam-si	Gyeonggido	Korea, Republic of	13620
243	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggido	Korea, Republic of	13620
244	Chungnam National University Hospital, Clinical Pharmacy	Daejeon		Korea, Republic of	35015
245	Chungnam National University Hospital	Daejeon		Korea, Republic of	35015
246	Severance Hospital Yonsei University Health System	Seoul		Korea, Republic of	03722
247	Asan Medical Center - Clinical Trial Pharmacy	Seoul		Korea, Republic of	05505
248	Asan Medical Center	Seoul		Korea, Republic of	05505
249	Samsung Medical Center Clinical Trial Pharmacy	Seoul		Korea, Republic of	06351
250	Samsung Medical Center	Seoul		Korea, Republic of	06351
251	Instituto Nacional de Cancerologia	Mexico	Ciudad DE Mexico	Mexico	14080
252	Phylasis Clinicas Research S. de R.L. de C.V.	Cuautitlan Izcalli	Estado DE Mexico	Mexico	54769
253	Centro de Investigación Clínica de Leon S.C.	Leon	Guanajuato	Mexico	37520
254	Hospital Médica Campestre (Administradora Hospitalaria S.A de C.V.)	León	Guanajuato	Mexico	37180
255	Rijnstate Arnhem	Arnhem		Netherlands	6815 AD
256	Ziekenhuis Rijnstate	Arnhem		Netherlands	6815 AD
257	St Apotheek der Haarlemse Ziekenhuizen	Haarlem		Netherlands	2035 RC
258	Spaarne Gasthuis	Hoofddorp		Netherlands	2134 TM
259	Maastricht University Medical Center	Maastricht		Netherlands	6229 HX
260	Radboud University Medical Center	Nijmegen		Netherlands	6525 GA
261	Radboudumc	Nijmegen		Netherlands	6525 GA
262	Auckland City Hospital Pharmacy	Grafton	Auckland	New Zealand	1023
263	Auckland City Hospital	Grafton	Auckland	New Zealand	1142
264	Christchurch Hospital	Christchurch		New Zealand	8140
265	Waikato Hospital	Hamilton		New Zealand	3240
266	Akershus University Hospital	Lorenskog		Norway	1478
267	Sykehusapoteket HF 23 Lørenskog	Lorenskog		Norway	1478
268	Sykehusapoteket HF 23 Lørenskog	Nordbyhagen		Norway	1474
269	Sykehusapoteket Lorenskog	Nordbyhagen		Norway	1474
270	Bildediagnostisk avdeling	Nordbyhagen		Norway	1478
271	Stavanger University Hospital	Stavanger		Norway	4011
272	Centralny Szpital Kliniczny MSWiA	Warszawa	Masovian	Poland	02-507
273	Centrum Onkologii Ziemi Lubelskiej im. Sw. Jana z Dukli	Lublin		Poland	20-090
274	Lecznice CITOMED Sp. z o.o.	Torun		Poland	87-100
275	Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu Szpital Obserwacyjno-Zakazny	Torun		Poland	87-100
276	Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu	Torun		Poland	87-100
277	Wojewodzki Szpital Zespolony im. L. Rydygiera, Szpital Specjalistyczny dla Dzieci I Doroslych	Torun		Poland	87-100
278	Instituto Português de Oncologia de Coimbra Francisco Gentil, EPE	Coimbra		Portugal	3000-075
279	Hospital Da Luz Coimbra, SA	Coimbra		Portugal	3020-479
280	Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santo António dos Capuchos	Lisboa		Portugal	1169-050
281	Hospital CUF Descobertas, SA	Lisboa		Portugal	1998-018
282	Dr. Campos Costa - Consultório de Tomografia Computorizada, S.A.	Porto		Portugal	4050-075
283	Instituto Português de Oncologia do Porto Francisco Gentil, EPE	Porto		Portugal	4200-072
284	Centro Hospitalar de São João, EPE	Porto		Portugal	4200-319
285	Dr. Campos Costa - Consultório de Tomografia Computorizada, S.A.- Matosinhos	Senhora da Hora		Portugal	4460-188
286	Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE	Vila Real		Portugal	5000-508
287	State Budgetary Healthcare Insti. Republican Clinical Oncology Dispensary of the MoH of Bashk. Rep.	Ufa	Bashkortostan Republic	Russian Federation	450054
288	Federal State Budgetary Institution "National medical research radiology center" MoH RF	Obninsk	Kaluzhskaya Region	Russian Federation	249036
289	Private Medical Institution "Evromedservice"	Pushkin	Saint Petersburg	Russian Federation	196603
290	Principal Military Clinical Hospital n.a. N.N. Burdenko	Moscow		Russian Federation	105229
291	Moscow Research Oncology Institute named after P. A. Gertsen	Moscow		Russian Federation	125284
292	BHI of Omsk region "Clinical oncological dispensary"	Omsk		Russian Federation	644013
293	FGBIH "Clinical Hospital #122 n.a. L.G. Sokolov of Federal Medico-biological agency"	St. Petersburg		Russian Federation	194291
294	Non-State Healthcare Institution "Railway Clinical Hospital JSC RZhD"	St. Petersburg		Russian Federation	195271
295	FSBEI HE "First St. Petersburg State Medical University n. a. academician l.P Pavlov" MoH RF	St. Petersburg		Russian Federation	197022
296	FSBEI HE "First St. Petersburg State Medical University n.a. academician I.P Pavlov" MoH RF	St. Petersburg		Russian Federation	197022
297	FSBEI HE "First St. Petersburg State Medical University n.a. academician I.P Pavlov"	St. Petersburg		Russian Federation	197022
298	"Ramsay Diagnostics Rus", LLC	St. Petersburg		Russian Federation	197046
299	FSBI "Russian Scientific Center For Radiology and Surgical Technologies n.a. Academician A.M. Granov	St. Petersburg		Russian Federation	197758
