Trial Outcomes & Findings for Avelumab in Metastatic or Locally Advanced Solid Tumors (JAVELIN Solid Tumor JPN) (NCT NCT01943461)

NCT ID: NCT01943461

Last Updated: 2020-09-30

Results Overview

DLT: any Grade greater than or equal to (\>=) 3 or Adverse Events (AE) according to National Cancer Institute Common Toxicity Criteria for AE Version 4.03 (NCI-CTCAE v4.03); observed during first 3 weeks of dose-escalation part and as being related to Avelumab by Investigator/Sponsor. Following events were not considered as DLT: Grade 3 infusion-related reaction resolving to (\<=) Grade 1 within 6 hours and controlled with medical management; Transient (\<=6 hours) Grade 3 flulike symptoms/fever controlled with medical management and resolved to \<= Grade 1;Transient (\<=24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolved to \<=Grade1 with/without medical management, Grade 3 diarrhea, Grade 3 skin toxicity, Grade3 out-of-range laboratory values without any clinical correlate that resolves to \<= Grade 1 or Baseline in \< 7 days after medical management; Tumor flare phenomenon defined as local pain, irritation, rash localized at sites of known or suspected tumor.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

57 participants

Primary outcome timeframe

Baseline up to 3 weeks

Results posted on

2020-09-30

Participant Flow

Participant milestones

Participant milestones
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Expansion Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Overall Study STARTED	5	6	6	40
Overall Study COMPLETED	5	6	6	40
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Expansion Cohort: Avelumab 10 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Total n=57 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	22 Participants n=4 Participants	32 Participants n=21 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	18 Participants n=4 Participants	25 Participants n=21 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	11 Participants n=4 Participants	18 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	29 Participants n=4 Participants	39 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	6 Participants n=7 Participants	6 Participants n=5 Participants	40 Participants n=4 Participants	57 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	5 Participants n=5 Participants	6 Participants n=7 Participants	6 Participants n=5 Participants	40 Participants n=4 Participants	57 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline up to 3 weeks

Population: DLT analysis set included all participants with data used for implementing the dose-escalation schedule.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=3 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs)	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

Population: Pharmacokinetic (PK) analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.

Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated by linear trapezoidal summation.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the Time of the Last Observation (AUC0-t) of Avelumab	5120 hourmicrogram per milliliter(hrmcg/mL) Geometric Coefficient of Variation 32.5	20100 hourmicrogram per milliliter(hrmcg/mL) Geometric Coefficient of Variation 40.0	46800 hourmicrogram per milliliter(hrmcg/mL) Geometric Coefficient of Variation 23.1

SECONDARY outcome

Timeframe: Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

Population: PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.

Area under the curve from the time of dosing extrapolated to infinity was calculated by the linear trapezoidal summation and extrapolated to infinity using Clast/Lambda z after the first intravenous infusion. "Clast" was the last quantifiable concentration and "Lambda z" was terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab	6040 hr*mcg/mL Geometric Coefficient of Variation 27.5	24000 hr*mcg/mL Geometric Coefficient of Variation 47.4	53700 hr*mcg/mL Geometric Coefficient of Variation 24.3

SECONDARY outcome

Timeframe: Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

Population: PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.

Cmax was obtained directly from the concentration versus time curve.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Maximum Observed Serum Concentration (Cmax) of Avelumab	64 mcg/mL Geometric Coefficient of Variation 22.2	179 mcg/mL Geometric Coefficient of Variation 19.6	459 mcg/mL Geometric Coefficient of Variation 13.6

SECONDARY outcome

Timeframe: Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

Population: PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.

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

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab	1.683 hour Interval 0.97 to 2.07	1.533 hour Interval 1.0 to 3.08	1.683 hour Interval 1.0 to 4.92

SECONDARY outcome

Timeframe: Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

Population: PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.

t1/2 was the time measured for the concentration to decrease by one half, determined as 0.693/Lambda z, here Lambda z was the terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Terminal Half-Life (t1/2) of Avelumab	94 hour Geometric Coefficient of Variation 31.7	122 hour Geometric Coefficient of Variation 33.1	112 hour Geometric Coefficient of Variation 11.6

SECONDARY outcome

Timeframe: Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

Population: PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration. The summarized data was not available for these arms therefore individual data was presented. Here, "Number Analyzed" signifies specific participant evaluated in respective arm.

