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    Clinical Trial Results:
    A Multicenter, Open-label, Phase 1B/2 Study to Evaluate Safety and Efficacy of Avelumab (MSB0010718C) in Combination With Chemotherapy With or Without Other Anti-cancer Immunotherapies As First-line Treatment in Subjects With Advanced Malignancies

    Summary
    EudraCT number
    		 2017-001741-27
    Trial protocol
    		 CZ   ES   HU   GB   IT  
    Global end of trial date
    20 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2023
    First version publication date
    29 Jun 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B9991023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03317496
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess DLT rate and objective response rate (ORR) of avelumab in combination with chemotherapy, as first-line treatment in subjects with locally advanced or metastatic solid tumors.
    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 Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 60 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    66
    EEA total number of subjects
    37
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted in 2 phases: Phase 1b (lead-in phase) and Phase 2 (cohort expansion phase). Phase 2 was conducted at the highest dose level of avelumab which was determined safe for subjects in Phase 1b.

    Pre-assignment
    Screening details
    		 Phase 1b lead-in:49 subjects signed inform consent form(ICF).18 subjects did not meet eligibility criteria and not enrolled,31 subjects enrolled and assigned to treatment. Phase 2:52 subjects signed ICF.16 subjects did not meet eligibility criteria and not enrolled,36 subjects enrolled,1 was not assigned to treatment and 35 assigned to treatment

    Period 1
    Period 1 title
    Overall study
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin
    Arm description
    		 Subjects with advanced non-squamous non-small cell lung cancer (NSCLC) received avelumab 800 milligrams (mg) as an intravenous (IV) infusion over 1 hour every 3 weeks (Q3W) in combination with IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) and carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate[GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) over 10 minutes on Day 1 of each 21-day cycle. It was administered for a maximum of 4 to 6 cycles. Maintenance therapy with pemetrexed was administered at the discretion of the Investigator.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection, Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate [GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. It was administered for a maximum of 4 to 6 cycles.

    Investigational medicinal product name
    Avelumab 800mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use, Intravenous use
    Dosage and administration details
    Subjects received avelumab 800 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Arm title
    		 Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Arm description
    		 Subjects (cisplatin-eligible) with urothelial cancer (UC) received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 800mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received avelumab 800 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV administration of cisplatin 70 mg/m^2 over 60 minutes on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion, Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use, Intravenous use
    Dosage and administration details
    Subjects received an IV administration of gemcitabine 1000 mg/m^2 over 30 minutes on Day 1 and 8 of each 21-day cycle.

    Arm title
    		 Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin
    Arm description
    		 Subjects with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25), and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 1200mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received avelumab 1200 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate [GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. It was administered for a maximum of 4 to 6 cycles.

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) over 10 minutes on Day 1 of each 21-day cycle. It was administered for a maximum of 4 to 6 cycles.

    Arm title
    		 Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Arm description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first. Participants from both Phase 1b and Phase 2 Avelumab 1200 mg + Gemcitabine/Cisplatin were included in this arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 1200mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received avelumab 1200 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV administration of cisplatin 70 mg/m^2 over 60 minutes on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV administration of gemcitabine 1000 mg/m^2 over 30 minutes on Day 1 and 8 of each 21-day cycle.

    Number of subjects in period 1
    		Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Started
    6
    13
    6
    41
    Completed
    6
    13
    6
    41
    Period 2
    Period 2 title
    Phase 1b Lead-in: Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin
    Arm description
    		 Subjects with advanced non-squamous non-small cell lung cancer (NSCLC) received avelumab 800 milligrams (mg) as an intravenous (IV) infusion over 1 hour every 3 weeks (Q3W) in combination with IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) and carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate[GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 800mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use, Intravenous use
    Dosage and administration details
    Subjects received avelumab 800 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection, Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate [GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. It was administered for a maximum of 4 to 6 cycles.

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) over 10 minutes on Day 1 of each 21-day cycle. It was administered for a maximum of 4 to 6 cycles. Maintenance therapy with pemetrexed was administered at the discretion of the Investigator.

    Arm title
    		 Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Arm description
    		 Subjects (cisplatin-eligible) with urothelial cancer (UC) received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 800mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received avelumab 800 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV administration of cisplatin 70 mg/m^2 over 60 minutes on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion, Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use, Intravenous use
    Dosage and administration details
    Subjects received an IV administration of gemcitabine 1000 mg/m^2 over 30 minutes on Day 1 and 8 of each 21-day cycle.

