secondary Outcome Measures

  1. Dose Escalation and Expansion Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and TEAEs as Per Severity [ Time Frame: Up to Day 2511 ] adverse event ( AE ) : any unfavorable and unintended sign ( including an abnormal lab finding ), symptom, or disease temporally associated with function of study drug, whether or not related to study drug. A unplayful adverse event ( SAE ) was an AE that resulted in any of following outcomes : death ; life threaten ; persistent/significant disability/incapacity ; initial or drawn-out inpatient hospitalization ; congenital anomaly/birth defect or was differently considered medically authoritative. Treatment-emergent events were events between first dose of analyze drug that were absent ahead treatment or that worsened relative to pre-treatment department of state up to 30 days after last administration.TEAEs included both Serious TEAEs and non-serious TEAEs. Severity of TEAEs were graded using National Cancer Institute-Common Terminology Criteria for Adverse Events ( NCI-CTCAE ) adaptation 4.0 perniciousness grades, as follows : Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= dangerous and Grade 5= Death .
  2. Dose Escalation and Expansion Cohorts: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs as Per Severity [ Time Frame: Baseline up to Day 2511 ] AE was defined as any unfavorable and unintended sign ( including an abnormal lab finding ), symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. Treatment-emergent events were the events between first dose of sketch drug that were absent ahead treatment or that worsened proportional to pre-treatment express up to 30 days after last government. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment related AE was defined as having a “ possible ” or “ Related ” kinship to study discussion, as assessed by the Investigator. Severity of Treatment-Related TEAEs were graded using NCI-CTCAE interpretation 4.0 toxicity grades, as follows : Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= dangerous and Grade 5= Death .
  3. Dose Escalation Cohort (Excluding Once Weekly Avelumab 10 mg/kg Cohort): Area Under Serum Concentration-Time Curve From the Time of Dosing to the Time of the Last Observation (AUC0-t) of Avelumab [ Time Frame: Pre-infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48 hours after end of infusion ] Area under the serum assiduity versus fourth dimension bend from time zero to the last sampling time thymine at which the concentration is at or above the lower limit of quantification ( LLLQ ). AUC ( 0-t ) was calculated according to the interracial log-linear trapezoidal govern.

  4. Dose Escalation Cohort (Excluding Once Weekly Avelumab 10 mg/kg Cohort): Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Avelumab [ Time Frame: Pre-infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48 hours after end of infusion ] The AUC ( 0-inf ) was estimated by determining the total area under the curvature of the concentration versus time crook extrapolated to eternity .
  5. Dose Escalation Cohort (Excluding Once Weekly Avelumab 10 mg/kg Cohort): Maximum Observed Serum Concentration (Cmax) of Avelumab [ Time Frame: Pre-infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48 hours after end of infusion ] Cmax is the maximal observe serum concentration obtained directly from the concentration versus prison term crook .
  6. Dose Escalation Cohort (Excluding Once Weekly Avelumab 10 mg/kg Cohort): Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab [ Time Frame: Pre-infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48 hours after end of infusion ] Tmax is time to reach utmost observe serum concentration obtained directly from the assiduity versus time curvature .
  7. Dose Escalation Cohort (Excluding Once Weekly Avelumab 10 mg/kg Cohort): Apparent Terminal Half-Life (t1/2) of Avelumab [ Time Frame: Pre-infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48 hours after end of infusion ] apparent terminal half life was defined as the time required for the serum assiduity of drug to decrease 50 percentage in the final stagecoach of its elimination .
  8. Dose Expansion Phase: Serum Concentration at End of Infusion (CEOI) of Avelumab [ Time Frame: At Day 1, 15, 29, 43, 85, 127 and 169 ] Serum concentration at goal of infusion ( CEOI ) of Avelumab is reported .
  9. Dose Expansion Phase: Minimum Serum Post-dose (Ctrough) Concentration of Avelumab [ Time Frame: At Day 15, 29, 43, 57, 71, 85, 99, 127 and 169 ] Serum Ctrough concentration of Avelumab is reported .