Terminal elimination rate constant was determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. Participant wise data was reported for this outcome measure.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab Participant 6	—	0.00662 per hour	0.00562 per hour
Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab Participant 1	0.00667 per hour	0.0103 per hour	0.00568 per hour
Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab Participant 2	0.0114 per hour	0.00456 per hour	0.00750 per hour
Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab Participant 3	0.00868 per hour	0.00456 per hour	0.00604 per hour
Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab Participant 4	0.00663 per hour	0.00508 per hour	0.00568 per hour
Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab Participant 5	0.00501 per hour	0.00476 per hour	0.00666 per hour

SECONDARY outcome

Timeframe: Pre-infusion on Day 1; 4 and 48 hours after infusion on Day 3; Pre-infusion on Days 15, 29, 43, and 85

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+ 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.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Programmed Death Ligand 1 (PD-L1) Receptor Occupancy	NA percentage of receptors Standard Deviation NA Data could not analyzed because the analysis criterion was not met as all the PBMCs collected in the study had viability less than 85%.	NA percentage of receptors Standard Deviation NA Data could not analyzed because the analysis criterion was not met as all the PBMCs collected in the study had viability less than 85%.	NA percentage of receptors Standard Deviation NA Data could not analyzed because the analysis criterion was not met as all the PBMCs collected in the study had viability less than 85%.

SECONDARY outcome

Timeframe: Day 1 (Pre-infusion), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion)

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

Outcome measures

SECONDARY outcome

Timeframe: Baseline (Day 1 [Pre-infusion]), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion)

Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline).

