Trial Outcomes & Findings for A Study Of Avelumab In Patients With Locally Advanced Or Metastatic Urothelial Cancer (JAVELIN Bladder 100) (NCT NCT02603432)

Last Updated: 2024-03-27

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

700 participants

Primary outcome timeframe

From randomization to discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months)

Results posted on

2024-03-27

Participant Flow

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).

Participant milestones

Participant milestones
Measure	Avelumab + Best Supportive Care (BSC) 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.	Best Supportive Care 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.
Overall Study STARTED	350	350
Overall Study COMPLETED	16	1
Overall Study NOT COMPLETED	334	349

Reasons for withdrawal

Reasons for withdrawal
Measure	Avelumab + Best Supportive Care (BSC) 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.	Best Supportive Care 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.
Overall Study Adverse Event	1	0
Overall Study Death	221	242
Overall Study Lost to Follow-up	3	9
Overall Study Progressive Disease	7	5
Overall Study Withdrawal by Subject	12	18
Overall Study No Longer Meets Eligibility Criteria	3	0
Overall Study Study terminated by sponsor	74	75
Overall Study Other	13	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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 n=700 Participants Total of all reporting groups
Age, Continuous	67.20 Years STANDARD_DEVIATION 9.52 • n=5 Participants	67.7 Years STANDARD_DEVIATION 9.20 • n=7 Participants	67.44 Years STANDARD_DEVIATION 9.40 • n=5 Participants
Sex: Female, Male Female	84 Participants n=5 Participants	75 Participants n=7 Participants	159 Participants n=5 Participants
Sex: Female, Male Male	266 Participants n=5 Participants	275 Participants n=7 Participants	541 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	18 Participants n=5 Participants	12 Participants n=7 Participants	30 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	286 Participants n=5 Participants	298 Participants n=7 Participants	584 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	46 Participants n=5 Participants	40 Participants n=7 Participants	86 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	75 Participants n=5 Participants	81 Participants n=7 Participants	156 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	232 Participants n=5 Participants	238 Participants n=7 Participants	470 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	41 Participants n=5 Participants	31 Participants n=7 Participants	72 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months)

Population: The full analysis set included all randomized participants.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
Overall Survival (OS)	21.4 months Interval 18.9 to 26.1	14.3 months Interval 12.9 to 17.9

SECONDARY outcome

Timeframe: From randomization to date of progression of disease, discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months)

Population: The full analysis set included all randomized participants.

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 (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 millimeters. 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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)	3.7 months Interval 3.5 to 5.5	2.0 months Interval 1.9 to 2.7

SECONDARY outcome

Timeframe: From randomization to date of progression of disease, discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months)

Population: The full analysis set included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
Progression-Free Survival (PFS) as Assessed by Investigator	5.5 months Interval 4.2 to 7.2	2.1 months Interval 1.9 to 3.0

SECONDARY outcome

Timeframe: From randomization to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (for a maximum duration of 41 months)

Population: The full analysis set included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
Percentage of Participants With Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)	9.7 percentage of participants Interval 6.8 to 13.3	1.4 percentage of participants Interval 0.5 to 3.3

SECONDARY outcome

Timeframe: From randomization to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (for a maximum duration of 41 months)

Population: The full analysis set included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
Percentage of Participants With Objective Response as Assessed by Investigator	12.3 percentage of participants Interval 9.0 to 16.2	3.4 percentage of participants Interval 1.8 to 5.9

SECONDARY outcome

Timeframe: From the date of randomization to the first documentation of objective response (CR or PR) (for a maximum duration of 41 months)

Population: 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).

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=34 Participants 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.	Best Supportive Care n=5 Participants 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.
Time to Tumor Response (TTR) as Assessed by Blinded Independent Central Review (BICR)	2.0 months Interval 1.7 to 16.4	2.0 months Interval 1.8 to 7.0

SECONDARY outcome

Timeframe: From the date of randomization to the first documentation of objective response (CR or PR) (for a maximum duration of 41 months)

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

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=43 Participants 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.	Best Supportive Care n=12 Participants 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.
Time to Tumor Response (TTR) as Assessed by Investigator	2.0 months Interval 1.8 to 22.2	1.9 months Interval 1.1 to 10.9

SECONDARY outcome

Timeframe: 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 (for a maximum duration of 41 months)

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

BICR assessed DOR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR: complete disappearance of all target and non-target lesions, with exception of nodal disease sustained for 4 weeks. Any pathological lymph nodes reduced in short axis to \<10 mm. PR: at least 30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD for target disease: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study and relative increase of 20%, sum also demonstrated absolute increase of at least 5 mm. PD for non-target disease: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=34 Participants 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.	Best Supportive Care n=5 Participants 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.
Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR)	NA months Interval 15.6 to Median and upper limit of 95% Confidence Interval (CI) were not estimable due to limited number of events.	NA months Median and 95% CI were not estimable due to limited number of events.