    Arm title
    		 Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin
    Arm description
    		 Subjects with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25), and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 1200mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received avelumab 1200 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate [GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. It was administered for a maximum of 4 to 6 cycles.

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) over 10 minutes on Day 1 of each 21-day cycle. It was administered for a maximum of 4 to 6 cycles.

    Arm title
    		 Phase 1b Lead-in: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Arm description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 1200mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received avelumab 1200 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV administration of gemcitabine 1000 mg/m^2 over 30 minutes on Day 1 and 8 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV administration of gemcitabine 1000 mg/m^2 over 30 minutes on Day 1 and 8 of each 21-day cycle.

    Number of subjects in period 2 [1]
    		Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Started
    6
    13
    6
    6
    Completed
    0
    0
    0
    0
    Not completed
    6
    13
    6
    6
         Physician decision
    -
    1
    -
    -
         Global deterioration of health status
    -
    -
    1
    -
         Death
    -
    -
    1
    -
         Progressive Disease
    1
    6
    3
    4
         Adverse event
    3
    4
    1
    1
         Study terminated by sponsor
    -
    1
    -
    1
         Unspecified
    2
    1
    -
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of subjects specified equals the number of subjects entered for this period.
    Period 3
    Period 3 title
    Phase 1b Lead-in: Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin
    Arm description
    		 Subjects with advanced non-squamous non-small cell lung cancer (NSCLC) received avelumab 800 milligrams (mg) as an intravenous (IV) infusion over 1 hour every 3 weeks (Q3W) in combination with IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) and carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate[GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Arm description
    		 Subjects (cisplatin-eligible) with urothelial cancer (UC) received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin
    Arm description
    		 Subjects with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25), and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Phase 1b Lead-in: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Arm description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Started
    6
    12
    5
    6
    Completed
    0
    0
    0
    0
    Not completed
    6
    12
    5
    6
         Consent withdrawn by subject
    -
    -
    1
    -
         Death
    3
    8
    4
    4
         Study terminated by sponsor
    2
    3
    -
    1
         Unspecified
    -
    1
    -
    1
         Lost to follow-up
    1
    -
    -
    -
    Period 4
    Period 4 title
    Phase 2: Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Phase 2: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Arm description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 1200mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received avelumab 1200 mg as an IV infusion over 1 hour every three weeks on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion, Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use, Intravenous use
    Dosage and administration details
    Subjects received an IV administration of cisplatin 70 mg/m^2 over 60 minutes on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV administration of gemcitabine 1000 mg/m^2 over 30 minutes on Day 1 and 8 of each 21-day cycle.

    Number of subjects in period 4
    		Phase 2: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Started
    35
    Completed
    33
    Not completed
    2
         Consent withdrawn by subject
    1
         Death
    1
    Period 5
    Period 5 title
    Phase 2: Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Phase 2: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Arm description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 5
    		Phase 2: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Started
    33
    Completed
    0
    Not completed
    33
         Death
    24
         Study terminated by sponsor
    7
         Unspecified
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Subjects with advanced non-squamous non-small cell lung cancer (NSCLC) received avelumab 800 milligrams (mg) as an intravenous (IV) infusion over 1 hour every 3 weeks (Q3W) in combination with IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) and carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate[GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with urothelial cancer (UC) received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Subjects with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25), and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first. Participants from both Phase 1b and Phase 2 Avelumab 1200 mg + Gemcitabine/Cisplatin were included in this arm.

    Reporting group values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin Total
    Number of subjects
    		 6 13 6 41 66
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 7 3 14 25
        From 65-84 years
    		 5 6 3 27 41
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 69.67 ( 6.65 ) 63.00 ( 10.15 ) 64.67 ( 9.16 ) 65.24 ( 10.48 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 2 5 0 10 17
        Male
    		 4 8 6 31 49
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 0 1 1 1 3
        Black or African American
    		 0 1 0 0 1
        White
    		 6 11 5 37 59
        Unknown or not reported
    		 0 0 0 3 3
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 0 1
        Not Hispanic or Latino
    		 6 11 6 37 60
        Unknown or Not Reported
    		 0 1 0 4 5