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IFN-gamma: Day 15: Pre-Infusion	0.396 log fold change Standard Deviation 1.958	0.779 log fold change Standard Deviation 0.654	0.867 log fold change Standard Deviation 0.690
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-2: Day 43: Pre- Infusion	0.296 log fold change Standard Deviation 1.375	0.211 log fold change Standard Deviation 0.754	-0.193 log fold change Standard Deviation 0.243
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-6: Day 3: 48 hours After Infusion	0.153 log fold change Standard Deviation 0.897	0.660 log fold change Standard Deviation 0.816	1.196 log fold change Standard Deviation 1.614
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels Rantes: Day 15: Pre-Infusion	0.997 log fold change Standard Deviation 1.992	0.582 log fold change Standard Deviation 0.649	-0.025 log fold change Standard Deviation 0.360
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-8: Day 43: Pre-Infusion	0.773 log fold change Standard Deviation 1.073	0.241 log fold change Standard Deviation 0.388	0.033 log fold change Standard Deviation 0.367
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-8: Day 45: 48 hours After Infusion	0.858 log fold change Standard Deviation 0.885	0.451 log fold change Standard Deviation 0.330	0.283 log fold change Standard Deviation 0.499
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-8: Day 50: 168 hours After Infusion	0.924 log fold change Standard Deviation 1.088	0.441 log fold change Standard Deviation 0.284	0.081 log fold change Standard Deviation 0.798
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IFN-gamma: Day 3: 48 hours After Infusion	0.903 log fold change Standard Deviation 1.258	1.038 log fold change Standard Deviation 0.689	1.096 log fold change Standard Deviation 0.975
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IFN-gamma: Day 8: 168 hours After Infusion	0.280 log fold change Standard Deviation 1.365	0.722 log fold change Standard Deviation 0.945	0.600 log fold change Standard Deviation 0.243
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IFN-gamma: Day 43: Pre-Infusion	0.071 log fold change Standard Deviation 0.800	1.335 log fold change Standard Deviation 1.735	0.631 log fold change Standard Deviation 0.593
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IFN-gamma: Day 45: 48 hours After Infusion	0.768 log fold change Standard Deviation 1.925	1.617 log fold change Standard Deviation 2.037	1.215 log fold change Standard Deviation 1.576
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IFN-gamma: Day 50: 168 hours After Infusion	0.234 log fold change Standard Deviation 1.385	1.045 log fold change Standard Deviation 2.010	0.273 log fold change Standard Deviation 0.249
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-12P70: Day 3: 48 hours After Infusion	0.000 log fold change Standard Deviation 0.000	-0.030 log fold change Standard Deviation 0.750	0.272 log fold change Standard Deviation 0.666
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-12P70: Day 8: 168 hours After Infusion	0.000 log fold change Standard Deviation 0.000	-0.203 log fold change Standard Deviation 0.504	0.178 log fold change Standard Deviation 0.437
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-12P70: Day 15: Pre- Infusion	0.000 log fold change Standard Deviation 0.000	-0.174 log fold change Standard Deviation 0.524	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-12P70: Day 43: Pre- Infusion	0.000 log fold change Standard Deviation 0.000	0.239 log fold change Standard Deviation 0.990	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-12P70: Day 45: 48 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.087 log fold change Standard Deviation 0.950	0.300 log fold change Standard Deviation 0.601
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-12P70: Day 50: 168 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.151 log fold change Standard Deviation 1.033	0.643 log fold change Standard Deviation 0.770
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-10: Day 3: 48 hours After Infusion	1.103 log fold change Standard Deviation 0.888	0.743 log fold change Standard Deviation 0.371	0.942 log fold change Standard Deviation 0.199
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-10: Day 8: 168 hours After Infusion	0.624 log fold change Standard Deviation 1.081	0.704 log fold change Standard Deviation 0.962	1.088 log fold change Standard Deviation 0.348
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-10: Day 15: Pre- Infusion	0.972 log fold change Standard Deviation 0.691	0.720 log fold change Standard Deviation 0.978	0.942 log fold change Standard Deviation 0.444
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-10: Day 43: Pre-Infusion	0.919 log fold change Standard Deviation 0.736	1.072 log fold change Standard Deviation 1.452	1.317 log fold change Standard Deviation 1.238
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-10: Day 45: 48 hours After Infusion	0.976 log fold change Standard Deviation 1.416	1.375 log fold change Standard Deviation 1.767	1.467 log fold change Standard Deviation 1.758
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-10: Day 50:168 hours After Infusion	0.633 log fold change Standard Deviation 1.122	1.041 log fold change Standard Deviation 1.680	0.761 log fold change Standard Deviation 0.713
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-13: Day 3: 48 hours After Infusion	-0.541 log fold change Standard Deviation 0.980	-0.170 log fold change Standard Deviation 0.844	-0.416 log fold change Standard Deviation 1.245
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-13: Day 8: 168 hours After Infusion	0.407 log fold change Standard Deviation 0.896	-0.004 log fold change Standard Deviation 0.245	-0.581 log fold change Standard Deviation 0.490
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-13: Day 15: Pre- Infusion	-0.133 log fold change Standard Deviation 1.191	0.125 log fold change Standard Deviation 0.467	-0.603 log fold change Standard Deviation 0.519
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-13: Day 43: Pre- Infusion	0.353 log fold change Standard Deviation 1.670	-0.044 log fold change Standard Deviation 0.866	0.200 log fold change Standard Deviation 0.391
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-13: Day 45: 48 hours After Infusion	0.769 log fold change Standard Deviation 1.778	-0.327 log fold change Standard Deviation 0.729	-0.660 log fold change Standard Deviation 0.560
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-13: Day 50:168 hours After Infusion 4	0.867 log fold change Standard Deviation 1.796	-0.427 log fold change Standard Deviation 1.082	-0.319 log fold change Standard Deviation 0.615
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-1beta: Day 3: 48 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000	0.275 log fold change Standard Deviation 0.673
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-1beta: Day 8: 168 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.278 log fold change Standard Deviation 0.681	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-1beta: Day 15: Pre- Infusion	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-1beta: Day 43: Pre-Infusion	0.000 log fold change Standard Deviation 0.000	0.303 log fold change Standard Deviation 0.743	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-1beta: Day 45: 48 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.493 log fold change Standard Deviation 1.207	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-1beta: Day 50: 168 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.473 log fold change Standard Deviation 1.158	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-2: Day 3: 48 hours After Infusion	0.108 log fold change Standard Deviation 1.340	0.664 log fold change Standard Deviation 0.749	0.531 log fold change Standard Deviation 0.628
