Clinical Trial Results:
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
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Summary
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EudraCT number |
2015-003262-86 |
Trial protocol |
NL GB SE BE CZ PT DK ES IT FR GR |
Global end of trial date |
28 Mar 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Mar 2024
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First version publication date |
16 Mar 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
B9991001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02603432 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
JAVELIN BLADDER 100: Other Study ID | ||
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Sponsors
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Sponsor organisation name |
Pfizer Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
04 May 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Mar 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate the benefit of maintenance treatment with avelumab plus BSC vs. BSC alone in prolonging overall survival (OS) in subjects with unresectable locally advanced or metastatic UC whose disease did not progress on or following completion of first-line platinum-containing chemotherapy in each co-primary UC subject population: 1) subjects determined to have Programmed Death-Ligand 1 (PD-L1) positive tumors (including infiltrating immune cells) by a verified Good Manufacturing Practice (GMP) PD-L1 Immunohistochemistry (IHC) test , and 2) all randomized subjects.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Apr 2016
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
70 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Argentina: 4
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Country: Number of subjects enrolled |
Australia: 59
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Country: Number of subjects enrolled |
Belgium: 24
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Country: Number of subjects enrolled |
Brazil: 13
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Country: Number of subjects enrolled |
Canada: 15
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Country: Number of subjects enrolled |
Czechia: 1
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Country: Number of subjects enrolled |
Denmark: 23
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Country: Number of subjects enrolled |
France: 85
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Country: Number of subjects enrolled |
Greece: 25
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Country: Number of subjects enrolled |
Hong Kong: 2
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Country: Number of subjects enrolled |
Hungary: 1
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Country: Number of subjects enrolled |
India: 6
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Country: Number of subjects enrolled |
Israel: 7
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Country: Number of subjects enrolled |
Italy: 62
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Country: Number of subjects enrolled |
Japan: 73
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Country: Number of subjects enrolled |
Korea, Republic of: 45
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Country: Number of subjects enrolled |
Mexico: 7
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Country: Number of subjects enrolled |
Netherlands: 15
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Country: Number of subjects enrolled |
New Zealand: 12
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Country: Number of subjects enrolled |
Norway: 7
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Country: Number of subjects enrolled |
Poland: 5
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Country: Number of subjects enrolled |
Portugal: 6
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Country: Number of subjects enrolled |
Russian Federation: 17
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Country: Number of subjects enrolled |
Serbia: 10
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Country: Number of subjects enrolled |
Spain: 110
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Country: Number of subjects enrolled |
Sweden: 7
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Country: Number of subjects enrolled |
Taiwan: 21
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Country: Number of subjects enrolled |
United Kingdom: 19
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Country: Number of subjects enrolled |
United States: 19
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Worldwide total number of subjects |
700
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EEA total number of subjects |
371
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
236
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From 65 to 84 years |
457
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85 years and over |
7
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Recruitment
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Recruitment details |
This study included only those subjects 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). | ||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 1005 subjects were screened, out of which 305 subjects discontinued during the screening phase and 700 subjects were enrolled into the study. | ||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Avelumab + Best Supportive Care (BSC) | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects 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, subject refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Subjects were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Avelumab 10 mg/kg
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Investigational medicinal product code |
MSB0010718C
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received avelumab 10 mg/kg intravenously on day 1 and day 15 of each 4-week treatment cycle.
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Arm title
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Best Supportive Care | ||||||||||||||||||||||||||||||||||||
Arm description |
As prescribed by the treating physician, subjects received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, subject refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Subjects were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | ||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Avelumab + Best Supportive Care (BSC)
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Reporting group description |
Subjects 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, subject refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Subjects were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Best Supportive Care
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Reporting group description |
As prescribed by the treating physician, subjects received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, subject refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Subjects were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Avelumab + Best Supportive Care (BSC)
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Reporting group description |
Subjects 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, subject refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Subjects were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | ||
Reporting group title |
Best Supportive Care
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Reporting group description |
As prescribed by the treating physician, subjects received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, subject refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Subjects were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | ||
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End point title |
Overall Survival (OS) | ||||||||||||
End point description |
Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Subjects last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. The Full Analysis Set (FAS) included all randomized subjects.