300	Hospital Orkli, LLC	St. Petersburg		Russian Federation	199178
301	Mart, Llc	St. Petersburg		Russian Federation	199178
302	SHI YR "Regional Clinical Oncology Hospital"	Yaroslavl		Russian Federation	150054
303	Institute for Oncology and Radiology of Serbia	Belgrade		Serbia	11000
304	Clinical Centre Nis, Clinic of Oncology	Nis		Serbia	18000
305	Oncology Institute of Vojvodina	Sremska Kamenica		Serbia	21204
306	C.H. Univ. Santiago de Compostela	Santiago de Compostela	A Coruña	Spain	15706
307	Hospital Comarcal General de Elda de Virgen de la Salud	Elda	Alicante	Spain	03600
308	Hospital Universitario Central de Asturias	Oviedo	Asturias	Spain	33011
309	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
310	Institut Catalá d'Oncología - Hospital Duran i Reynals	l´Hospitalet de LLobregat	Barcelona	Spain	08908
311	Institut Catalá d'Oncología	L´Hospitalet de Llobregat	Barcelona	Spain	08908
312	Althaia. Xarxa Assistencial Universitaria de Manresa	Manresa	Barcelona	Spain	08243
313	Corporacio Sanitaria Parc Tauli	Sabadell	Barcelona	Spain	08208
314	Hospital General Universitario de Elche	Elche	Comunidad Valenciana	Spain	03203
315	Hospital Clinico Universitario de Valencia	Valencia	Comunidad Valenciana	Spain	46010
316	C. H. Universitario de Vigo- Hospital Álvaro Cunqueiro	Vigo	Galicia	Spain	36312
317	C.H. Universitario de Vigo- Hospital Meixoeiro	Vigo	Galicia	Spain	36313
318	Hospital Universitario Infanta Sofia	San Sebastian de los Reyes	Madrid	Spain	28702
319	Hospital Universitario Infanta Sofia	San Sebastián de los Reyes	Madrid	Spain	28702
320	Clinica Universidad de Navarra	Pamplona	Navarra	Spain	31008
321	Complejo Hospitalario de Navarra	Pamplona	Navarra	Spain	31008
322	Hospital Vithas Internacional Medimar	Alicante		Spain	03016
323	Hospital Universitario Infanta Cristina	Badajoz		Spain	06080
324	Hospital del Mar	Barcelona		Spain	08003
325	Hospital Quiron of Barcelona	Barcelona		Spain	08023
326	Hospital Quirón de Barcelona	Barcelona		Spain	08023
327	Hospital de La Santa Creu i Sant pau_Oncology department	Barcelona		Spain	08025
328	Hospital de La Santa Creu i Sant Pau	Barcelona		Spain	08025
329	CETIR Grup Medic	Barcelona		Spain	08029
330	Cetir, Centre Mèdic, S.L	Barcelona		Spain	08029
331	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
332	Hospital Clinic de Barcelona	Barcelona		Spain	08036
333	Hospital Universitario Reina Sofia	Cordoba		Spain	14004
334	Hospital Universitario Reina Sofía	Cordoba		Spain	14004
335	Institut Catala d'Oncologia	Gerona		Spain	17007
336	Institut Diagnostic de la lmatge	Gerona		Spain	17007
337	Hospital Universitario Lucus Augusti	Lugo		Spain	27003
338	Fundacion Maria Rafols para la investigacion del Diagnostico de la imagen	Madrid		Spain	28006
339	Gabinete Radiologico Doctor Pita	Madrid		Spain	28006
340	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
341	Hospital Ruber Internacional	Madrid		Spain	28034
342	Hospital Ruber International	Madrid		Spain	28034
343	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
344	Hospital Clinico San Carlos	Madrid		Spain	28040
345	Hospital Clínico San Carlos	Madrid		Spain	28040
346	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
347	Hospital Universitario La Paz	Madrid		Spain	28046
348	Hospital Universitario HM Sanchinarro - CIOCC	Madrid		Spain	28050
349	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
350	Instituto Valenciano de Oncología	Valencia		Spain	46009
351	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010
352	Hospital Clinico Universitario de Valencia	Valencia		Spain	4610
353	APL	Stockholm		Sweden	171 64
354	Karolinska University Hospital	Stockholm		Sweden	171 76
355	Clinical Trial Pharmacy, China Medical University Hospital	Taichung		Taiwan	40447
356	China Medical University Hospital	Taichung		Taiwan	404
357	Department of Pharmacy, National Cheng Kung University Hospital	Tainan		Taiwan	704
358	National Cheng Kung University Hospital	Tainan		Taiwan	704
359	Investigational Drug services, National Taiwan University Hospital	Taipei		Taiwan	100
360	National Taiwan University Hospital	Taipei		Taiwan	100
361	Koo Foundation Sun Yat-Sen Cancer Center	Taipei		Taiwan	112
362	Chang Gung Memorial Hospital, Linkou	Taoyuan		Taiwan	333
363	Chemotherapy pharmacy, Chang Gung Memorial Hospital, Linkou	Taoyuan		Taiwan	333
364	Royal United Hospitals Bath NHS Foundation Trust	Bath		United Kingdom	BA1 3NG
365	St Bartholomew 's Hospital, Barts Health NHS Trust	London		United Kingdom	EC1A 7BE
366	St. Bartholomew's Hospital, Barts Health NHS Trust	London		United Kingdom	EC1A 7BE
367	Guy's & St. Thomas' NHS Foundation Trust	London		United Kingdom	SE1 9RT
368	Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital	London		United Kingdom	SE1 9RT
369	Churchill Hospital, Oxford University Hospitals NHS Trust	Oxford		United Kingdom	OX3 7LE