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Subjects with advanced non-squamous non-small cell lung cancer (NSCLC) received avelumab 800 milligrams (mg) as an intravenous (IV) infusion over 1 hour every 3 weeks (Q3W) in combination with IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) and carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate[GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with urothelial cancer (UC) received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Subjects with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25), and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first. Participants from both Phase 1b and Phase 2 Avelumab 1200 mg + Gemcitabine/Cisplatin were included in this arm.
    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Subjects with advanced non-squamous non-small cell lung cancer (NSCLC) received avelumab 800 milligrams (mg) as an intravenous (IV) infusion over 1 hour every 3 weeks (Q3W) in combination with IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) and carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate[GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with urothelial cancer (UC) received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Subjects with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25), and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Subjects with advanced non-squamous non-small cell lung cancer (NSCLC) received avelumab 800 milligrams (mg) as an intravenous (IV) infusion over 1 hour every 3 weeks (Q3W) in combination with IV infusion of pemetrexed 500 milligram per square meter (mg/m^2) and carboplatin dose at area under curve (AUC) 5 (carboplatin dose [mg] = target AUC * glomerular filtration rate[GFR] milliliter per minute [mL/min] + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with urothelial cancer (UC) received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Subjects with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25), and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Reporting group title
    Phase 2: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.
    Reporting group title
    Phase 2: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Subjects (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Primary: Phase 1b Lead-in: Number of Subjects With Dose-Limiting Toxicities (DLT)

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    End point title
    		 Phase 1b Lead-in: Number of Subjects With Dose-Limiting Toxicities (DLT) [1]
    End point description
    DLTs=occurrence of any AEs attributable to study treatment in first 2 treatment cycles:Hematologic: grade(G)4 neutropenia lasting >7days;febrile neutropenia with body temperature >=38 degree Celsius for >1hour; G>=3 neutropenic infection(absolute neutrophil count <1.0*10^9/L),G>=3 thrombocytopenia (platelet count<50.0–25.0*10^9/L)with bleeding;G4 thrombocytopenia(PC<25.0*10^9/L),G4 anemia(life-threatening).Non-hematologic: any G4 toxicities;G3 toxicities persisting for >3days despite medical treatment(nausea,vomiting,diarrhea)except endocrinopathies controlled with hormonal therapy;ALT/AST >3*upper limit of normal(ULN)if normal at baseline or 2*Baseline(>ULN at baseline)with total bilirubin >2*ULN and alkaline phosphatase <2*ULN;G3 QTcF prolongation after correction of any reversible cause(electrolyte abnormalities/hypoxia).Delay of >=3weeks in scheduled administration/failure to deliver 75% of doses due to toxicities attributable to any study treatment. DLT-evaluable analysis set.
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 6 (first 2 treatment cycles; 1 cycle = 21 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    12
    6
    6
    Units: Subjects
    0
    1
    0
    1
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Confirmed Objective Response (OR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment

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    End point title
    		 Percentage of Subjects With Confirmed Objective Response (OR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment [2]
    End point description
    OR: complete response(CR) or partial response(PR)determined by investigator according to RECIST v1.1 from date of first dose of study treatment until date of first documentation of progressive disease(PD),confirmed by repeat assessments performed no less than 4 weeks after first response. CR: disappearance of target/non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures <10 mm. PR: >=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. PD: >=20% increase in sum of diameters of target lesions, taking as reference smallest sum on study,relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of 1 or more new lesions was considered PD. FAS:all subjects who received at least 1 dose of any study drug.
    End point type
    Primary
    End point timeframe
    From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5 years approximately)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    41
    Units: Percentage of Subjects
        number (confidence interval 95%)
    50.0 (11.8 to 88.2)
    53.8 (25.1 to 80.8)
    33.3 (4.3 to 77.7)
    39.0 (24.2 to 55.5)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    Adverse event (AE) was any untoward medical occurrence in a subject who received any study drug without regard to possibility of causal relationship. Serious adverse event was any untoward medical occurrence that at any dose resulted in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Safety analysis set included all subjects who received at least 1 dose of any study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    41
    Units: Subjects
        TEAEs
    6
    13
    6
    40
        Serious TEAEs
    3
    9
    5
    20
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Related TEAEs

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    End point title
    		 Number of Subjects With Treatment Related TEAEs
    End point description
    A treatment related AE included AEs related to at least one study drug in the combination. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Relatedness to study drug was assessed by the investigator. Safety analysis set included all subjects who received at least 1 dose of any study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    41
    Units: Subjects
    6
    12
    6
    40
    No statistical analyses for this end point

    Secondary: Number of Subjects With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03

