Trial Outcomes & Findings for Phase I/Ib Multiple Ascending Dose Study in China (NCT NCT03523390)

Last Updated: 2024-02-23

Results Overview

DLT is defined as greater than or equal to \[\>=\] Grade (Gr)3 Adverse drug reaction (ADR) according to NCI-CTCAE v4.03, occurring during DLT observation period of dose escalation cohorts. ADR: any AE suspected to be related to avelumab by Investigator and/Sponsor. Following events were not considered as DLT: Gr3 infusion-related reaction resolving within 6 hours and controlled with medical management. Transient (less than or equal to \[\<=\] 6 hours) Gr3 flu-like symptoms/fever, controlled with medical management. Transient (\<=24 hours) Gr3 fatigue, local reactions, headache, nausea, emesis, resolves to \<= Gr1. Gr3 skin toxicity/Gr3 Liver function test increase that resolves to \<= Grade 1 in \< 7 days after medical management. Gr3 diarrhea, out-of-range laboratory values without any clinical correlate that resolves to \<= Grade 1 within 7 days with adequate 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

24 participants

Primary outcome timeframe

Day 1 to Day 21

Results posted on

2024-02-23

Participant Flow

Participant milestones

Participant milestones
Measure	Avelumab 3 mg/kg Q2W Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Overall Study STARTED	3	7	6	8
Overall Study COMPLETED	3	7	6	8
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Phase I/Ib Multiple Ascending Dose Study in China

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW n=8 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Total n=24 Participants Total of all reporting groups
Age, Continuous	54 years STANDARD_DEVIATION 17.7 • n=5 Participants	52 years STANDARD_DEVIATION 14.3 • n=7 Participants	50 years STANDARD_DEVIATION 16.6 • n=5 Participants	61 years STANDARD_DEVIATION 13.1 • n=4 Participants	55 years STANDARD_DEVIATION 14.7 • n=21 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	10 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	14 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	3 Participants n=5 Participants	7 Participants n=7 Participants	6 Participants n=5 Participants	8 Participants n=4 Participants	24 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: Day 1 to Day 21

Population: DLT analysis set included all participants with data used for implementing the dose escalation schedule (excluding 6 participants in 10 mg/kg once weekly cohort) and received all Avelumab administrations in the DLT observation period or should have stopped treatment because of DLTs in the DLT observation period.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=3 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Number of Participants With of Dose-limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03	0 Participants	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: Pharmacokinetics (PK) analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in statistical analysis plan (SAP), data for AUC0-t was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log linear trapezoidal rule.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Area Under the Serum Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Avelumab	7000 microgramhour per milliliter (mcgh/mL) Geometric Coefficient of Variation 3.0	20400 microgramhour per milliliter (mcgh/mL) Geometric Coefficient of Variation 31.3	35600 microgramhour per milliliter (mcgh/mL) Geometric Coefficient of Variation 20.6	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for AUCtau was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

AUCtau was defined as area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Avelumab	7000 mcg*h/mL Geometric Coefficient of Variation 2.9	20800 mcg*h/mL Geometric Coefficient of Variation 27.8	35800 mcg*h/mL Geometric Coefficient of Variation 22.3	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for AUC0-inf was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab	7710 mcg*h/mL Geometric Coefficient of Variation 6.2	22600 mcg*h/mL Geometric Coefficient of Variation 29.7	38300 mcg*h/mL Geometric Coefficient of Variation 23.4	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for Lambda z was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

Lambda z was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Terminal Elimination Rate Constant (Lambda z) of Avelumab	0.00719 1/hour Geometric Coefficient of Variation 18.6	0.00767 1/hour Geometric Coefficient of Variation 21.1	0.00811 1/hour Geometric Coefficient of Variation 9.1	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for Cmax was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

Cmax was obtained directly from the serum concentration versus time curve.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Maximum Observed Serum Concentration (Cmax) of Avelumab	77.6 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 13.9	294 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 44.7	450 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 36.5	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for Clast was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

Clast is the last measurable serum concentration of Avelumab.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Last Quantifiable Serum Concentration (Clast) of Avelumab	4.94 mcg/mL Geometric Coefficient of Variation 33.7	16.3 mcg/mL Geometric Coefficient of Variation 51.2	21.4 mcg/mL Geometric Coefficient of Variation 50.3	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to 1 hour infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure. As pre-specified in SAP, data for Ctrough was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

Ctrough is defined as the concentration observed immediately before next dosing.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Serum Trough Concentration Levels (Ctrough) of Avelumab	4.94 mcg/mL Geometric Coefficient of Variation 33.7	14.8 mcg/mL Geometric Coefficient of Variation 47.2	21.4 mcg/mL Geometric Coefficient of Variation 50.3	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for tmax was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

The time to reach the maximum observed serum concentration (tmax) was obtained directly from the concentration versus time curve.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab	1.55 hours Interval 1.53 to 1.62	1.52 hours Interval 1.0 to 6.9	1.97 hours Interval 1.05 to 5.0	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for t1/2 was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

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. t1/2 was calculated as log2/ lambda z. Lambda z was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Apparent Terminal Half Life (t1/2) of Avelumab	96.5 hours Geometric Coefficient of Variation 18.6	90.3 hours Geometric Coefficient of Variation 21.1	85.5 hours Geometric Coefficient of Variation 9.1	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for AUC0-t/dose was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

AUC0-t/Dose was defined as area under the serum concentration versus time curve from time of dosing to the time of the last measurable concentration divided by dose. AUC0-t/Dose was measured in (microgram\*hour per milliliter)/(milligram per kilogram) (mcg\*h/mL)/(mg/kg).