  10. Dose Escalation Cohort (Excluding Once Weekly Avelumab 10 mg/kg Cohort): Number of Participants With Immune Related Best Overall Response (irBOR) According to Modified Immune-Related Response Criteria (irRC) [ Time Frame: Dose Escalation: Baseline up to Day 1023 ] irBOR defined as best reaction of any of immune associate complete answer ( irCR ), immune related partial reaction ( irPR ), immune related stable disease ( irSD ) and immune related progressive disease ( irPD ) recorded from baseline until immune relate disease progression and determined according to modified irRC per investigator judgment. irCR : complete disappearance of all tumor lesions ( both index and non-index lesions with no new measurable/unmeasurable lesions ). irPR : At least 30 % reduction from baseline in the sum of the longest diameter ( SLD ) of all lesions ). irSD : SLD of target and new measurable lesions neither irCR, irPR, or irPD. irPD : SLD of target and new measurable lesions increases greater than or peer to [ > = ] 20 %, confirmed by a recur, back-to-back observations at least 4 weeks from the date first documented. Number of participants with immune-related best overall response in each category ( irCR, irPR, irSD, irPD ) was reported .
  11. Dose Expansion Cohort: Number of Participants With Immune Related Best Overall Response (irBOR) According to Modified Immune-Related Response Criteria (irRC) [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] irBOR defined as best response of any of immune relate complete response ( irCR ), immune related fond reaction ( irPR ), immune related stable disease ( irSD ) and immune relate liberal disease ( irPD ) recorded from service line until immune relate disease progression and determined according to modified irRC per research worker appraisal. irCR : complete disappearance of all tumor lesions ( both index and non-index lesions with no raw measurable/unmeasurable lesions ). irPR : At least 30 % decrease from baseline in the sum of the longest diameter ( SLD ) of all lesions ). irSD : SLD of target and newly measurable lesions neither irCR, irPR, or irPD. irPD : SLD of aim and new measurable lesions increases greater than or equal to [ > = ] 20 %, confirmed by a repeat, straight observations at least 4 weeks from the date beginning documented. Number of participants with immune-related best overall response in each category ( irCR, irPR, irSD, irPD ) was reported .
  12. Dose Escalation Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Dose Escalation: Baseline up to Day 2511 ] BOR was determined according to RECIST v1.1 and as per detective assessment. BOR is defined as the best reply of any of complete response ( CR ), partial derivative response ( PR ), stable disease ( SD ) and liberal disease ( PD ) recorded from date of randomization until disease progress or recurrence ( taking the smallest measurement recorded since depart of treatment as reference point ). chromium : disappearance of all attest of target and non-target lesions. public relations : At least 30 percentage ( % ) decrease from baseline in the sum of the longest diameter ( SLD ) of all lesions. SD =Neither sufficient increase to qualify for PD nor sufficient shrinking to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as character the smallest SLD recorded from service line or appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with best overall response in each class ( CR, PR, SD, PD ) was reported .
  13. Dose Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] BOR was determined according to RECIST v1.1 and as per research worker assessment. BOR is defined as the best reception of any of arrant response ( CR ), fond response ( PR ), stable disease ( SD ) and progressive disease ( PD ) recorded from date of randomization until disease progress or recurrence ( taking the smallest measurement recorded since start of treatment as address ). chromium : disappearance of all evidence of target and non-target lesions. praseodymium : At least 30 percentage ( % ) reduction from baseline in the union of the longest diameter ( SLD ) of all lesions. SD = Neither sufficient addition to qualify for PD nor sufficient shrinking to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference book the smallest SLD recorded from baseline or appearance of 1 or more new lesions and definitive progression of non-target lesions. Number of participants with best overall response in each category ( CR, PR, SD, PD ) was reported.