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    End point title
    		 Number of Subjects With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03
    End point description
    AE was any untoward medical occurrence in a subject who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. TEAEs were graded by the investigator using NCI CTCAE v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. In this outcome measure, number of subjects with grade 3 or higher TEAEs were reported. Safety analysis set included all subjects who received at least 1 dose of any study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    37
    Units: Subjects
    5
    12
    6
    40
    No statistical analyses for this end point

    Secondary: Number of Subjects With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade

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    End point title
    		 Number of Subjects With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade
    End point description
    The number of subjects with laboratory abnormalities of any Grade classified according to NCI CTCAE toxicity grading v4.03 were summarized: hematology(anemia,hemoglobin increased,lymphocyte count decreased,lymphocyte count increased, neutrophil count decreased,platelet count decreased and white blood cell decreased) and clinical chemistry(alanine aminotransferase increased,alkaline phosphatase increased,aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, creatinine phosphokinase[cpk] increased, creatinine increased, gamma-glutamyl transferase[ggt] increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypertriglyceridemia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, serum amylase increased and lipase increased).As per NCI CTCAE toxicity grading v4.03, Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening; Grade 5=death.Safety analysis set.
    End point type
    Secondary
    End point timeframe
    From screening up to 90 days after last dose of study drug (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    40
    Units: Subjects
        ALANINE AMINOTRANSFERAS E INCREASED
    1
    1
    0
    3
        ALKALINE PHOSPHATASE INCREASED
    0
    0
    0
    1
        ASPARTATE AMINOTRANSFERAS E INCREASED
    1
    1
    0
    2
        BLOOD BILIRUBIN INCREASED
    0
    1
    0
    0
        CPK INCREASED
    0
    0
    0
    1
        CREATININE INCREASED
    1
    1
    0
    0
        GGT INCREASED
    0
    2
    1
    4
        HYPERGLYCEMIA
    2
    2
    0
    4
        HYPERKALEMIA
    0
    1
    0
    2
        HYPOKALEMIA
    1
    0
    0
    5
        HYPONATREMIA
    0
    2
    1
    4
        LIPASE INCREASED
    1
    2
    1
    4
        SERUM AMYLASE INCREASED
    0
    2
    0
    4
        HYPOPHOSPHATEMIA
    2
    0
    1
    3
        HYPOMAGNESEMIA
    0
    0
    0
    2
        HYPOCALCEMIA
    2
    0
    0
    1
        HYPERTRIGLYCERIDEMIA
    0
    3
    0
    2
        HYPERNATREMIA
    0
    0
    0
    1
        HYPERMAGNESEMIA
    0
    0
    0
    1
        HYPERCALCEMIA
    0
    0
    0
    1
        ANEMIA
    2
    5
    0
    6
        LYMPHOCYTE COUNT DECREASED
    3
    5
    1
    7
        LYMPHOCYTE COUNT INCREASED
    0
    0
    0
    1
        NEUTROPHIL COUNT DECREASED
    3
    8
    3
    0
        PLATELET COUNT DECREASED
    3
    2
    0
    11
        WHITE BLOOD CELL DECREASED
    2
    7
    3
    21
    No statistical analyses for this end point