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Mar 8, 2021
• Statistical Analysis Plan - Apr 2, 2019

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02603432
• Other Study ID Numbers: B9991001; 2015-003262-86; JAVELIN BLADDER 100
• First Posted: Nov 11, 2015
• Last Update Posted: Jul 20, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pfizer: Bladder cancer; Urologic neoplasms; urothelial carcinoma; PD-L1; programmed cell death protein; maintenance treatment
• Additional relevant MeSH terms: Avelumab; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	This study included only those participants who did not show evidence of disease progression after completion of at least 4 and not more than 6 cycles of first-line platinum-containing chemotherapy (prior to this study).

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Period Title: Overall Study
STARTED	350	350
COMPLETED	0	0
NOT COMPLETED	350	350

Baseline Characteristics

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care	Total
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	Total of all reporting groups
Overall Participants	350	350	700
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.20 (9.52)	67.7 (9.20)	67.44 (9.40)
Sex: Female, Male (Count of Participants)
Female	84 24%	75 21.4%	159 22.7%
Male	266 76%	275 78.6%	541 77.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	18 5.1%	12 3.4%	30 4.3%
Not Hispanic or Latino	286 81.7%	298 85.1%	584 83.4%
Unknown or Not Reported	46 13.1%	40 11.4%	86 12.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	75 21.4%	81 23.1%	156 22.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 0.6%	0 0%	2 0.3%
White	232 66.3%	238 68%	470 67.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	41 11.7%	31 8.9%	72 10.3%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Median (95% Confidence Interval) [months]	21.4	14.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Avelumab + Best Supportive Care (BSC), Best Supportive Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments	One-sided log-rank test was used.
	Method	Log Rank
	Comments	Analysis was performed using a Cox's Proportional Hazard model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.556 to 0.863
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Median (95% Confidence Interval) [months]	3.7	2.0

3. Secondary Outcome

Title	Progression-Free Survival (PFS) as Assessed by Investigator
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Median (95% Confidence Interval) [months]	5.5	2.1

4. Secondary Outcome

Title	Percentage of Participants With Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Number (95% Confidence Interval) [percentage of participants]	9.7 2.8%	1.4 0.4%

5. Secondary Outcome

Title	Percentage of Participants With Objective Response as Assessed by Investigator
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Number (95% Confidence Interval) [percentage of participants]	12.3 3.5%	3.4 1%

6. Secondary Outcome

Title	Time to Tumor Response (TTR) as Assessed by Blinded Independent Central Review (BICR)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants. Here, 'Overall Number of participants analyzed (N)' signifies participants who were evaluable for this outcome measure (OM).

