Avelumab in Metastatic or Locally Advanced Solid Tumors (JAVELIN Solid Tumor)

DLT: defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0, as any one of following: any Grade (Gr) \>=3toxicity that is possibly/probably/ definitely related to avelumab, except for any of following: Gr 3 infusion-related reaction resolving within 6 hours and controlled with medical management, Transient Gr 3 flu-like symptoms/fever, which is controlled with medical management, Transient Gr 3 fatigue, local reactions, headache, nausea, emesis that resolves to \<= Gr 1, Gr3 diarrhea, Gr 3 skin toxicity, Gr 3 liver function test increase that resolves to \<= Gr1 in \< 7 days after medical management has been initiated, Single laboratory values out of normal range that were unlikely related to study treatment according to investigator, did not have any clinical correlate, and resolved to \<= Gr1 within 7 days with adequate medical management and tumor flare phenomenon defined as local pain, irritation/rash localized at sites of known/suspected tumor.

Time frame: Dose Escalation: Baseline up to Week 3

Population: DLT analysis set included all participants with data used for implementing the dose-escalation schedule. These participants should have received all study drug administrations in the DLT evaluation period, or should have stopped treatment because of DLTs in the DLT evaluation period.

Confirmed BOR was determined according to RECIST 1.1 and as adjudicated by an Independent Endpoint Review Committee (IERC) and defined as best response of any of complete response (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 reference). CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30% reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1 or more new lesions and unequivocal progression of non-target lesions.

Time frame: GC/GEJC, Third Line Efficacy Expansion: Baseline up to Day 871

Population: Full analysis set (FAS) included all participants who have received at least 1 dose of study treatment.

Confirmed BOR was determined according to RECIST 1.1 and as adjudicated by an Independent Endpoint Review Committee (IERC) and defined as best response of any of complete response (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 reference). CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30%reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions.

Time frame: HNSCC Efficacy Expansion: Baseline up to Day 1072

Population: Full analysis set (FAS) included all participants who have received at least 1 dose of study treatment.

Confirmed BOR was determined according to RECIST 1.1 and as adjudicated by an Independent Endpoint Review Committee (IERC) and defined as best response of any of complete response (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 reference). CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30%reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions.

Time frame: Ovarian Cancer Efficacy Expansion: Baseline up to Day 620

Population: Full analysis set (FAS) included all participants who have received at least 1 dose of study treatment.

Confirmed BOR was determined according to RECIST 1.1 and as adjudicated by an Independent Endpoint Review Committee (IERC) and defined as best response of any of complete response (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 reference). CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30% reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1 or more new lesions and unequivocal progression of non-target lesions.

Time frame: Urothelial Carcinoma Efficacy Expansion: Baseline up to Day 931

Population: Full analysis set (FAS) included all participants who have received at least 1 dose of study treatment. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.

Adverse event(AE): any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of study drug, whether or not related to study drug. A serious adverse event(SAE) was an AE that resulted in any of following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent events were events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment 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) version 4.0 toxicity grades, as follows: Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death.

Time frame: Up to Day 2511

Population: Safety analysis set (SAF) included all participants who have received at least 1 dose of study treatment.

AE was defined as any unfavorable and unintended sign (including an abnormal laboratory 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 study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment related AE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator. Severity of Treatment-Related TEAEs were graded using NCI-CTCAE version 4.0 toxicity grades, as follows: Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death.

Time frame: Baseline up to Day 2511

Population: SAF included all participants who have received at least 1 dose of study treatment.

Apparent terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination.

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

Population: Pharmacokinetic (PK) population included all participants who have completed at least 1 infusion of study drug, and who have provided sufficient concentration measurements. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure.

Area under the serum concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLLQ). AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule.

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

Population: Pharmacokinetic (PK) population included all participants who have completed at least 1 infusion of study drug, and who have provided sufficient concentration measurements.

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

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

Population: Pharmacokinetic (PK) population included all participants who have completed at least 1 infusion of study drug, and who have provided sufficient concentration measurements. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure.

Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.

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

Population: Pharmacokinetic (PK) population included all participants who have completed at least 1 infusion of study drug, and who have provided sufficient concentration measurements.

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.

Time frame: Dose Escalation: Baseline up to Day 1023

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure.

irBOR defined as best response of any of immune related complete response (irCR), immune related partial response (irPR), immune related stable disease (irSD) and immune related progressive disease (irPD) recorded from baseline until immune related disease progression and determined according to modified irRC per investigator assessment. 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 equal to \[\>=\] 20%, confirmed by a repeat, consecutive 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.

Time frame: Dose Escalation: Baseline up to Day 1023

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment.

Percentage of PD-L1 receptors occupied by avelumab on human lymphocytes (CD3+ T-cells) was assessed by flow cytometry on peripheral blood mononuclear cell (PBMC) samples. Greater than or equal to \[\>=\] 85 percent \[%\] of cell viability was required for reliable receptor occupancy assessment.

Time frame: Pre-infusion on Day 1; 48 hours after infusion on Day 3; Pre-infusion on Days 15, 43, and 85

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure and number analyzed signifies those who were evaluable for this outcome measure at specified time points.

Tmax is time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.

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

Population: Pharmacokinetic (PK) population included all participants who have completed at least 1 infusion of study drug, and who have provided sufficient concentration measurements.

BOR was determined according to RECIST v1.1 and as per investigator assessment. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD =Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with best overall response in each category (CR, PR, SD, PD) was reported.

Time frame: Dose Escalation: Baseline up to Day 2511

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment.