  14. Dose Expansion Cohort (Secondary Urothelial Carcinoma Cohort): Number of Participants With Confirmed Best Overall Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 as Adjudicated by an Independent Endpoint Review Committee [ Time Frame: Secondary Urothelial Carcinoma Dose Expansion: Baseline up to Day 931 ] Confirmed Best overall Response ( BOR ) was determined according to Response Evaluation Criteria in Solid Tumors ( RECIST ) v1.1and as adjudicated by an Independent Endpoint Review Committee ( IERC ) is defined as best reception of any of complete reply ( CR ), partial response ( PR ), stable disease ( SD ) and progressive disease ( PD ) recorded from date of randomization until disease progression/recurrence ( taking smallest measurement recorded since start of treatment as citation ). chromium : disappearance of all evidence of target/non-target lesions. public relations : At least 30 % reduction from baseline in sum of longest diameter ( SLD ) of all lesions. south dakota : Neither sufficient increase to qualify for PD nor sufficient shrinking to qualify for PR. palladium : at least a 20 % increase in SLD, taking as mention smallest SLD recorded from baseline/appearance of 1or more modern lesions and unequivocal progression of non-target lesions. Number of participants with BOR in each category ( CR, PR, SD, PD ) were reported .
  15. Dose Expansion Cohort: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] The PFS time ( based on research worker assessments ), according to the RECIST 1.1, was defined as the time from first base government of study treatment until first software documentation of progressive disease ( PD ) or end when death occurred within 12 weeks of the last tumor assessment or inaugural presidency of study treatment ( whichever was late ). PD was defined as at least a 20 % increase in the union of longest diameter ( SLD ), taking as reference the smallest SLD recorded from service line or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. The analysis of PFS was performed with a Kaplan-Meier method .
  16. Dose Expansion Cohort: Immune Related Progression-Free Survival (irPFS) Time According to Modified Immune-Related Response Criteria (irRC) [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] The irPFS time was defined as the time from first administration of study treatment until beginning documentation of immune-related progressive disease ( irPD ) or death when death occurred within 12 weeks of the end tumor judgment or first government of study treatment ( whichever was later ). irPD : kernel of the longest diameters of target and raw measurable lesions increases greater than or equal to [ > = ] 20 %, confirmed by a repeat, back-to-back observations at least 4 weeks from the date first documented. The analysis of irPFS will be performed with a Kaplan-Meier method acting. Data for immune relate progression-free survival time has been reported .
  17. Dose Expansion Cohort: Overall Survival (OS) Time [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] overall survival time was measured as time in months inaugural government of test discussion to death. The analysis of OS clock time was performed with a Kaplan-Meier method acting .
  18. Dose Escalation Cohort (Excluding Once Weekly Avelumab 10 mg/kg Cohort): Programmed Death Ligand 1 (PD-L1) Receptor Occupancy [ Time Frame: Pre-infusion on Day 1; 48 hours after infusion on Day 3; Pre-infusion on Days 15, 43, and 85 ] share of PD-L1 receptors occupied by avelumab on human lymphocytes ( CD3+ T-cells ) was assessed by stream cytometry on peripheral rake mononuclear cell ( PBMC ) samples. Greater than or equal to [ > = ] 85 percentage [ % ] of cellular telephone viability was required for dependable receptor occupancy assessment .
  19. Dose Expansion Cohort: Number of Participants With Positive Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] PD-L1 assessment was performed using immunohistochemistry. PD-L1 expression condition was classified as positivist or negative based on the follow cut-offs : For tumor cells : Participants were considered PD-L1 saying incontrovertible ( negative ) : – if at least ( less than ) 5 % of the tumor cells show PD-L1 membrane staining > = 1+, respectively. This was used as the primary cut-off ; – if at least ( less than ) 25 % of the tumor cells show PD-L1 membrane staining > =2+, respectively. This was considered as secondary cut-off ; – if at least ( less than ) 1 % of the tumor cells show PD-L1 membrane staining > =1+, respectively. This was used as the third cut-off ; – if at least ( less than ) 50 % of the tumor cells show PD-L1 membrane staining > =1+, respectively. This was used as the ’50 % cut-off ‘ ; – if at least ( less than ) 80 % of the tumor cells show PD-L1 membrane staining ≥1+, respectively. This was used as the ’80 % cut-off ‘ .