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	34	5
Median (Full Range) [months]	2.0	2.0

7. Secondary Outcome

Title	Time to Tumor Response (TTR) as Assessed by Investigator
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants. Here, 'Overall Number of participants analyzed' signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	43	12
Median (Full Range) [months]	2.0	1.9

8. Secondary Outcome

Title	Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Analysis was performed on subset of randomized participants, who had objective response, as assessed by BICR.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	34	5
Median (95% Confidence Interval) [months]	NA	NA

9. Secondary Outcome

Title	Duration of Response (DOR) as Assessed by Investigator
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Analysis was performed on subset of randomized participants, who had objective response, as assessed by Investigator.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	43	12
Median (95% Confidence Interval) [months]	25.6	NA

10. Secondary Outcome

Title	Percentage of Participants With Disease Control (DC) as Assessed by Blinded Independent Central Review (BICR)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Number (95% Confidence Interval) [percentage of participants]	41.1 11.7%	27.4 7.8%

11. Secondary Outcome

Title	Percentage of Participants With Disease Control (DC) as Assessed by Investigator
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Number (95% Confidence Interval) [percentage of participants]	50.9 14.5%	34.0 9.7%

12. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who had received at least one dose of study drug on arm 'Avelumab+BSC' or completed C1D1 on arm 'BSC'. Here "Overall number of participants analyzed" signifies participants with at least one treatment-emergent AE of Grade 1, Grade 2, Grade 3, Grade 4 or Grade 5.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	337	267
Grade 1	51 14.6%	77 22%
Grade 2	123 35.1%	103 29.4%
Grade 3	147 42%	56 16%
Grade 4	12 3.4%	7 2%
Grade 5	4 1.1%	24 6.9%

13. Secondary Outcome

Title	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
Description	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]).
Time Frame	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

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who had received at least one dose of study drug on arm 'Avelumab+BSC' or completed C1D1 on arm 'BSC'. Here, 'Number analyzed (n)' = Participants evaluable for this outcome measure for each specified rows.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	344	345
Anemia	15 4.3%	12 3.4%
Platelet Count Decreased	2 0.6%	1 0.3%
Lymphocyte Count Decreased	18 5.1%	11 3.1%
Neutrophil Count Decreased	6 1.7%	0 0%
Creatinine Increased	5 1.4%	4 1.1%
Serum Amylase Increased	20 5.7%	9 2.6%
Lipase Increased	29 8.3%	22 6.3%
ALT Increased	9 2.6%	2 0.6%
AST Increased	6 1.7%	3 0.9%
Blood Bilirubin Increased	0 0%	3 0.9%
CPK Increased	8 2.3%	0 0%
Hyperglycemia	27 7.7%	18 5.1%

14. Secondary Outcome

Title	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
Description	Vital signs included blood pressure and pulse rate. Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP).
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Safety set analyzed. Here, 'Number analyzed' = participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	344	345
Baseline (C1D1): Sitting DBP	75.7 (10.81)	77.0 (10.48)
Change at Cycle 2, Day 1: Sitting DBP	-0.9 (9.37)	-0.0 (9.06)
Change at Cycle 3, Day 1: Sitting DBP	-1.7 (10.36)	-1.6 (9.38)
Change at Cycle 4, Day 1: Sitting DBP	-1.7 (9.97)	-1.0 (9.90)
Change at Cycle 5, Day 1: Sitting DBP	-1.1 (10.60)	-1.0 (10.22)
Change at Cycle 6, Day 1: Sitting DBP	-1.2 (10.89)	-1.1 (10.89)
Change at Cycle 7, Day 1: Sitting DBP	-0.7 (10.90)	0.2 (9.95)
Change at End of Treatment: Sitting DBP	-0.1 (12.09)	-1.7 (10.23)
Baseline (C1D1): Sitting SBP	131.3 (17.34)	130.6 (16.32)
Change at Cycle 2, Day 1: Sitting SBP	-2.2 (14.85)	-0.3 (13.79)
Change at Cycle 3, Day 1: Sitting SBP	-1.9 (16.10)	1.0 (14.94)
Change at Cycle 4, Day 1: Sitting SBP	-0.6 (16.54)	1.3 (16.54)
Change at Cycle 5, Day 1: Sitting SBP	-1.9 (15.49)	1.9 (15.85)
Change at Cycle 6, Day 1: Sitting SBP	-2.3 (15.77)	3.3 (16.81)
Change at Cycle 7, Day 1: Sitting SBP	-1.8 (16.13)	2.7 (19.86)
Change at End of Treatment: Sitting SBP	-0.9 (18.99)	-0.3 (16.78)

15. Secondary Outcome

Title	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
Description	Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Safety set analyzed. Here, 'Number analyzed' = participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	344	345
Baseline (C1D1)	76.1 (12.84)	77.1 (12.95)
Change at Cycle 2, Day 1	0.3 (11.81)	0.1 (9.98)
Change at Cycle 3, Day 1	-0.2 (12.10)	-0.4 (10.20)
Change at Cycle 4, Day 1	-0.5 (12.84)	-0.1 (11.26)
Change at Cycle 5, Day 1	0.4 (12.32)	-1.0 (11.45)
Change at Cycle 6, Day 1	-0.8 (11.54)	-2.6 (10.52)
Change at Cycle 7, Day 1	-0.6 (11.89)	-2.6 (11.48)
Change at End of Treatment	2.5 (12.25)	1.4 (12.45)

16. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Avelumab
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Avelumab pharmacokinetic (PK) parameter analysis set: all participants who received at least one dose of avelumab and who had at least one post-dose concentration measurement above the LLQ for avelumab. Here, 'n' signifies participants evaluable for this OM at specified time points.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	344
Cycle 1, Day 1	192.7 (68.4)
Cycle 1, Day 15	216.2 (49.6)
Cycle 2, Day 1	201.5 (54.5)
Cycle 2, Day 15	208.5 (60.2)
Cycle 3, Day 1	213.1 (39.6)
Cycle 3, Day 15	213.1 (52.7)
Cycle 5, Day 1	197.5 (67.7)
Cycle 7, Day 1	191.9 (86.2)
Cycle 9, Day 1	168.9 (84.4)
Cycle 11, Day 1	203.4 (51.6)
Cycle 13, Day 1	222.8 (30.3)

17. Secondary Outcome

Title	Predose Plasma Concentration (Ctrough) of Avelumab
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Avelumab PK parameter analysis set: all participants who received at least one dose of avelumab and who had at least one post-dose concentration measurement above the LLQ for avelumab. Here, 'n' signifies participants evaluable for this OM at specified time points.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	344
Cycle 1, Day 1	3.1 (247.6)
Cycle 1, Day 15	22.2 (48.6)
Cycle 2, Day 1	25.2 (64.2)
Cycle 2, Day 15	26.5 (65.4)
Cycle 3, Day 1	26.4 (76.2)
Cycle 3, Day 15	25.7 (85.2)
Cycle 5, Day 1	26.8 (67.5)
Cycle 7, Day 1	29.7 (60.2)
Cycle 9, Day 1	32.4 (55.9)
Cycle 11, Day 1	29.8 (68.9)
Cycle 13, Day 1	32.4 (54.9)

18. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status
Description	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.
Time Frame	From randomization up to the 30-Day Follow-up visit (maximum duration of up to 41 months at the time of the analysis)

Outcome Measure Data

Analysis Population Description

The immunogenicity analysis set included all participants who had received at least one dose of study drug and who had at least one ADA sample collected for avelumab in the avelumab containing arm.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	344
Never-positive	278 79.4%
Ever-positve	66 18.9%

19. Secondary Outcome

Title	Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab
Description	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.
Time Frame	From randomization up to the 30-Day Follow-up visit (maximum duration of up to 41 months at the time of the analysis)

Outcome Measure Data

Analysis Population Description

Analysis was performed on participants who had received at least one dose of study drug and who had ADA ever-positive results. Here "Overall number of participants analyzed" signifies participants who had data available for this outcome measure.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	66
60	4 1.1%
180	14 4%
540	18 5.1%
1620	11 3.1%
4860	11 3.1%
14580	7 2%
43740	1 0.3%

20. Secondary Outcome

Title	Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status
Time Frame	Up to approximately 60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

21. Secondary Outcome

Title	Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)
Description	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.
Time Frame	Up to 41 months at the time of the analysis

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Positive	189 54%	169 48.3%
Negative	139 39.7%	131 37.4%
Unknown	22 6.3%	50 14.3%

22. Secondary Outcome

Title	Number of Participants With Cluster of Differentiation 8 (CD8) T Lymphocytes (Cytotoxic T Lymphocytes)
Time Frame	Up to approximately 60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

23. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Day 1 of Cycle 6

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants who had data available for this outcome measure and 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	332	329
Baseline	53.3 (9.59)	52.7 (9.31)
Change at Day 1 of Cycle 6	1.0 (8.25)	1.6 (8.35)

24. Secondary Outcome

Title	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
Description	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.
Time Frame	From randomization up to the 90-Day Follow-up Visit (maximum duration of up to 41 months at the time of the analysis)

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	350	350
Median (95% Confidence Interval) [months]	NA	13.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Avelumab + Best Supportive Care (BSC), Best Supportive Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9130
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.26
	Confidence Interval	(1-Sided) 95%; 0.901 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6
Description	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.
Time Frame	Baseline, Day 1 of Cycle 6

Outcome Measure Data

Analysis Population Description

The full analysis set included all participants who were randomized. Here, 'Overall number of participants analyzed' signifies participants who had data available for this outcome measure and 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	336	327
Baseline	0.814 (0.1794)	0.792 (0.2013)
Change at Day 1 of Cycle 6	-0.029 (0.1919)	-0.020 (0.1684)

26. Secondary Outcome

Title	Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6
Description	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.
Time Frame	Baseline, Day 1 of Cycle 6