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End point type |
Primary
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End point timeframe |
From randomization to discontinuation from the study, death or date of censoring, whichever occurred first (for a maximum duration of 41 months)
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Statistical analysis title |
Avelumab+BSC Versus BSC | ||||||||||||
Comparison groups |
Avelumab + Best Supportive Care (BSC) v Best Supportive Care
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Number of subjects included in analysis |
700
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.0005 [1] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.69
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.556 | ||||||||||||
upper limit |
0.863 | ||||||||||||
| Notes [1] - One-sided log-rank test was used. |
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End point title |
Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) | ||||||||||||
End point description |
BICR assessed PFS: 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: 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 subjects 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. Full analysis set was analysed.
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End point type |
Secondary
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End point 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)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Progression-Free Survival (PFS) as Assessed by Investigator | ||||||||||||
End point description |
Investigator assessed PFS: 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: 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 subjects 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. Full analysis set was analysed.
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End point type |
Secondary
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End point 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)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects With OR as Assessed by BICR | ||||||||||||
End point description |
BICR assessed objective response according to RECIST version 1.1, was defined as subjects 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. The full analysis set included all randomized subjects.
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End point type |
Secondary
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End point 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)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects With OR as Assessed by Investigator | ||||||||||||
End point description |
Investigator assessed objective response according to RECIST version 1.1, was defined as subjects 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. The full analysis set included all randomized subjects.
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End point type |
Secondary
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End point 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)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR) | ||||||||||||
End point description |
BICR assessed DOR: time from first documentation of OR(confirmed CR/PR) to date of first PD/death due to any cause. Per RECISTv1.1,CR:complete disappearance of all target(T)&non-target(NT)lesions,with exception of nodal disease sustained 4 weeks. Additionally, normalization of tumor marker level&pathological lymph nodes reduced short axis<10mm. PR:at least 30%decrease in sum of longest dimensions of T lesions taking as reference baseline sum longest dimensions. PD for T: at least 20% increase(inc) in sum of diameters of T lesions,taking as reference smallest sum on study and relative inc of 20%,sum also demonstrated absolute inc of at least 5mm. PD for NT: unequivocal progression of pre-existing lesions and if overall tumor burden inc sufficiently to merit discontinuation of therapy.Appearance of any new unequivocal malignant lesion was also considered PD. 99999=data not estimated due to limited number of events. Analysis=subset of randomized subjects who had OR, as assessed by BICR.
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End point type |
Secondary
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End point 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)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to Tumor Response (TTR) as Assessed by BICR | ||||||||||||
End point description |
TTR was defined, for subjects 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. The full analysis set included all randomized subjects. Here, 'Overall Number of subjects analyzed (N)' signifies subjects who were evaluable for this outcome measure (OM).
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End point type |
Secondary
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End point timeframe |
From the date of randomization to the first documentation of objective response (CR or PR) (for a maximum duration of 41 months)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
TTR as Assessed by Investigator | ||||||||||||
End point description |
TTR was defined, for subjects 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. The full analysis set included all randomized subjects. Here, 'Overall Number of subjects analyzed' signifies subjects who were evaluable for this outcome measure.
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End point type |
Secondary
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End point timeframe |
From the date of randomization to the first documentation of objective response (CR or PR) (for a maximum duration of 41 months)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | ||||||||||||||||||||||||
End point description |
An AE was any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. Per NCI CTCAEv4.03,Grade(G)1:asymptomatic/mild symptoms,clinical/diagnostic observations,intervention not indicated; G2:moderate,minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life(ADL); G3:severe/medically significant but not immediately life-threatening,hospitalization/prolongation of existing indicated,disabling,limiting self-care ADL;G4:life-threatening consequence,urgent intervention indicated;G5:death related to AE.Treatment-emergent AEs are events between first dose&up to90 days after last dose of study drug/end of treatment visit, that were absent before treatment/worsened relative to pretreatment.Safety analysis set=subjects who had received at least one dose of study drug on arm‘Avelumab+BSC’/completed Cycle1Day1(C1D1) on arm ‘BSC’.