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-2: Day 8: 168 hours After Infusion	-0.118 log fold change Standard Deviation 1.230	0.035 log fold change Standard Deviation 0.906	0.326 log fold change Standard Deviation 0.545
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-2: Day 15: Pre-Infusion	-0.228 log fold change Standard Deviation 1.134	-0.577 log fold change Standard Deviation 1.055	-0.059 log fold change Standard Deviation 0.096
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-2: Day 45: 48 hours After Infusion	0.194 log fold change Standard Deviation 1.675	0.009 log fold change Standard Deviation 0.892	-0.175 log fold change Standard Deviation 0.202
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-2: Day 50: 168 hours After Infusion	0.432 log fold change Standard Deviation 1.547	0.099 log fold change Standard Deviation 0.608	-0.188 log fold change Standard Deviation 0.220
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-4: Day 3: 48 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-4: Day 8: 168 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000	0.248 log fold change Standard Deviation 0.606
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-4: Day 15: Pre-Infusion	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-4: Day 43: Pre- Infusion	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-4: Day 45: 48 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-4: Day 50: 168 hours After Infusion	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000	0.000 log fold change Standard Deviation 0.000
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-6: Day 8: 168 hours After Infusion	0.314 log fold change Standard Deviation 0.421	0.194 log fold change Standard Deviation 0.618	0.498 log fold change Standard Deviation 0.321
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-6: Day 15: Pre- Infusion	0.069 log fold change Standard Deviation 1.455	0.451 log fold change Standard Deviation 1.457	0.474 log fold change Standard Deviation 0.572
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-6: Day 43: Pre- Infusion	0.068 log fold change Standard Deviation 0.949	-0.009 log fold change Standard Deviation 0.980	1.112 log fold change Standard Deviation 0.898
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-6: Day 45: 48 hours After Infusion	0.273 log fold change Standard Deviation 1.187	0.116 log fold change Standard Deviation 0.676	1.158 log fold change Standard Deviation 0.998
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-6: Day 50: 168 hours After Infusion	0.064 log fold change Standard Deviation 0.573	0.279 log fold change Standard Deviation 0.690	1.883 log fold change Standard Deviation 1.287
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels MCP-1: Day 3: 48 hours After Infusion	0.242 log fold change Standard Deviation 0.206	0.213 log fold change Standard Deviation 0.296	0.062 log fold change Standard Deviation 0.234
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels MCP-1: Day 8: 168 hours After Infusion	0.067 log fold change Standard Deviation 0.278	0.110 log fold change Standard Deviation 0.297	0.132 log fold change Standard Deviation 0.202
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels MCP-1: Day 15: Pre- Infusion	-0.010 log fold change Standard Deviation 0.684	0.120 log fold change Standard Deviation 0.141	0.005 log fold change Standard Deviation 0.211
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels MCP-1: Day 43: Pre- Infusion	0.173 log fold change Standard Deviation 0.358	0.055 log fold change Standard Deviation 0.343	-0.232 log fold change Standard Deviation 0.150
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels MCP-1: Day 45: 48 hours After Infusion	0.045 log fold change Standard Deviation 0.209	0.318 log fold change Standard Deviation 0.383	-0.176 log fold change Standard Deviation 0.183
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels MCP-1: Day 50: 168 hours After Infusion	0.144 log fold change Standard Deviation 0.226	0.180 log fold change Standard Deviation 0.394	-0.118 log fold change Standard Deviation 0.420
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels Rantes: Day 3: 48 hours After Infusion	0.198 log fold change Standard Deviation 0.849	0.589 log fold change Standard Deviation 0.927	-0.242 log fold change Standard Deviation 0.383
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels Rantes: Day 8: 168 hours After Infusion	0.289 log fold change Standard Deviation 1.709	0.615 log fold change Standard Deviation 0.866	-0.325 log fold change Standard Deviation 0.625
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels Rantes: Day 43: Pre-Infusion	0.389 log fold change Standard Deviation 1.452	0.450 log fold change Standard Deviation 0.765	-0.079 log fold change Standard Deviation 0.306
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels Rantes: Day 45: 48 hours After Infusion	0.249 log fold change Standard Deviation 1.947	0.353 log fold change Standard Deviation 0.809	-0.257 log fold change Standard Deviation 0.487
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels Rantes: Day 50: 168 hours After Infusion	0.718 log fold change Standard Deviation 1.386	0.656 log fold change Standard Deviation 0.634	0.107 log fold change Standard Deviation 0.326
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels TNF-alpha: Day 3: 48 hours After Infusion	0.589 log fold change Standard Deviation 0.443	0.770 log fold change Standard Deviation 0.314	0.646 log fold change Standard Deviation 0.388
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels TNF-alpha: Day 8: 168 hours After Infusion	0.065 log fold change Standard Deviation 0.378	0.343 log fold change Standard Deviation 0.195	0.262 log fold change Standard Deviation 0.144
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels TNF-alpha: Day 15: Pre-Infusion	0.182 log fold change Standard Deviation 0.805	0.301 log fold change Standard Deviation 0.090	0.292 log fold change Standard Deviation 0.158
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels TNF-alpha: Day 43: Pre-Infusion	0.329 log fold change Standard Deviation 0.253	0.365 log fold change Standard Deviation 0.304	0.216 log fold change Standard Deviation 0.184
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels TNF-alpha: Day 45: 48 hours After Infusion	0.612 log fold change Standard Deviation 0.848	0.527 log fold change Standard Deviation 0.376	0.382 log fold change Standard Deviation 0.422
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels TNF-alpha: Day 50: 168 hours After Infusion	0.400 log fold change Standard Deviation 0.672	0.507 log fold change Standard Deviation 0.378	0.119 log fold change Standard Deviation 0.134
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-8: Day 3: 48 hours After Infusion	0.604 log fold change Standard Deviation 0.553	0.539 log fold change Standard Deviation 0.400	0.554 log fold change Standard Deviation 0.484
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-8: Day 8: 168 hours After Infusion	0.444 log fold change Standard Deviation 0.313	0.393 log fold change Standard Deviation 0.406	0.189 log fold change Standard Deviation 0.145
Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels IL-8: Day 15: Pre- Infusion	0.201 log fold change Standard Deviation 0.560	0.118 log fold change Standard Deviation 0.467	0.256 log fold change Standard Deviation 0.536