Outcome Measure Data

Analysis Population Description

The full analysis set included all participants who were randomized. Here, 'Overall number of participants analyzed' signifies participants who had data available for this outcome measure and 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Avelumab + Best Supportive Care (BSC)	Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.	As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
Measure Participants	335	325
Baseline	74.9 (18.87)	74.9 (16.34)
Change at Day 1 of Cycle 6	1.6 (17.74)	0.2 (14.74)

Adverse Events

Time Frame	For ''Avelumab + Best Supportive Care (BSC)'' reporting group: Day 1 up to 90 days after last dose of study drug and for ''Best Supportive Care'' reporting group: Day 1 up to 90 days after end of treatment visit, for a maximum duration of up to 41 months at the time of the analysis
Adverse Event Reporting Description	Same event may appear as both an AE and Serious Adverse Events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. All-Cause Mortality was assessed in the full analysis set. Serious and Other (Not including Serious) Adverse Events were monitored/assessed in the Safety Analysis set.
Arm/Group Title	Avelumab + Best Supportive Care (BSC)		Best Supportive Care
Arm/Group Description	Participants received an intravenous (IV) infusion of 10 milligrams per kilograms (mg/kg) of Avelumab along with BSC, on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.		As prescribed by the treating physician, participants received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.
All Cause Mortality
	Avelumab + Best Supportive Care (BSC)		Best Supportive Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	144/344 (41.9%)		177/345 (51.3%)
Serious Adverse Events
	Avelumab + Best Supportive Care (BSC)		Best Supportive Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	96/344 (27.9%)		69/345 (20%)
Blood and lymphatic system disorders
Anaemia	1/344 (0.3%)		2/345 (0.6%)
Cardiac disorders
Acute myocardial infarction	1/344 (0.3%)		0/345 (0%)
Atrial fibrillation	3/344 (0.9%)		1/345 (0.3%)
Cardiogenic shock	0/344 (0%)		1/345 (0.3%)
Coronary artery disease	1/344 (0.3%)		0/345 (0%)
Coronary artery stenosis	1/344 (0.3%)		0/345 (0%)
Myocardial infarction	2/344 (0.6%)		0/345 (0%)
Sinus tachycardia	1/344 (0.3%)		0/345 (0%)
Supraventricular tachycardia	1/344 (0.3%)		0/345 (0%)
Ear and labyrinth disorders
Vertigo positional	1/344 (0.3%)		0/345 (0%)
Endocrine disorders
Hyperthyroidism	1/344 (0.3%)		0/345 (0%)
Hypothyroidism	1/344 (0.3%)		0/345 (0%)
Eye disorders
Erythema of eyelid	0/344 (0%)		1/345 (0.3%)
Eyelid pain	0/344 (0%)		1/345 (0.3%)
Swelling of eyelid	0/344 (0%)		1/345 (0.3%)
Gastrointestinal disorders
Abdominal pain	1/344 (0.3%)		3/345 (0.9%)
Autoimmune pancreatitis	1/344 (0.3%)		0/345 (0%)
Colitis	2/344 (0.6%)		0/345 (0%)
Constipation	2/344 (0.6%)		0/345 (0%)
Diarrhoea	0/344 (0%)		1/345 (0.3%)
Enteritis	1/344 (0.3%)		0/345 (0%)
Gastric ulcer	1/344 (0.3%)		0/345 (0%)
Gastric ulcer haemorrhage	1/344 (0.3%)		0/345 (0%)
Ileus	3/344 (0.9%)		1/345 (0.3%)
Pancreatitis acute	1/344 (0.3%)		0/345 (0%)
Pancreatitis chronic	0/344 (0%)		1/345 (0.3%)
Vomiting	3/344 (0.9%)		0/345 (0%)
General disorders
Chest pain	0/344 (0%)		1/345 (0.3%)
Disease progression	3/344 (0.9%)		16/345 (4.6%)
Fatigue	0/344 (0%)		1/345 (0.3%)
General physical health deterioration	1/344 (0.3%)		1/345 (0.3%)
Incarcerated hernia	0/344 (0%)		1/345 (0.3%)
Malaise	1/344 (0.3%)		1/345 (0.3%)