SECONDARY outcome

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

Investigator assessed DOR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR: complete disappearance of all target and non-target lesions, with exception of nodal disease sustained for 4 weeks. Additionally, normalization of tumor marker levels and any pathological lymph nodes reduced in short axis to \<10 mm. PR: at least 30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD for target disease: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study and relative increase of 20%, sum also demonstrated absolute increase of at least 5 mm. PD for non-target disease: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Appearance of any new unequivocal malignant lesion was also considered PD.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=43 Participants 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.	Best Supportive Care n=12 Participants 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.
Duration of Response (DOR) as Assessed by Investigator	25.6 months Interval 12.0 to The upper limit of 95% CI was not estimable due to limited number of events.	NA months Interval 3.6 to Median and upper limit of 95% CI were not estimable due to limited number of events.

SECONDARY outcome

Timeframe: From randomization to PD, death or start of new anti-cancer therapy (for a maximum duration of 41 months)

Population: The full analysis set included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
Percentage of Participants With Disease Control (DC) as Assessed by Blinded Independent Central Review (BICR)	41.1 percentage of participants Interval 35.9 to 46.5	27.4 percentage of participants Interval 22.8 to 32.4

SECONDARY outcome

Timeframe: From randomization to PD, death or start of new anti-cancer therapy (for a maximum duration of 41 months)

Population: The full analysis set included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
Percentage of Participants With Disease Control (DC) as Assessed by Investigator	50.9 percentage of participants Interval 45.5 to 56.2	34.0 percentage of participants Interval 29.0 to 39.2

SECONDARY outcome

Timeframe: For "Avelumab + Best Supportive Care (BSC)'' group: Day1 up to 90 days after last dose of study drug; for BSC group: Day1 up to 90 days after EOT visit (for a maximum duration of up to approximately 70 months for both groups)

Population: Safety analysis set included all participants who had received at least one dose of study drug on arm 'Avelumab+BSC' or completed Cycle 1 Day (C1D1) on arm 'BSC'.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=344 Participants 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.	Best Supportive Care n=345 Participants 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.
Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 Grade 4	18 Participants	8 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 Grade 1	37 Participants	76 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 Grade 2	113 Participants	104 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 Grade 3	163 Participants	58 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 Grade 5	7 Participants	24 Participants

SECONDARY outcome

Population: 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'. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'Number analyzed (n)' = Participants evaluable for this outcome measure for each specified row.

Hematology (Anemia G3: hemoglobin\<8.0 grams per deciliter \[g/dL\],\<4.9 millimoles (mmol)/liter (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-\[G3:\>250 to 500 mg/dL; \>13.9 to 27.8 mmol/L hospitalization indicated, G4:\>500 mg/DL; \>27.8 mmol/L life-threatening consequences\]).

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=344 Participants 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.	Best Supportive Care n=345 Participants 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.
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 Lipase Increased	37 Participants	22 Participants
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 Anemia	16 Participants	12 Participants
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 Platelet Count Decreased	3 Participants	1 Participants
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 Lymphocyte Count Decreased	20 Participants	11 Participants
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 Neutrophil Count Decreased	7 Participants	0 Participants
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 Creatinine Increased	7 Participants	5 Participants
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 Serum Amylase Increased	25 Participants	9 Participants
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 ALT Increased	11 Participants	3 Participants
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 AST Increased	6 Participants	3 Participants
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 Blood Bilirubin Increased	0 Participants	3 Participants
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 CPK Increased	9 Participants	0 Participants
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 Hyperglycemia	28 Participants	16 Participants

SECONDARY outcome

Timeframe: Baseline (Day [D] 1 of Cycle [C] 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7 , EOT visit (for a maximum duration of 41 months) (each cycle=28 days)

Population: Safety set analyzed. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'Number analyzed' = participants evaluable for this outcome measure at specified time points.

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

Outcome measures

SECONDARY outcome

Timeframe: Baseline (Day [D] 1 of Cycle [C] 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7 , EOT visit (for a maximum duration of 41 months) (each cycle=28 days)