SECONDARY outcome

Timeframe: Day 15 up to Day 2205

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

Participants not having positive HAHA prior to treatment with Avelumab and with at least one positive post-baseline result in the HAHA assay were termed as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive. Participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result greater than or equal to \[\>=\] 16 weeks apart or a positive evaluation at the most recent visit. Number of participants with treatment-emergent positive HAHA were reported.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA) Transient positive treatment emergent	0 Participants	0 Participants	0 Participants
Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA) Persistent positive treatment emergent	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Time from first dose of study treatment up to 2205 days

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

An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs Leading To Death	1 Participants	0 Participants	0 Participants
Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs	5 Participants	6 Participants	5 Participants
Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation Serious TEAEs	1 Participants	0 Participants	2 Participants
Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs Leading To Discontinuation	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Within 6 hours before and the end of the 1-hour infusion (Day 1) and 336 hours after end of infusion

Population: PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

AUC0-336hour was defined as area under the serum concentration-time curve from the time of dosing to the end of dose interval (336 hr). It was calculated by linear trapezoidal summation.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=37 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the End of Dose Interval (AUC0-336hour [hr]) of Avelumab	14.525 mcg/mL Standard Deviation 6.3064	—	—

SECONDARY outcome

Timeframe: Within 6 hours before the 1-hour infusion on Day 15, Day 29, Day 43, Day 85, Day 127 and Day 169.

Population: PK analysis set: all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration. "Overall Number of Participants Analyzed" = participants evaluable for this outcome measure and "Number analyzed" = participants who were evaluable at the specified time points for the given category.

Ctrough was defined as the trough or minimum serum concentration.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=37 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab Day 15	14.525 mcg/mL Standard Deviation 6.3064	—	—
Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab Day 29	17.366 mcg/mL Standard Deviation 9.2981	—	—
Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab Day 43	19.686 mcg/mL Standard Deviation 9.0747	—	—
Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab Day 85	25.125 mcg/mL Standard Deviation 14.4089	—	—
Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab Day 127	22.544 mcg/mL Standard Deviation 16.7706	—	—
Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab Day 169	20.857 mcg/mL Standard Deviation 23.2820	—	—

SECONDARY outcome

Timeframe: Time from first dose of study treatment up to 1906 days

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

The PD-L1 expression was evaluated using an established antiPD-L1 immunohistochemistry (IHC) assay.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Number of Participants With Programmed Death Ligand 1 (PD-L1) Tumor Expression	11 Participants	—	—