    Secondary: Serum Concentration of Avelumab

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    End point title
    		 Serum Concentration of Avelumab
    End point description
    The lower limit of quantification (LLOQ) for avelumab was 0.2 micrograms per milliliter. Pharmacokinetic concentration analysis set was subset of safety analysis set and included subjects who had at least one concentration measurement for avelumab or other study drugs which they were assigned to receive. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. Overall number of subjects analyzed= subjects evaluable for this outcome measure. Number analyzed= subjects evaluable at specified time point. Here 99999 signifies not applicable/not estimable since data was not estimable due to low number of subjects analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour post-dose on Day 1 of Cycle 1, 2, 3, 6, 10, 14; 336 hours post-dose on Day 15 of Cycle 1, 2, 3 (each cycle of 21 days)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    40
    Units: Micrograms per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1/Day 1- 1 hour (n= 4, 10, 1, 32)
    173.3 ( 26 )
    172.2 ( 18 )
    284.1 ( 33 )
    300.2 ( 32 )
        Cycle 1/Day 15- 336 hours (n= 6,12,6,34)
    12.32 ( 47 )
    9.570 ( 92 )
    16.51 ( 68 )
    14.71 ( 74 )
        Cycle 2/Day 1- pre-dose (n= 6, 8, 6, 24)
    4.780 ( 44 )
    3.754 ( 115 )
    4.328 ( 332 )
    5.013 ( 196 )
        Cycle 2/Day 1- 1 hour (n= 4, 8, 4, 20)
    164.2 ( 33 )
    197.0 ( 18 )
    104.5 ( 1474 )
    311.9 ( 36 )
        Cycle 2/Day 15- 336 hours (n= 6, 8, 5, 27)
    16.87 ( 24 )
    13.55 ( 33 )
    16.82 ( 137 )
    18.66 ( 75 )
        Cycle 3/Day 1- pre-dose (n= 5, 9, 5, 19)
    8.122 ( 40 )
    5.651 ( 75 )
    4.878 ( 662 )
    6.771 ( 104 )
        Cycle 3/Day 1- 1 hour (n= 4, 7, 4, 11)
    147.0 ( 35 )
    204.0 ( 28 )
    93.81 ( 2989 )
    296.8 ( 36 )
        Cycle 3/Day 15- 336 hours (n= 5, 7, 6, 16)
    19.40 ( 14 )
    17.15 ( 40 )
    26.17 ( 74 )
    22.55 ( 79 )
        Cycle 6/Day 1- pre-dose (n= 5, 7, 4, 8)
    11.38 ( 24 )
    9.518 ( 65 )
    10.86 ( 165 )
    10.39 ( 233 )
        Cycle 6/Day 1- 1 hour (n= 4, 7, 3, 12)
    92.53 ( 203 )
    208.3 ( 23 )
    245.4 ( 6 )
    344.0 ( 27 )
        Cycle 10/Day 1- pre-dose (n= 4, 6, 1, 14)
    9.523 ( 33 )
    8.695 ( 115 )
    6.620 ( 99999 )
    18.55 ( 58 )
        Cycle 10/Day 1- 1 hour (n= 3, 6, 1, 6)
    179.0 ( 38 )
    222.0 ( 27 )
    6.040 ( 99999 )
    242.9 ( 121 )
        Cycle 14/Day 1- pre-dose (n=3, 4, 2, 8)
    14.97 ( 28 )
    13.37 ( 77 )
    12.24 ( 523 )
    16.49 ( 57 )
        Cycle 14/Day 1- 1 hour (n=3, 4, 2, 5)
    215.3 ( 20 )
    216.6 ( 22 )
    29.05 ( 20555 )
    402.2 ( 19 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab

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    End point title
    		 Number of Subjects With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab
    End point description
    Blood samples were collected for assessment of avelumab ADAs using a tiered assay and confirmed positive samples were tested for neutralizing antibodies (nAb). No positive ADA results at any time point; ADA-negative patients (titer < cutpoint). Here 99999 signifies not applicable/not estimable since data for NAB was not collected due to low observed immunogenicity.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to last dose of study drug (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    41
    Units: Subjects
        ADA ever positive (n=6,13,6,41)
    0
    5
    1
    9
        NAB ever positive (n=0,0,0,0)
    99999
    99999
    99999
    99999
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) as per RECIST v 1.1 by Investigator Assessment

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    End point title
    		 Progression Free Survival (PFS) as per RECIST v 1.1 by Investigator Assessment
    End point description
    PFS was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurred first. PD = at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or appearance of one or more new lesions was considered progression. The median duration of OS was planned not to derive for less than (<) 10 subjects. Here 99999 signifies not applicable/not estimable since data was not estimable due to low number of subjects analyzed.
    End point type
    Secondary
    End point timeframe
    From start of treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    41
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    9.8 (2.2 to 99999)
    99999 (99999 to 99999)
    5.4 (2.9 to 6.0)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the first dose of study treatment to the date of death from any cause. Subjects who were alive at the study end date or the last visit date available were censored at the date of last contact. The median duration of OS was planned not to derive for less than (<) 10 subjects. Here 99999 signifies not applicable/not estimable since data was not estimable due to low number of subjects analyzed.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment until death due to any cause (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    41
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    18.1 (5.0 to 99999)
    99999 (99999 to 99999)
    15.1 (8.7 to 22.0)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as per RECIST v 1.1 by Investigator Assessment