Mass	0/344 (0%)		1/345 (0.3%)
Pain	4/344 (1.2%)		1/345 (0.3%)
Pyrexia	2/344 (0.6%)		1/345 (0.3%)
Systemic inflammatory response syndrome	1/344 (0.3%)		0/345 (0%)
Thirst	1/344 (0.3%)		0/345 (0%)
Hepatobiliary disorders
Autoimmune hepatitis	1/344 (0.3%)		0/345 (0%)
Bile duct obstruction	0/344 (0%)		1/345 (0.3%)
Cholangitis acute	1/344 (0.3%)		0/345 (0%)
Hepatotoxicity	1/344 (0.3%)		0/345 (0%)
Immune system disorders
Anaphylactic reaction	0/344 (0%)		1/345 (0.3%)
Infections and infestations
Bacteraemia	0/344 (0%)		1/345 (0.3%)
Biliary sepsis	0/344 (0%)		1/345 (0.3%)
Cellulitis	0/344 (0%)		1/345 (0.3%)
Cellulitis orbital	0/344 (0%)		1/345 (0.3%)
Device related infection	0/344 (0%)		1/345 (0.3%)
Diverticulitis	1/344 (0.3%)		1/345 (0.3%)
Gallbladder abscess	0/344 (0%)		1/345 (0.3%)
Herpes zoster	1/344 (0.3%)		0/345 (0%)
Infection	1/344 (0.3%)		0/345 (0%)
Kidney infection	2/344 (0.6%)		0/345 (0%)
Pneumonia	1/344 (0.3%)		0/345 (0%)
Pyelonephritis	3/344 (0.9%)		3/345 (0.9%)
Pyelonephritis acute	1/344 (0.3%)		1/345 (0.3%)
Sepsis	4/344 (1.2%)		1/345 (0.3%)
Tracheobronchitis	0/344 (0%)		1/345 (0.3%)
Upper respiratory tract infection	1/344 (0.3%)		0/345 (0%)
Urinary tract infection	16/344 (4.7%)		7/345 (2%)
Urosepsis	1/344 (0.3%)		2/345 (0.6%)
Vascular device infection	2/344 (0.6%)		0/345 (0%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	1/344 (0.3%)		0/345 (0%)
Chest injury	1/344 (0.3%)		0/345 (0%)
Contusion	1/344 (0.3%)		0/345 (0%)
Fall	1/344 (0.3%)		0/345 (0%)
Fractured sacrum	1/344 (0.3%)		0/345 (0%)
Infusion related reaction	4/344 (1.2%)		0/345 (0%)
Road traffic accident	1/344 (0.3%)		0/345 (0%)
Stomal hernia	1/344 (0.3%)		0/345 (0%)
Subdural haematoma	1/344 (0.3%)		0/345 (0%)
Urinary tract stoma complication	0/344 (0%)		1/345 (0.3%)
Investigations
Blood creatine phosphokinase increased	2/344 (0.6%)		0/345 (0%)
Hepatic enzyme increased	0/344 (0%)		1/345 (0.3%)
Liver function test increased	0/344 (0%)		1/345 (0.3%)
Platelet count decreased	1/344 (0.3%)		0/345 (0%)
Troponin T increased	1/344 (0.3%)		0/345 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	1/344 (0.3%)		0/345 (0%)
Hyperkalaemia	1/344 (0.3%)		0/345 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/344 (0.9%)		1/345 (0.3%)
Bone pain	1/344 (0.3%)		0/345 (0%)
Flank pain	1/344 (0.3%)		0/345 (0%)
Muscular weakness	1/344 (0.3%)		0/345 (0%)
Musculoskeletal pain	0/344 (0%)		1/345 (0.3%)
Myositis	1/344 (0.3%)		0/345 (0%)
Pain in extremity	1/344 (0.3%)		0/345 (0%)
Pathological fracture	0/344 (0%)		1/345 (0.3%)
Synovial cyst	0/344 (0%)		1/345 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric	0/344 (0%)		1/345 (0.3%)
Adenocarcinoma of colon	0/344 (0%)		1/345 (0.3%)
Basal cell carcinoma	1/344 (0.3%)		2/345 (0.6%)
Bladder cancer	0/344 (0%)		1/345 (0.3%)
Bladder transitional cell carcinoma	0/344 (0%)		1/345 (0.3%)
Malignant melanoma	1/344 (0.3%)		0/345 (0%)
Malignant melanoma in situ	0/344 (0%)		1/345 (0.3%)
Malignant neoplasm progression	0/344 (0%)		1/345 (0.3%)
Metastatic carcinoma of the bladder	0/344 (0%)		1/345 (0.3%)
Neoplasm progression	0/344 (0%)		1/345 (0.3%)
Oesophageal squamous cell carcinoma	1/344 (0.3%)		0/345 (0%)
Transitional cell carcinoma	1/344 (0.3%)		0/345 (0%)
Tumour pain	0/344 (0%)		2/345 (0.6%)
Nervous system disorders
Cerebrovascular accident	1/344 (0.3%)		1/345 (0.3%)
Cognitive disorder	1/344 (0.3%)		0/345 (0%)
Headache	0/344 (0%)		1/345 (0.3%)
Ischaemic stroke	0/344 (0%)		1/345 (0.3%)
Seizure	1/344 (0.3%)		1/345 (0.3%)