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End point type |
Secondary
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End point timeframe |
For "Avelumab + Best Supportive Care (BSC)’’ group: Day 1 up to 90 days after last dose of study drug; for BSC group: Day 1 up to 90 days after EOT visit (for a maximum duration of up to approximately 70 months)
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Percentage of Subjects With DC as Assessed by Investigator | ||||||||||||
End point 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. The full analysis set included all randomized subjects.
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End point type |
Secondary
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End point timeframe |
From randomization to PD, death or start of new anti-cancer therapy (for a maximum duration of 41 months)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects With Disease Control (DC) as Assessed by BICR | ||||||||||||
End point description |
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. The full analysis set included all randomized subjects.
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End point type |
Secondary
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End point timeframe |
From randomization to PD, death or start of new anti-cancer therapy (for a maximum duration of 41 months)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
DOR as Assessed by Investigator | ||||||||||||
End point description |
Investigator assessed DOR: time from first documentation of OR(confirmed CR/PR) to date of first PD/death due to any cause. Per RECISTv1.1,CR:complete disappearance of all target(T)&non-target(NT)lesions,with exception of nodal disease sustained 4 weeks. Additionally, normalization of tumor marker level&pathological lymph nodes reduced short axis<10mm. PR:at least 30%decrease in sum of longest dimensions of T lesions taking as reference baseline sum longest dimensions. PD for T: at least 20%inc in sum of diameters of T lesions,taking as reference smallest sum on study and relative inc of 20%,sum also demonstrated absolute inc of at least 5mm. PD for NT: unequivocal progression of pre-existing lesions and if overall tumor burden inc sufficiently to merit discontinuation of therapy.Appearance of any new unequivocal malignant lesion was considered PD. 99999=data not estimated due to limited number of events. Analysis=subset of randomized subjects who had OR, as assessed by Investigator.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point 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)
|
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|
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Number of Subjects With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3 (G3), Based on NCI-CTCAE, V4.03 | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Hematology:(Anemia G3:hemoglobin<8.0 g/dL,<4.9 mmol/L,<80 g/L, transfusion indicated,Grade[G]4: life-threatening consequence, urgent intervention indicated,G5:death; platelet count decreased[dec]-G3:<50.0-25.0*10^9/L, G4: <25.0*10^9/L; lymphocyte count dec-G3:<0.5-0.2*10^9/L, G4:<0.2*10^9/L; neutrophil count dec-G3:<1.0-0.5*10^9 /L, G4:<0.5*10^9/L). Chemistry:(creatinine increased[inc]-G3:>3.0-6.0*upper limit of normal [ULN], G4:>6.0*ULN; serum amylase inc, lipase inc-G3:>2.0-5.0*ULN, G4:>5.0*ULN. Aspartate aminotransferase[AST], alanine aminotransferase[ALT]-G3:>5.0-20.0*ULN, G4:>20.0*ULN].Blood bilirubin inc-[G3:>3.0-10.0*ULN, G4:>10.0*ULN], Creatine phosphokinase inc- [G3:>5.0-10.0*ULN, G4:>10.0*ULN], Hyperglycemia-[G3:>250-500 mg/dL; >13.9-27.8 mmol/L hospitalization indicated,G4:>500 mg/DL;>27.8 mmol/L life-threatening consequence]).Safety analysis set. All subject reported under ‘Number of Participants Analyzed’contributed data to table may not have evaluable data for each row.