SECONDARY outcome

Timeframe: Day 1 (Pre-infusion), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment. Here "Number Analyzed" = participants who were evaluable for this outcome measure at the specified time points for the given category.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Absolute Values of Cytokine Levels IFN-gamma: Day 1: Pre-Infusion	28.125 nanogram per liter (ng/L) Standard Deviation 97.504	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IFN-gamma: Day 8: 168 hours post Infusion	23.063 nanogram per liter (ng/L) Standard Deviation 25.899	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IFN-gamma: Day 43: Pre-Infusion	19.215 nanogram per liter (ng/L) Standard Deviation 22.041	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-5: Day 1: Pre-Infusion	1.139 nanogram per liter (ng/L) Standard Deviation 1.596	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-5: Day 8: 168 hours Post Infusion	1.492 nanogram per liter (ng/L) Standard Deviation 2.135	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-5: Day 43: Pre-Infusion	1.632 nanogram per liter (ng/L) Standard Deviation 1.958	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-6: Day 1: Pre-Infusion	3.502 nanogram per liter (ng/L) Standard Deviation 7.968	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-6: Day 8: 168 hours Post Infusion	4.102 nanogram per liter (ng/L) Standard Deviation 8.479	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-6: Day 43: Pre-Infusion	1.501 nanogram per liter (ng/L) Standard Deviation 1.555	—	—
Expansion Cohort: Absolute Values of Cytokine Levels MCP-1: Day 1: Pre-Infusion	671.025 nanogram per liter (ng/L) Standard Deviation 203.263	—	—
Expansion Cohort: Absolute Values of Cytokine Levels MCP-1: Day 8: 168 hours Post Infusion	730.466 nanogram per liter (ng/L) Standard Deviation 284.028	—	—
Expansion Cohort: Absolute Values of Cytokine Levels MCP-1: Day 43: Pre-Infusion	775.411 nanogram per liter (ng/L) Standard Deviation 280.839	—	—
Expansion Cohort: Absolute Values of Cytokine Levels TNF-alpha: Day 1: Pre-Infusion	3.674 nanogram per liter (ng/L) Standard Deviation 2.081	—	—
Expansion Cohort: Absolute Values of Cytokine Levels TNF-alpha: Day 8: 168 hours Post Infusion	4.475 nanogram per liter (ng/L) Standard Deviation 4.195	—	—
Expansion Cohort: Absolute Values of Cytokine Levels TNF-alpha: Day 43: Pre-Infusion	3.694 nanogram per liter (ng/L) Standard Deviation 1.195	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-8: Day 1: Pre-Infusion	46.254 nanogram per liter (ng/L) Standard Deviation 43.728	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-8: Day 8: 168 hours Post Infusion	54.107 nanogram per liter (ng/L) Standard Deviation 56.734	—	—
Expansion Cohort: Absolute Values of Cytokine Levels IL-8: Day 43: Pre-Infusion	38.674 nanogram per liter (ng/L) Standard Deviation 30.178	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1 [Pre-infusion]), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment. Here "Number analyzed" = participants who were evaluable for this outcome measure at the specified time points for the given category.

Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline).

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels IFN-gamma: Day 43: Pre-Infusion	0.484 log fold change Standard Deviation 1.371	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels IL-5: Day 43: Pre-Infusion	0.192 log fold change Standard Deviation 1.466	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels IFN-gamma: Day 8: 168 hours Post Infusion	0.697 log fold change Standard Deviation 1.140	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels IL-5: Day 8: 168 hours Post Infusion	0.080 log fold change Standard Deviation 1.209	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels IL-6: Day 8: 168 hours Post Infusion	0.476 log fold change Standard Deviation 2.172	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels IL-6: Day 43: Pre-Infusion	0.880 log fold change Standard Deviation 2.184	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels MCP-1: Day 8: 168 hours Post Infusion	0.082 log fold change Standard Deviation 0.353	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels MCP-1: Day 43: Pre-Infusion	0.115 log fold change Standard Deviation 0.420	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels TNF-alpha: Day 8: 168 hours Post Infusion	0.209 log fold change Standard Deviation 0.377	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels TNF-alpha: Day 43: Pre-Infusion	0.156 log fold change Standard Deviation 0.366	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels IL-8: Day 8: 168 hours Post Infusion	0.199 log fold change Standard Deviation 0.444	—	—
Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels IL-8: Day 43: Pre-Infusion	0.256 log fold change Standard Deviation 0.664	—	—

SECONDARY outcome

Timeframe: Time from first dose of study treatment up to 1906 days

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

Confirmed BOR was defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% 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 was defined as at least a 20% increase in the 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. Number of participants with best overall response in each category (CR, PR, SD, PD) was reported.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Complete response (CR)	1 Participants	—	—
Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Partial Response (PR)	3 Participants	—	—
Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Stable disease (SD)	17 Participants	—	—
Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Progressive disease (PD)	17 Participants	—	—
Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Non-evaluable (NE)	2 Participants	—	—