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

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=344 Participants 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.	Best Supportive Care n=345 Participants 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.
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 (C1D1)	76.1 beats per minute Standard Deviation 12.84	77.1 beats per minute Standard Deviation 12.95
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 Change at Cycle 2, Day 1	0.3 beats per minute Standard Deviation 11.81	0.1 beats per minute Standard Deviation 9.98
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 Change at Cycle 3, Day 1	-0.2 beats per minute Standard Deviation 12.10	-0.4 beats per minute Standard Deviation 10.20
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 Change at Cycle 4, Day 1	-0.5 beats per minute Standard Deviation 12.84	-0.1 beats per minute Standard Deviation 11.26
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 Change at Cycle 5, Day 1	0.4 beats per minute Standard Deviation 12.32	-1.0 beats per minute Standard Deviation 11.45
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 Change at Cycle 6, Day 1	-0.8 beats per minute Standard Deviation 11.54	-2.6 beats per minute Standard Deviation 10.52
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 Change at Cycle 7, Day 1	-0.6 beats per minute Standard Deviation 11.89	-2.6 beats per minute Standard Deviation 11.48
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 Change at End of Treatment	2.5 beats per minute Standard Deviation 12.25	1.4 beats per minute Standard Deviation 12.45

SECONDARY outcome

Timeframe: 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 (each cycle=28 days)

Population: 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. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'n' signifies participants evaluable for this OM at specified time points.

The Lower Limit of Quantitation (LLQ) of avelumab was 0.20 micrograms (mcg)/milliliter (mL). Data for this outcome measure was not collected for reporting group "Best Supportive Care", since avelumab was not administered in this arm.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=344 Participants 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.	Best Supportive Care 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.
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 13, Day 1	222.8 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 30.3	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 1, Day 1	192.7 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 68.4	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 1, Day 15	216.2 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 49.6	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 2, Day 1	201.5 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 54.5	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 2, Day 15	208.5 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 60.2	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 3, Day 1	213.1 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 39.6	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 3, Day 15	213.1 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 52.7	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 5, Day 1	197.5 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 67.7	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 7, Day 1	191.9 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 86.2	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 9, Day 1	168.9 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 84.4	—
Maximum Plasma Concentration (Cmax) of Avelumab Cycle 11, Day 1	203.4 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 51.6	—

SECONDARY outcome

Timeframe: 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 (each cycle=28 days)

Population: 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. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here, 'n' signifies participants evaluable for this OM at specified time points.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=344 Participants 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.	Best Supportive Care 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.
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 1, Day 1	3.1 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 247.6	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 1, Day 15	22.2 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 48.6	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 2, Day 1	25.2 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 64.2	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 2, Day 15	26.5 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 65.4	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 3, Day 1	26.4 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 76.2	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 3, Day 15	25.7 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 85.2	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 5, Day 1	26.8 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 67.5	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 7, Day 1	29.7 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 60.2	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 9, Day 1	32.4 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 55.9	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 11, Day 1	29.8 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 68.9	—
Predose Plasma Concentration (Ctrough) of Avelumab Cycle 13, Day 1	32.4 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 54.9	—

SECONDARY outcome

Timeframe: From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=344 Participants 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.	Best Supportive Care 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.
Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status Never-positive	278 Participants	—
Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status Ever-positive	66 Participants	—

SECONDARY outcome

Timeframe: From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)

Population: The immunogenicity analysis set included 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.

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 131220) are reported.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=66 Participants 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.	Best Supportive Care 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.
Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab 60	4 Participants	—
Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab 180	14 Participants	—
Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab 540	19 Participants	—
Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab 1620	10 Participants	—
Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab 4860	11 Participants	—
Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab 14580	7 Participants	—
Number of ADA Ever Positive Participants For Each Serum of ADA Titers for Avelumab 131220	1 Participants	—

SECONDARY outcome

Timeframe: From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)

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

nAb against avelumab in serum samples was determined and reported separately for nAb never positive and nAb ever positive participants. Participants were considered nAb ever-positive if they had at least one positive nAb result at any time point during study and were otherwise considered negative.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=344 Participants 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.	Best Supportive Care 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.
Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status Never-positive	284 Participants	—
Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status Ever-positive	60 Participants	—

SECONDARY outcome

Timeframe: Up to 41 months at the time of the analysis

Population: The full analysis set included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) Unknown	22 Participants	50 Participants
Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) Positive	189 Participants	169 Participants
Number of Participants With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) Negative	139 Participants	131 Participants

SECONDARY outcome

Timeframe: Up to approximately 60 months

Population: Biomarker analysis set is a subset of the safety analysis set and included participants who have at least one baseline biomarker assessment performed. Here, 'Overall Number of participants analyzed' signifies participants who were evaluable for this outcome measure.

Number of Participants With CD8 T Lymphocytes (Cytotoxic T lymphocytes) were presented in this outcome.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=337 Participants 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.	Best Supportive Care n=326 Participants 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.
Number of Participants With Cluster of Differentiation 8 (CD8) T Lymphocytes (Cytotoxic T Lymphocytes)	148 Participants	134 Participants

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycle 6 (1 cycle=28 days)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=332 Participants 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.	Best Supportive Care n=329 Participants 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.
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	53.3 units on a scale Standard Deviation 9.59	52.7 units on a scale Standard Deviation 9.31
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 Change at Day 1 of Cycle 6	1.0 units on a scale Standard Deviation 8.25	1.6 units on a scale Standard Deviation 8.35

SECONDARY outcome

Timeframe: From randomization up to the 90-Day Follow-up Visit (maximum duration of up to 41 months)

Population: The full analysis set included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=350 Participants 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.	Best Supportive Care n=350 Participants 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.
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	NA months Interval 13.9 to Median and upper limit of 95% CI were not estimable due to the small number of events.	13.8 months Interval 12.9 to The upper limit of 95% CI was not estimable due to the small number of events.