|
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End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
For "Avelumab + Best Supportive Care (BSC)’’ group: Day 1 up to 90 days after last dose of study drug; for BSC group: Day 1 up to 90 days after EOT visit (for a maximum duration of up to approximately 70 months)
|
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|
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||
|
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End point 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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Vital signs included blood pressure and pulse rate. Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP). Safety set analyzed. All subjects reported under ‘Overall Number of subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, ‘Number analyzed’ = subjects evaluable for this outcome measure at specified time points.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (D1 of Cycle 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7, EOT visit (for a maximum duration of 41 months) (each cycle=28 days)
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|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and EOT Visit | ||||||||||||||||||||||||||||||||||||
End point description |
Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized. Safety set analyzed. All subjects reported under ‘Overall Number of subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, ‘Number analyzed’ = subjects evaluable for this outcome measure at specified time points.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (D1 of Cycle 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7, EOT visit (for a maximum duration of 41 months) (each cycle=28 days)
|
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|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
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End point title |
Maximum Plasma Concentration (Cmax) of Avelumab [2] | ||||||||||||||||||||||||||||||
End point description |
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. Avelumab pharmacokinetic (PK) parameter analysis set: all subjects who received at least one dose of avelumab and who had at least one post-dose concentration measurement above the LLQ for avelumab. All subjects reported under ‘Overall Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, ‘n’ signifies subjects evaluable for this OM at specified time points.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point 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)
|
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| Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is reporting for the arms specified. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
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End point title |
Predose Plasma Concentration (Ctrough) of Avelumab [3] | ||||||||||||||||||||||||||||||
End point 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. Avelumab pharmacokinetic (PK) parameter analysis set: all subjects who received at least one dose of avelumab and who had at least one post-dose concentration measurement above the LLQ for avelumab. All subjects reported under ‘Overall Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, ‘n’ signifies subjects evaluable for this OM at specified time points.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point 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)
|
||||||||||||||||||||||||||||||
| Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is reporting for the arms specified. |
|||||||||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||
End point title |
Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status [4] | ||||||||||
End point description |
ADA against avelumab in serum samples was determined and reported separately for ADA never positive and ADA ever positive subjects. Subjects 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. The immunogenicity analysis set included all subjects 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.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)
|
||||||||||
| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is reporting for the arms specified. |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||||||||||
End point title |
Number of ADA Ever Positive Subjects For Each Serum of ADA Titers for Avelumab [5] | ||||||||||||||||||||
End point description |
Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive subjects for each serum of ADA titer (60, 180, 540, 1620, 4860, 14580, and 131220) are reported. The immunogenicity analysis set included subjects who had received at least one dose of study drug and who had ADA ever-positive results. Here “Overall number of subjects analyzed” signifies subjects who had data available for this outcome measure.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)
|
||||||||||||||||||||
| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is reporting for the arms specified. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||
End point title |
Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never Positive and Ever Positive Status [6] | ||||||||||
End point description |
nAb against avelumab in serum samples was determined and reported separately for nAb never positive and nAb ever positive subjects. Subjects 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. The immunogenicity analysis set included all subjects 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.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
From randomization up to the 30-Day Follow-up visit (maximum duration of up to approximately 68 months)
|
||||||||||
| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint is reporting for the arms specified. |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||||||||
End point title |