SECONDARY outcome

Timeframe: Time from first dose of study treatment up to 1906 days

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

BOR: 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 the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). 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.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Immune-related Complete response (irCR)	1 Participants	—	—
Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Immune-related Partial Response (irPR)	3 Participants	—	—
Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Immune-related Stable disease (irSD)	21 Participants	—	—
Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Immune-related Progressive disease (irPD)	9 Participants	—	—
Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Non-evaluable (NE)	6 Participants	—	—

SECONDARY outcome

Timeframe: Time from first dose of study treatment up to 1906 days

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

PFS was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined as at least a 20 percent (%) 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. PFS was measured using Kaplan-Meier (KM) estimates.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	10.64 weeks Interval 6.0 to 12.0	—	—

SECONDARY outcome

Timeframe: Time from first dose of study treatment up to 1906 days

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

irPFS was defined as the time from the first dose of study treatment to the date of first documentation of immune-related progressive disease \[irPD\] (which was subsequently confirmed) or death due to any cause, whichever occurred first. irPD was defined as the sum of the longest diameters of target and new measurable lesions increases greater than or equal to \[\>=\] 20 percent (%), confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Immune-related Progression-Free Survival (irPFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	12.00 weeks Interval 10.14 to 12.86	—	—

SECONDARY outcome

Timeframe: Time from first dose of study treatment up to 1906 days

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

The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Overall Survival (OS) Time	8.87 months Interval 7.23 to 10.97	—	—

SECONDARY outcome

Timeframe: Time from first dose of study treatment up to 1906 days

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

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=40 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs	40 Participants	—	—
Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation Serious TEAEs	11 Participants	—	—
Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs Leading to Discontinuation	7 Participants	—	—
Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs Leading To Death	3 Participants	—	—

SECONDARY outcome

Timeframe: Day 15 up to Day 1906

Population: Safety analysis set included all participants who have received at least 1 dose of study treatment. Here, "Overall Number of Participants Analyzed" signified participants who were evaluable for this outcome measure.

Number of participants with positive HAHA were reported. Participants not having positive HAHA prior to treatment with avelumab and with at least one positive post-baseline result in the HAHA assay were characterized as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result \>=16 weeks apart or a positive evaluation at the most recent visit.

Outcome measures

Outcome measures
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=38 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Expansion Cohort: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA) Transient positive treatment emergent	2 Participants	—	—
Expansion Cohort: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA) Persistent positive treatment emergent	5 Participants	—	—

Adverse Events

Dose-escalation Cohort: Avelumab 3 mg/kg

Serious events: 1 serious events

Other events: 5 other events

Deaths: 4 deaths

Dose-escalation Cohort: Avelumab 10 mg/kg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 3 deaths

Dose-escalation Cohort: Avelumab 20 mg/kg

Serious events: 2 serious events

Other events: 5 other events

Deaths: 4 deaths

Expansion Cohort: Avelumab 10 mg/kg

Serious events: 11 serious events

Other events: 38 other events

Deaths: 36 deaths

Serious adverse events

Serious adverse events
Measure	Dose-escalation Cohort: Avelumab 3 mg/kg n=5 participants at risk Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 10 mg/kg n=6 participants at risk Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Dose-escalation Cohort: Avelumab 20 mg/kg n=6 participants at risk Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.	Expansion Cohort: Avelumab 10 mg/kg n=40 participants at risk Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Gastrointestinal disorders Ileus	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	5.0% 2/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Gastrointestinal disorders Gastric haemorrhage	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	5.0% 2/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Gastrointestinal disorders Intestinal obstruction	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	2.5% 1/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	2.5% 1/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Cardiac disorders Myocardial infarction	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	2.5% 1/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Infections and infestations Biliary tract infection	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	2.5% 1/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	2.5% 1/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
General disorders Disease progression	20.0% 1/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	5.0% 2/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
General disorders Multiple organ dysfunction syndrome	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	2.5% 1/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	2.5% 1/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Nervous system disorders Altered state of consciousness	20.0% 1/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Nervous system disorders Headache	20.0% 1/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Nervous system disorders Tonic convulsion	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	16.7% 1/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
Investigations Platelet count decreased	0.00% 0/5 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	16.7% 1/6 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days	0.00% 0/40 • Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days

Other adverse events

Additional Information

Communication Center

Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place