Syncope	0/344 (0%)		2/345 (0.6%)
Product Issues
Device occlusion	1/344 (0.3%)		0/345 (0%)
Psychiatric disorders
Anxiety disorder	0/344 (0%)		1/345 (0.3%)
Depression	1/344 (0.3%)		0/345 (0%)
Renal and urinary disorders
Acute kidney injury	6/344 (1.7%)		6/345 (1.7%)
Anuria	0/344 (0%)		1/345 (0.3%)
Bladder perforation	0/344 (0%)		1/345 (0.3%)
Haematuria	5/344 (1.5%)		2/345 (0.6%)
Haemorrhage urinary tract	1/344 (0.3%)		0/345 (0%)
Hydronephrosis	3/344 (0.9%)		1/345 (0.3%)
Nephritis	1/344 (0.3%)		0/345 (0%)
Renal impairment	0/344 (0%)		1/345 (0.3%)
Tubulointerstitial nephritis	1/344 (0.3%)		0/345 (0%)
Ureteric obstruction	1/344 (0.3%)		0/345 (0%)
Urinary tract obstruction	0/344 (0%)		2/345 (0.6%)
Reproductive system and breast disorders
Pelvic pain	1/344 (0.3%)		1/345 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/344 (0.3%)		0/345 (0%)
Chronic obstructive pulmonary disease	0/344 (0%)		1/345 (0.3%)
Dyspnoea	2/344 (0.6%)		1/345 (0.3%)
Interstitial lung disease	1/344 (0.3%)		0/345 (0%)
Pneumonitis	1/344 (0.3%)		0/345 (0%)
Pulmonary embolism	1/344 (0.3%)		0/345 (0%)
Respiratory distress	1/344 (0.3%)		0/345 (0%)
Vascular disorders
Deep vein thrombosis	1/344 (0.3%)		0/345 (0%)
Embolism	1/344 (0.3%)		0/345 (0%)
Hypotension	1/344 (0.3%)		0/345 (0%)
Orthostatic hypotension	1/344 (0.3%)		0/345 (0%)
Other (Not Including Serious) Adverse Events
	Avelumab + Best Supportive Care (BSC)		Best Supportive Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	313/344 (91%)		206/345 (59.7%)
Blood and lymphatic system disorders
Anaemia	38/344 (11%)		21/345 (6.1%)
Endocrine disorders
Hyperthyroidism	21/344 (6.1%)		1/345 (0.3%)
Hypothyroidism	40/344 (11.6%)		2/345 (0.6%)
Gastrointestinal disorders
Abdominal pain	30/344 (8.7%)		22/345 (6.4%)
Constipation	54/344 (15.7%)		31/345 (9%)
Diarrhoea	57/344 (16.6%)		16/345 (4.6%)
Nausea	54/344 (15.7%)		22/345 (6.4%)
Vomiting	41/344 (11.9%)		12/345 (3.5%)
General disorders
Asthenia	56/344 (16.3%)		19/345 (5.5%)
Chills	28/344 (8.1%)		3/345 (0.9%)
Fatigue	61/344 (17.7%)		23/345 (6.7%)
Oedema peripheral	22/344 (6.4%)		20/345 (5.8%)
Pyrexia	49/344 (14.2%)		11/345 (3.2%)
Infections and infestations
Influenza	20/344 (5.8%)		10/345 (2.9%)
Nasopharyngitis	26/344 (7.6%)		13/345 (3.8%)
Upper respiratory tract infection	20/344 (5.8%)		8/345 (2.3%)
Urinary tract infection	49/344 (14.2%)		31/345 (9%)
Injury, poisoning and procedural complications
Infusion related reaction	31/344 (9%)		0/345 (0%)
Investigations
Alanine aminotransferase increased	18/344 (5.2%)		2/345 (0.6%)
Amylase increased	23/344 (6.7%)		3/345 (0.9%)
Blood creatinine increased	22/344 (6.4%)		4/345 (1.2%)
Metabolism and nutrition disorders
Decreased appetite	47/344 (13.7%)		23/345 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	56/344 (16.3%)		19/345 (5.5%)
Back pain	54/344 (15.7%)		33/345 (9.6%)
Myalgia	29/344 (8.4%)		10/345 (2.9%)
Pain in extremity	18/344 (5.2%)		21/345 (6.1%)
Nervous system disorders
Dizziness	22/344 (6.4%)		12/345 (3.5%)
Headache	24/344 (7%)		8/345 (2.3%)
Psychiatric disorders
Insomnia	21/344 (6.1%)		8/345 (2.3%)
Renal and urinary disorders
Haematuria	35/344 (10.2%)		35/345 (10.1%)
Respiratory, thoracic and mediastinal disorders
Cough	44/344 (12.8%)		16/345 (4.6%)
Dyspnoea	21/344 (6.1%)		10/345 (2.9%)
Skin and subcutaneous tissue disorders
Dry skin	22/344 (6.4%)		3/345 (0.9%)
Pruritus	59/344 (17.2%)		6/345 (1.7%)
Rash	40/344 (11.6%)		4/345 (1.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.