  20. Primary Expansion Cohorts: Number of Participants With Unconfirmed Response at Week 13 According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Week 13 ] The reply criterion evaluation was carried out according to Response Evaluation Criteria in Solid Tumors ( RECIST ) 1.1. CR and PR did not need to be confirmed by a subsequent tumor judgment due to blind central assessment. chromium : disappearance of all prey lesions since baseline ; PR : At least a 30 % decrease in the sum of the diameters of prey lesions, taking as address the baseline sum of diameters ; SD : Neither sufficient increase to qualify for PD nor sufficient shoplifting to qualify for PR and PD : at least a 20 % increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progress of non-target lesions. Number of participants with unconfirmed answer at week 13 according to response evaluation criteria in solid tumors ( RECIST ) version 1.1 were reported .
  21. Dose Expansion Cohort: Duration of Response According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Per Investigator Assessment [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] duration of response according to RECIST 1.1, per research worker appraisal was calculated for each participant with a confirmed response ( complete response [ CR ] or partial response [ PR ] ) as the time from the first observation of response to the first observation of document disease progress ( or death within 12 weeks of the last tumor appraisal ). chromium : fade of all evidence of target and non-target lesions. puerto rico : At least 30 percentage ( % ) decrease from baseline in the total of the longest diameter ( SLD ) of all lesions. Results were calculated based on Kaplan-Meier estimates .
  22. Dose Expansion Cohort: Duration of Response According to Modified Immune-Related Response Criteria (irRC) Per Investigator Assessment [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] duration of reply according to modified irRC, per investigator assessment was calculated for each participant with a confirmed response ( immune-related complete reply [ irCR ] or immune-related overtone response [ irPR ] ) as the clock from the foremost observation of answer to the first notice of document disease progress ( or death within 12 weeks of the last tumor judgment ). irCR : arrant fade of all tumor lesions ( both index and non-index lesions with no new measurable/unmeasurable lesions ). irPR : At least 30 % reduction from service line in the total of the longest diameter ( SLD ) of all lesions ). Results were calculated based on Kaplan-Meier estimates .
  23. Efficacy Expansion Cohorts: Duration of Response According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Per Independent Endpoint Review Committee (IERC) [ Time Frame: Efficacy Expansion: Baseline up to Day 1072 ] duration of response according to modified irRC, per investigator assessment was calculated for each participant with a confirmed reception ( immune-related dispatch response [ irCR ] or immune-related overtone reaction [ irPR ] ) as the time from the first observation of reception to the beginning observation of document disease progression ( or end within 12 weeks of the last tumor judgment ). irCR : complete disappearance of all tumor lesions ( both index and non-index lesions with no new measurable/unmeasurable lesions ). irPR : At least 30 % reduction from baseline in the total of the longest diameter ( SLD ) of all lesions ). Results were calculated based on Kaplan-Meier estimates.

  24. Efficacy Expansion Cohorts: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Per Independent Endpoint Review Committee (IERC) [ Time Frame: Efficacy Expansion: Baseline up to Day 1072 ] The PFS clock time ( based on IERC ), according to the RECIST 1.1, was defined as the prison term from first administration of study treatment until first software documentation of progressive disease ( PD ) or end when death occurred within 12 weeks of the last tumor assessment or first administration of report treatment ( whichever was later ). PD was defined as at least a 20 % increase in the summarize of longest diameter ( SLD ), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and definitive progress of non-target lesions. The psychoanalysis of PFS was performed with a Kaplan-Meier method acting .
  25. Dose Escalation Cohort (Excluding Once Weekly Avelumab 10 mg/kg Cohort): Number of Participants With at Least 1 Positive Anti Drug Antibodies (ADA) [ Time Frame: Dose Escalation: Baseline up to Day 1023 ] serum samples were analyzed by a validate electrochemiluminescence immunoassay to detect the presence of antidrug antibodies ( ADA ). Number of participants with ADA positive results for Avelumab were reported .
  26. Dose Expansion Cohort: Number of Participants With Atleast 1 Positive Anti Drug Antibodies (ADA) Assay [ Time Frame: Dose Expansion: Baseline up to Day 2023 ] serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of antidrug antibodies ( ADA ). Number of participants with ADA positive results for Avelumab were reported .

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