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    End point title
    		 Duration of Response (DOR) as per RECIST v 1.1 by Investigator Assessment
    End point description
    DOR was defined as time from first documentation of objective response (confirmed CR or PR) to the date of first PD documentation or death due to any cause, whichever occurs first. Per RECIST v1.1, CR =disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. Target and non-target nodes must have short axis measures <10 mm. PR = at least a 30% decrease in the sum of measures (diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. PD = at least a 20% increase in sum of diameters of target lesions, moreover, the sum must demonstrate an absolute increase of at least 5 mm or appearance of one or more new lesions was considered progression. Median DOR was not derived for < 5 subjects. Here 99999 signifies not applicable/not estimable due to low number of subjects analyzed.
    End point type
    Secondary
    End point timeframe
    From date of first documented response to date of first documented PD or death due to any cause, whichever occurred first (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    3
    7
    2
    16
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    9.6 (4.0 to 99999)
    99999 (99999 to 99999)
    99999 (4.2 to 99999)
    No statistical analyses for this end point

    Secondary: Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue

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    End point title
    		 Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue
    End point description
    Mutational load within tumor tissue was defined as number per megabase of the genome, coding, base substitution, and indel mutations present in the sample. Mutational load was determined in whole blood samples using next generation deoxyribonucleic acid (DNA) sequencing followed by computational analysis. The tumor tissue based biomarker analysis set was subset of the safety analysis set and included subjects who had at least one baseline and one on-treatment biomarker assessment for the same biomarker. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycle 1
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    4
    13
    5
    39
    Units: Mutations per megabase
        arithmetic mean (standard deviation)
    4.3 ( 6.75 )
    2.8 ( 2.76 )
    4.4 ( 5.15 )
    2.5 ( 2.88 )
    No statistical analyses for this end point

    Secondary: Time-to-Tumor Response (TTR) as per RECIST v 1.1 by Investigator Assessment

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    End point title
    		 Time-to-Tumor Response (TTR) as per RECIST v 1.1 by Investigator Assessment
    End point description
    TTR was defined as the time from the date of first dose of study treatment to the first documentation of objective response (CR or PR) as assessed by investigator according to RECIST v 1.1. As per RECIST v 1.1, CR was defined as disappearance of all target and non-target lesions, with exception of nodal disease. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment until first documentation of CR or PR (maximum up to 5 years approximately)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    3
    7
    2
    16
    Units: Months
        median (full range (min-max))
    2.8 (1.3 to 4.1)
    1.4 (1.1 to 1.5)
    1.3 (1.3 to 1.3)
    1.5 (1.3 to 4.3)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Programmed Death-Ligand 1 (PD-L1) Expression

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    End point title
    		 Number of Subjects With Programmed Death-Ligand 1 (PD-L1) Expression
    End point description
    PD-L1 expression was determined using the Ventana PD-L1 SP263 IHC assay. PD-L1–positive status in UC cohorts was defined using an algorithm that combines assessments of PD-L1 staining on tumor and immune cells scored by pathologists and in NSCLC cohorts was defined as PD-L1 expression on >=1% of tumor cells. PD-L1 expression at baseline and on-treatment were reported in this outcome measure. FAS included all subjects who received at least one dose of study drug. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Baseline and Cycle 2 Day 8 (each cycle of 21 days)
    End point values
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in+Phase 2:Avelumab 1200mg+Gemcitabine/Cisplatin
    Number of subjects analysed
    6
    13
    6
    41
    Units: Subjects
        Baseline- Positive PD-L1
    0
    6
    1
    28
        Baseline- Negative PD-L1
    4
    7
    4
    13
        Baseline- Unknown PD-L1
    2
    0
    1
    0
        On-treatment (Cycle 2 Day 8)- Positive PD-L1
    0
    2
    1
    3
        On-treatment (Cycle 2 Day 8)- Negative PD-L1
    2
    1
    0
    6
        On-treatment (Cycle 2 Day 8)- Unknown PD-L1
    4
    10
    5
    32
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality: From start of the treatment up to 90 days post last dose of study treatment, TEAEs and Serious TEAEs: From start of the treatment up to 30 days post last dose of study treatment (maximum of 5 years approximately)
    Adverse event reporting additional description
    Same event may appear as both an AE and SAE. Safety set was evaluated. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan. TEAEs: events with onset dates occurring during on-treatment period (time from1st dose of any study treatment and up to 30 days after last dose).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Participants with advanced NSCLC received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25, and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b and 2: Avelumab 1200 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Participants (cisplatin-eligible) with UC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first. Participants from both Phase 1b and Phase 2 Avelumab 1200 mg + Gemcitabine/Cisplatin were included in this arm.