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycle 6 (1 cycle=28 days)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=336 Participants 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.	Best Supportive Care n=327 Participants 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.
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 Baseline	0.814 units on a scale Standard Deviation 0.1794	0.792 units on a scale Standard Deviation 0.2013
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 Change at Day 1 of Cycle 6	-0.029 units on a scale Standard Deviation 0.1919	-0.020 units on a scale Standard Deviation 0.1684

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycle 6 (1 cycle=28 days)

Outcome measures

Outcome measures
Measure	Avelumab + Best Supportive Care (BSC) n=335 Participants 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.	Best Supportive Care n=325 Participants 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.
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 Baseline	74.9 units on a scale Standard Deviation 18.87	74.9 units on a scale Standard Deviation 16.34
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) - Visual Analog Scale (VAS) Score at Cycle 6 Change at Day 1 of Cycle 6	1.6 units on a scale Standard Deviation 17.74	0.2 units on a scale Standard Deviation 14.74

Adverse Events

Avelumab + Best Supportive Care (BSC)

Serious events: 111 serious events

Other events: 321 other events

Deaths: 225 deaths

Best Supportive Care

Serious events: 73 serious events

Other events: 214 other events

Deaths: 242 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Avelumab + Best Supportive Care (BSC) n=344 Participants 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.	Best Supportive Care n=345 Participants 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.
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 (C1D1): Sitting DBP	75.7 millimeters of mercury Standard Deviation 10.81	77.0 millimeters of mercury Standard Deviation 10.48
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 Change at Cycle 2, Day 1: Sitting DBP	-0.9 millimeters of mercury Standard Deviation 9.37	-0.0 millimeters of mercury Standard Deviation 9.06
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 Change at Cycle 3, Day 1: Sitting DBP	-1.7 millimeters of mercury Standard Deviation 10.36	-1.6 millimeters of mercury Standard Deviation 9.38
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 Change at Cycle 4, Day 1: Sitting DBP	-1.7 millimeters of mercury Standard Deviation 9.97	-1.0 millimeters of mercury Standard Deviation 9.90
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 Change at Cycle 5, Day 1: Sitting DBP	-1.1 millimeters of mercury Standard Deviation 10.60	-1.0 millimeters of mercury Standard Deviation 10.22
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 Change at Cycle 6, Day 1: Sitting DBP	-1.2 millimeters of mercury Standard Deviation 10.89	-1.1 millimeters of mercury Standard Deviation 10.89
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 Change at Cycle 7, Day 1: Sitting DBP	-0.7 millimeters of mercury Standard Deviation 10.90	0.2 millimeters of mercury Standard Deviation 9.95
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 Change at End of Treatment: Sitting DBP	-0.1 millimeters of mercury Standard Deviation 12.09	-1.7 millimeters of mercury Standard Deviation 10.23
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 (C1D1): Sitting SBP	131.3 millimeters of mercury Standard Deviation 17.34	130.6 millimeters of mercury Standard Deviation 16.32
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 Change at Cycle 2, Day 1: Sitting SBP	-2.2 millimeters of mercury Standard Deviation 14.85	-0.3 millimeters of mercury Standard Deviation 13.79
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 Change at Cycle 3, Day 1: Sitting SBP	-1.9 millimeters of mercury Standard Deviation 16.10	1.0 millimeters of mercury Standard Deviation 14.94
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 Change at Cycle 4, Day 1: Sitting SBP	-0.6 millimeters of mercury Standard Deviation 16.54	1.3 millimeters of mercury Standard Deviation 16.54
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 Change at Cycle 5, Day 1: Sitting SBP	-1.9 millimeters of mercury Standard Deviation 15.49	1.9 millimeters of mercury Standard Deviation 15.85
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 Change at Cycle 6, Day 1: Sitting SBP	-2.3 millimeters of mercury Standard Deviation 15.77	3.3 millimeters of mercury Standard Deviation 16.81
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 Change at Cycle 7, Day 1: Sitting SBP	-1.8 millimeters of mercury Standard Deviation 16.13	2.7 millimeters of mercury Standard Deviation 19.86
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 Change at End of Treatment: Sitting SBP	-0.9 millimeters of mercury Standard Deviation 18.99	-0.3 millimeters of mercury Standard Deviation 16.78