Number of Subjects With Programmed Death Receptor-1 Ligand 1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | ||||||||||||||||||
End point description |
PD-L1 assessment was performed using immunohistochemistry on pre-treatment tumor tissue samples. Subjects 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. The full analysis set included all randomized subjects.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Up to 41 months at the time of the analysis
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
TTD Based on NCCN-FACT Bladder Symptom Index- 18 (FBlSI-18) Disease Related Symptoms-Physical subscale (DRS-P) Scores | ||||||||||||
End point description |
NCCN-FACT FBlSI-18: an 18-item subject completed questionnaire, designed to assess impact of cancer therapy on urothelial cancer-related symptoms and quality of life(QOL) based on numerical point scoring of symptoms/concerns. It included 4 subscales: Disease related symptoms(DRS)-physical subscale (9), DRS-emotional subscale (2), treatment side effects subscale (5), general function/well-being subscale-(2). Subjects rated 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 higher scores= good QOL. 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 subjects score showed 3 point/greater decrease from baseline in FBlSI-DRS-P subscale for 2 consecutive assessments. 99999=data could not be estimated due to small number of events. Full analysis set.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization up to the 90-Day Follow-up Visit (maximum duration of up to 41 months)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Avelumab+BSC Versus BSC | ||||||||||||
Comparison groups |
Avelumab + Best Supportive Care (BSC) v Best Supportive Care
|
||||||||||||
Number of subjects included in analysis |
700
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.913 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Cox proportional hazard | ||||||||||||
Point estimate |
1.26
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
1-sided
|
||||||||||||
lower limit |
0.901 | ||||||||||||
upper limit |
- | ||||||||||||
|
|||||||||||||||||||
End point 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 | ||||||||||||||||||
End point description |
NCCN-FACT FBlSI-18 is an 18-item subject completed questionnaire, designed to assess impact of cancer therapy/urothelial cancer-related symptoms and quality of life based on numerical point scoring of symptoms/concerns.Included four subscales: Disease related symptoms(DRS)-physical subscale (9 items), DRS-emotional subscale(2), treatment side effects subscale with (5)&general function/well-being subscale(2). Subjects 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. Full analysis set. Here N=subjects who had data available for this outcome measure and n=subjects evaluable for this outcome at specified time points.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline, Day 1 of Cycle 6
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||
End point title |
Number of Subjects With Cluster of differentiation 8 (CD8) T Lymphocytes (Cytotoxic T lymphocytes) | |||||||||
End point description |
Number of subjects with CD8 T Lymphocytes (Cytotoxic T lymphocytes) were presented in this outcome. Biomarker analysis set is a subset of the safety analysis set and included subjects who have at least one baseline biomarker assessment performed. Here, 'Overall Number of subjects analyzed' signifies subjects who were evaluable for this outcome measure.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 60 months
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in Levels EQ-5D-5L - Visual Analog Scale (VAS) Score at Cycle 6 | ||||||||||||||||||
End point description |
The EQ-5D-5L was a 6-item subject-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 subject rated their overall health status from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state. The full analysis set included all randomized subjects. Here, 'Overall number of subjects analyzed' signifies subjects who had data available for this outcome measure and ‘number analyzed’ signifies subjects evaluable for this outcome measure at specified time points.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline, Day 1 of Cycle 6
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score at Cycle 6 | ||||||||||||||||||
End point description |
EQ-5D-5L was a 6-item subject -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 subject 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. The full analysis set included all randomized subjects. Here, 'Overall number of subjects analyzed' signifies subjects who had data available for this outcome measure and ‘number analyzed’ signifies subjects evaluable for this outcome measure at specified time points.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline, Day 1 of Cycle 6
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
For ‘’Avelumab+Best Supportive Care (BSC)’’ reporting group: Day1 up to 90 days after last dose of study drug and for ‘’BSC’’ group: Day1 up to 90 days after end of treatment visit, for a maximum duration of up to 70 months at the time of the analysis.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Same event may appear as both as Non SAE and Serious Adverse Events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both SAE and non-SAE. All-Cause Mortality, SAEs and non-SAEs were assessed in Safety Analysis set.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.0
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Reporting groups
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Reporting group title |
Best Supportive Care
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Reporting group description |