    Reporting group title
    Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin
    Reporting group description
    		 Participants with advanced NSCLC received avelumab 1200 mg as an IV infusion over 1 hour Q3W in combination with IV infusion of pemetrexed 500 mg/m^2 and carboplatin dose at AUC 5 (carboplatin dose [mg] = target AUC * GFR mL/min + 25), and maximum carboplatin dose = target AUC [mg*min/mL] * 150 mL/min) on Day 1 of each 21-day cycle. Pemetrexed/carboplatin were administered for a maximum of 4 to 6 cycles. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Reporting group title
    Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Reporting group description
    		 Participants (cisplatin-eligible) with UC received avelumab 800 mg as an IV infusion over 1 hour Q3W in combination with IV administration of cisplatin 70 mg/m^2 and gemcitabine 1000 mg/m^2 on Day 1 of each 21-day cycle with gemcitabine being administered on Day 1 and Day 8. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

    Serious adverse events
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b and 2: Avelumab 1200 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    20 / 41 (48.78%)
    5 / 6 (83.33%)
    9 / 13 (69.23%)
         number of deaths (all causes)
    3
    29
    5
    8
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    2 / 6 (33.33%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Other
    Additional description: Near drowning
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fasciitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 41 (12.20%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 8
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteriuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b Lead-in: Avelumab 800 mg + Pemetrexed/Carboplatin Phase 1b and 2: Avelumab 1200 mg + Gemcitabine/Cisplatin Phase 1b Lead-in: Avelumab 1200 mg + Pemetrexed/Carboplatin Phase 1b Lead-in: Avelumab 800 mg + Gemcitabine/Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    40 / 41 (97.56%)
    6 / 6 (100.00%)
    13 / 13 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 41 (14.63%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    14
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Superficial vein thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    4
    0
    3
    Mucosal inflammation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    0
    2
    Fatigue
         subjects affected / exposed
    3 / 6 (50.00%)
    15 / 41 (36.59%)
    3 / 6 (50.00%)
    8 / 13 (61.54%)
         occurrences all number
    3
    36
    5
    16
    Extravasation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 41 (2.44%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Asthenia
         subjects affected / exposed
    2 / 6 (33.33%)
    11 / 41 (26.83%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    5
    39
    0
    3
    Thirst
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 6 (33.33%)
    11 / 41 (26.83%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    16
    0
    1
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 41 (9.76%)
    1 / 6 (16.67%)
    2 / 13 (15.38%)
         occurrences all number
    0
    5
    1
    2
    Dyspnoea
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 41 (12.20%)
    2 / 6 (33.33%)
    1 / 13 (7.69%)
         occurrences all number
    2
    6
    2
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Haemoptysis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Pneumonitis
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    1
    2
    Pulmonary embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 41 (9.76%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    0
    1
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    5
    3
    0
    Insomnia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    0
    1
    Irritability
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Mood altered
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    13 / 41 (31.71%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
         occurrences all number
    3
    30
    1
    4
    Amylase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    3
    5
    0
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    9 / 41 (21.95%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    13
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    8 / 41 (19.51%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    12
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    2
    Blood calcium increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Blood cholesterol increased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    3 / 6 (50.00%)
    13 / 41 (31.71%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    5
    28
    13
    16
    Blood pressure increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    0
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    0
    2
    Body temperature increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    7 / 41 (17.07%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    15
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 41 (9.76%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    1 / 6 (16.67%)
    2 / 13 (15.38%)
         occurrences all number
    0
    4
    1
    3
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    3
    0
    6
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 41 (12.20%)
    0 / 6 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    14
    0
    12
    Platelet count decreased
         subjects affected / exposed
    4 / 6 (66.67%)
    9 / 41 (21.95%)
    1 / 6 (16.67%)
    4 / 13 (30.77%)
         occurrences all number
    15
    18
    1
    8
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Troponin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    7 / 41 (17.07%)
    2 / 6 (33.33%)
    2 / 13 (15.38%)
         occurrences all number
    0
    7
    2
    2
    White blood cell count decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    6 / 41 (14.63%)
    0 / 6 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    12
    30
    0
    10
    Injury, poisoning and procedural complications
    Back injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    0
    1
    Fall
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Femur fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Infusion related reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Pelvic fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Procedural pneumothorax
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract stoma complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Intracardiac thrombus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Ataxia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Cognitive disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 41 (14.63%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    6
    0
    0
    Dizziness postural
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 6 (16.67%)
    5 / 41 (12.20%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    6
    0
    2
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 41 (4.88%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
         occurrences all number
    2
    3
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    0
    1
    Neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Presyncope
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    0
    1
    Sciatica