Duration of response according to modified irRC, per investigator assessment was calculated for each participant with a confirmed response (immune-related complete response \[irCR\] or immune-related partial response \[irPR\]) as the time from the first observation of response to the first observation of documented disease progression (or death within 12 weeks of the last tumor assessment). 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). Results were calculated based on Kaplan-Meier estimates.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: FAS included all participants who have received at least 1 dose of study treatment. Data for this outcome measure is reported for the participants with Complete or Partial response.

Duration of response according to RECIST 1.1, per investigator assessment 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 documented disease progression (or death within 12 weeks of the last tumor assessment). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Results were calculated based on Kaplan-Meier estimates.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: FAS included all participants who have received at least 1 dose of study treatment. Data for this outcome measure is reported for the participants with Complete or Partial response.

The irPFS time was defined as the time from first administration of study treatment until first documentation of immune-related progressive disease (irPD) or death when death occurred within 12 weeks of the last tumor assessment or first administration of study treatment (whichever was later). irPD: sum of the longest diameters of target and new measurable lesions increases greater than or equal to \[\>=\] 20%, confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented. The analysis of irPFS will be performed with a Kaplan-Meier method. Data for immune related progression-free survival time has been reported.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: FAS included all participants who have received at least 1 dose of study treatment. Here Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.

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.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure.

BOR was determined according to RECIST v1.1 and as per investigator assessment. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD = Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with best overall response in each category (CR, PR, SD, PD) was reported.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: Full analysis set (FAS) included all participants who have received at least 1 dose of study treatment. Here Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.

irBOR defined as best response of any of immune related complete response (irCR), immune related partial response (irPR), immune related stable disease (irSD) and immune related progressive disease (irPD) recorded from baseline until immune related disease progression and determined according to modified irRC per investigator assessment. 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 equal to \[\>=\] 20%, confirmed by a repeat, consecutive 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.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: Full analysis set (FAS) included all participants who have received at least 1 dose of study treatment. Here Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.

PD-L1 assessment was performed using immunohistochemistry. PD-L1 expression status was classified as positive or negative based on the following cut-offs: For tumor cells: Participants were considered PD-L1 expression positive (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 tertiary 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'.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment. Here number analyzed signifies those participants who were evaluable for this outcome measure at specified category.

Overall survival time was measured as time in months first administration of trial treatment to death. The analysis of OS time was performed with a Kaplan-Meier method.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: FAS included all participants who have received at least 1 dose of study treatment. Here Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.

The PFS time (based on investigator assessments), according to the RECIST 1.1, was defined as the time from first administration of study treatment until first documentation of progressive disease (PD) or death when death occurred within 12 weeks of the last tumor assessment or first administration of study treatment (whichever was later). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline 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.

Time frame: Dose Expansion: Baseline up to Day 2023

Population: FAS included all participants who have received at least 1 dose of study treatment. Here Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.

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 response of any of complete response (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 reference). CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30% reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions. Number of participants with BOR in each category (CR, PR, SD, PD) were reported.

Time frame: Secondary Urothelial Carcinoma Dose Expansion: Baseline up to Day 931

Population: FAS included all participants who have received at least 1 dose of study treatment. This outcome measure was planned to be analyzed in Secondary Urothelial Carcinoma Cohort only.

Serum Ctrough concentration of Avelumab is reported.

Time frame: At Day 15, 29, 43, 57, 71, 85, 99, 127 and 169

Population: Pharmacokinetic analysis set was used. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure and Number analyzed signifies those who were evaluable at specified time points. Data for primary expansion cohort: GC/GEJC Progressed and primary expansion cohort: GC/GEJC Non progressed arms was reported as a single arm primary expansion cohort: GC/GEJC Progressed/Non progressed for this outcome measure as per planned analysis.

Serum concentration at end of infusion (CEOI) of Avelumab is reported.

Time frame: At Day 1, 15, 29, 43, 85, 127 and 169

Population: Pharmacokinetic analysis set was used. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure and Number analyzed signifies those who were evaluable at specified time points. Data was reported for those arms for which end of infusion sample were collected as per planned analysis.

Duration of response according to modified irRC, per investigator assessment was calculated for each participant with a confirmed response (immune-related complete response \[irCR\] or immune-related partial response \[irPR\]) as the time from the first observation of response to the first observation of documented disease progression (or death within 12 weeks of the last tumor assessment). 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). Results were calculated based on Kaplan-Meier estimates.

Time frame: Efficacy Expansion: Baseline up to Day 1072

Population: FAS included all participants who have received at least 1 dose of study treatment. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure. This outcome measure was planned to be analyzed in Efficacy expansion cohorts only.

The PFS time (based on IERC), according to the RECIST 1.1, was defined as the time from first administration of study treatment until first documentation of progressive disease (PD) or death when death occurred within 12 weeks of the last tumor assessment or first administration of study treatment (whichever was later). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline 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.

Time frame: Efficacy Expansion: Baseline up to Day 1072

Population: FAS included all participants who have received at least 1 dose of study treatment. Here Overall number of participants analyzed signifies those who were evaluable for this outcome measure. This outcome measure was planned to be analyzed in Efficacy expansion cohorts only.

The response criteria 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 assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters; SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage 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 progression of non-target lesions. Number of participants with unconfirmed response at week 13 according to response evaluation criteria in solid tumors (RECIST) version 1.1 were reported.

Time frame: Week 13

Population: Efficacy analysis set included all participants who have received at least 1 dose of study treatment and have measurable disease at baseline according to investigator assessment. This outcome measure was planned to be analyzed in Primary expansion cohorts only