As prescribed by the treating physician, subjects received BSC which included treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management, until confirmed disease progression, subject refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. Subjects were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Avelumab + Best Supportive Care (BSC)
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Reporting group description |
Subjects 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, subject refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered as per the treating physician. Subjects were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anti-cancer therapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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17 Dec 2015 |
Amendment 1: Per FDA request, implemented clarifications in section 5.4.3.5, table 5 management of Avelumab irAEs: Clarified requirement for delaying or discontinuing avelumab for Grade 3 or 4 dermatological irAEs. Clarified requirement to delay or discontinue avelumab therapy for suspicion of adrenal crisis. Per FDA request, added a requirement in section 5.4.3.5, table 5, to permanently discontinue avelumab therapy for subjects with AST/ALT >3 x ULN with concurrent elevation of total bilirubin >2 x ULN without another obvious cause. Inclusion criterion #11 was revised to allow enrollment of patients with a creatinine clearance (CrCl) ≥30 mL/min (changed from ≥50 mL/min). |
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24 Mar 2016 |
Amendment 2: Added an HIV screening test unless not permitted by local laws and regulations (schedule of activities table and footnote #12; and table 6, section 7.1.3) and exclusion of HIV positive subjects (exclusion criterion #16, Section 4.2). Clarified that exclusion criterion #21 (section 4.2) includes but is not limited to those medical conditions listed, and add ‘pulmonary fibrosis’ as a listed condition. Clarified in Section 7.1.3 that the requirement to repeat abnormal laboratory test results applies only for clinically significant abnormal results. |
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19 Dec 2016 |
Amendment 3: To mitigate the potential for bias in determining disease progression, an expedited blinded independent central review (BICR) for investigator-assessed disease progression was added. To optimize trial logistics, removed the requirement for central eligibility review of first-line chemotherapy response. Per United States FDA request, to assess the utility of serum troponin measurements in early detection of myocarditis, a rare and potentially fatal risk associated with avelumab and other check-point inhibitors, the following additions were made: Mandatory measurement of cardiac troponin levels at screening and at each clinic visit ending on Cycle 4 Day 1 (ie, for a total of 12 weeks), and as clinically indicated; Management guidelines for myocarditis. Clarified that first-line chemotherapy must have been completed no less than 4 weeks and no more than 10 weeks prior to randomization (inclusion criterion 2a). |
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28 Mar 2019 |
Amendment 4: immune-related Response Criteria (irRECIST) has been removed as an exploratory endpoint and required study assessment. Management of avelumab-related toxicity has been updated to reflect current avelumab program standard recommendations (Section 5.4.3). Premedications to mitigate avelumab infusion-related reactions were revised such that premedication is only required for the first 4 infusions. Contraception requirements have been updated for females and males in accordance with the current Pfizer and avelumab program standards. The contraception check and pregnancy test were removed as required study procedures at the 60 Day Follow-up visit, in accordance with the current avelumab program standard. It has been added that if new cancer therapy is started, reporting of concomitant medications should end at the time the new cancer therapy starts in order to match the AE reporting period, and in accordance with the current avelumab program standard.Survival assessments for long-term follow-up (every 3 months) were clarified to begin after the last study clinic visit, and to allow additional timepoints at a sponsor request in preparation for interim and final analyses in order to update survival information and add uniformity in the time since most recent contact. |
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13 Feb 2020 |
Amendment 5: The purpose of this protocol amendment is to implement the External-Data Monitoring Committee (E-DMC) recommendation at the pre-specified interim analysis (section 9.6) that remaining patients on Arm B who are progression-free are offered crossover to avelumab. Also, added section 17, supplement 1: crossover from BSC alone (arm B) to avelumab plus best supportive care. This supplement provided details for arm B subjects who crossover to receive avelumab plus BSC including required eligibility criteria, general treatment or study plan, and schedule of activities for screening, treatment period, end of treatment or withdrawal and short and long term follow-up. |
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08 Mar 2021 |
Amendment 6: Following a final OS update, the frequency of study procedures was reduced while providing continued treatment for patients actively receiving avelumab and ending study participation for all patients who were not actively receiving avelumab. A new Schedule of Activities (SoA) table and a new required laboratory tests table (Table 7) were added, BICR tumor assessments were no longer performed, arm B subjects who are eligible to crossover to avelumab plus best supportive care (BSC) as per supplement 1 were permitted to do so until 60 days after the final OS update or approval of amendment 6, whichever is later and CRF data collection was reduced to those items relating to study drug exposure and adverse events. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