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    1
    Taste disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    4
    Neuropathy peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Neutropenia
         subjects affected / exposed
    3 / 6 (50.00%)
    23 / 41 (56.10%)
    4 / 6 (66.67%)
    8 / 13 (61.54%)
         occurrences all number
    14
    74
    12
    32
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    20 / 41 (48.78%)
    4 / 6 (66.67%)
    4 / 13 (30.77%)
         occurrences all number
    0
    56
    8
    12
    Thrombocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Anaemia
         subjects affected / exposed
    3 / 6 (50.00%)
    26 / 41 (63.41%)
    1 / 6 (16.67%)
    10 / 13 (76.92%)
         occurrences all number
    10
    94
    1
    26
    Haemolytic anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 41 (14.63%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    14
    0
    7
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 41 (9.76%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    12
    0
    2
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dry eye
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    2
    10
    0
    6
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    3
    0
    5
    Dry mouth
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    0
    2
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    8 / 41 (19.51%)
    3 / 6 (50.00%)
    4 / 13 (30.77%)
         occurrences all number
    4
    12
    6
    11
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    17 / 41 (41.46%)
    1 / 6 (16.67%)
    4 / 13 (30.77%)
         occurrences all number
    0
    26
    1
    8
    Ascites
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Abdominal rigidity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    6
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 41 (12.20%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Melaena
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Glossodynia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    3 / 6 (50.00%)
    19 / 41 (46.34%)
    4 / 6 (66.67%)
    9 / 13 (69.23%)
         occurrences all number
    10
    56
    4
    27
    Oral disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    14 / 41 (34.15%)
    1 / 6 (16.67%)
    5 / 13 (38.46%)
         occurrences all number
    2
    22
    4
    8
    Stomatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Pancreatic failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    4
    Dermal cyst
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 41 (7.32%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 41 (9.76%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    4
    4
    0
    1
    Psoriasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
    5 / 41 (12.20%)
    1 / 6 (16.67%)
    3 / 13 (23.08%)
         occurrences all number
    1
    7
    1
    5
    Rash pruritic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    3
    0
    4
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    0
    2
    Chronic kidney disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    2
    Genitourinary symptom
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Polyuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urine odour abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Renal impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypothyroidism
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
         occurrences all number
    4
    0
    1
    1
    Hyperthyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    2 / 6 (33.33%)
    9 / 41 (21.95%)
    1 / 6 (16.67%)
    2 / 13 (15.38%)
         occurrences all number
    2
    14
    2
    4
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 41 (17.07%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    8
    0
    0
    Chondropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    2
    Clubbing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Myositis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Osteolysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Spinal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Arthritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Localised infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Mucosal infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Cellulitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sepsis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    4
    2
    0
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 6 (33.33%)
    6 / 41 (14.63%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
         occurrences all number
    2
    9
    1
    2
    Urosepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 6 (33.33%)
    11 / 41 (26.83%)
    1 / 6 (16.67%)
    3 / 13 (23.08%)
         occurrences all number
    2
    19
    1
    3
    Hypercalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 41 (7.32%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    3
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    0
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 41 (9.76%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    6
    0
    6
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    1
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    2
    Hypochloraemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 41 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 41 (12.20%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    9
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 41 (9.76%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    5
    0
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 41 (9.76%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
         occurrences all number
    0
    8
    2
    2
    Hypophosphataemia
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 41 (4.88%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    4
    3
    0
    0
    Increased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 41 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 41 (2.44%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2018
    • Introduction of a higher fixed dose of avelumab (based on US FDA feedback). • Summary of Benefit/Risk Assessment was revised to include safety information from clinical trials for the 20 mg/kg every 2 weeks dose of avelumab. • Biomarker Rationale was revised to include information about the use of biopsy data from subjects received the 1200 mg avelumab fixed dose. • Updates regarding dose adjustments following dose delays due to toxicities, should start at the subsequent dose rather than “start of a subsequent cycle”. • Treatment after Initial Evidence of Radiological Disease Progression was updated to clarify that avelumab should be permanently discontinued in case of further disease progression. • A clarification is also added about the timelines of subsequent radiologic imaging. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Guidelines, update was added to clarify that all required scans must be done within 28 days prior to first dose of study treatment instead of prior to enrollment.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated since there was no need for further safety or efficacy data to be collected. The subjects having benefit from the investigational treatments have been moved to a continuation study NCT05059522
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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