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of Avelumab	2330 (mcg*h/mL)/(mg/kg) Geometric Coefficient of Variation 3.0	2040 (mcg*h/mL)/(mg/kg) Geometric Coefficient of Variation 31.3	1780 (mcg*h/mL)/(mg/kg) Geometric Coefficient of Variation 20.6	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for AUCtau/dose was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

AUCtau/Dose was calculated by as dose normalized area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Dose Normalized Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau/Dose) of Avelumab	2330 (mcg*h/mL)/(mg/kg) Geometric Coefficient of Variation 2.9	2080 (mcg*h/mL)/(mg/kg) Geometric Coefficient of Variation 27.8	1790 (mcg*h/mL)/(mg/kg) Geometric Coefficient of Variation 22.3	—

PRIMARY outcome

Timeframe: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion

Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for Cmax/dose was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.

Cmax/Dose was defined as maximum observed serum concentration divided by dose.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Avelumab	25.9 (mcg/mL)/(mg/kg) Geometric Coefficient of Variation 13.9	29.4 (mcg/mL)/(mg/kg) Geometric Coefficient of Variation 44.7	22.5 (mcg/mL)/(mg/kg) Geometric Coefficient of Variation 36.5	—

SECONDARY outcome

Timeframe: Time from first study treatment up to 139 weeks

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

An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 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 defined as events that emerge during treatment having been absent pre-treatment, or worsen relative to the pre-treatment state and with onset dates occurring within the first dosing day of study treatment until 30 days after the last dose of study treatment. TEAEs include both Serious TEAEs and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW n=8 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) Participants with TEAEs	3 Participants	7 Participants	6 Participants	8 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) Participants with Treatment Related TEAEs	3 Participants	6 Participants	6 Participants	6 Participants

SECONDARY outcome

Timeframe: Time from first study treatment up to 139 weeks

Population: Immunogenicity Analysis Set included all participants who have any dose of avelumab and who have at least one valid ADA result.

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.

Outcome measures

Outcome measures
Measure	Avelumab 3 mg/kg Q2W 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW n=8 Participants Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA)	2 Participants	0 Participants	0 Participants	0 Participants

Adverse Events

Avelumab 3 mg/kg Q2W

Serious events: 1 serious events

Other events: 3 other events

Deaths: 1 deaths

Avelumab 10 mg/kg Q2W

Serious events: 3 serious events

Other events: 7 other events

Deaths: 4 deaths

Avelumab 20 mg/kg Q2W

Serious events: 2 serious events

Other events: 6 other events

Deaths: 6 deaths

Avelumab 10 mg/kg QW

Serious events: 2 serious events

Other events: 8 other events

Deaths: 7 deaths

Serious adverse events

Serious adverse events
Measure	Avelumab 3 mg/kg Q2W n=3 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 (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg Q2W n=7 participants at risk Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 20 mg/kg Q2W n=6 participants at risk Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.	Avelumab 10 mg/kg QW n=8 participants at risk Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Respiratory, thoracic and mediastinal disorders Bronchostenosis	0.00% 0/3 • Time from first study treatment up to 139 weeks	14.3% 1/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/3 • Time from first study treatment up to 139 weeks	0.00% 0/7 • Time from first study treatment up to 139 weeks	16.7% 1/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Blood and lymphatic system disorders Anemia	33.3% 1/3 • Time from first study treatment up to 139 weeks	0.00% 0/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Gastrointestinal disorders Dysphagia	0.00% 0/3 • Time from first study treatment up to 139 weeks	14.3% 1/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • Time from first study treatment up to 139 weeks	0.00% 0/7 • Time from first study treatment up to 139 weeks	16.7% 1/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Hepatobiliary disorders Hepatic failure	0.00% 0/3 • Time from first study treatment up to 139 weeks	0.00% 0/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	12.5% 1/8 • Time from first study treatment up to 139 weeks
Infections and infestations Pneumonia	0.00% 0/3 • Time from first study treatment up to 139 weeks	0.00% 0/7 • Time from first study treatment up to 139 weeks	16.7% 1/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Injury, poisoning and procedural complications Head injury	0.00% 0/3 • Time from first study treatment up to 139 weeks	14.3% 1/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Investigations Blood bilirubin increased	0.00% 0/3 • Time from first study treatment up to 139 weeks	0.00% 0/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	12.5% 1/8 • Time from first study treatment up to 139 weeks
Metabolism and nutrition disorders Hyperuricemia	0.00% 0/3 • Time from first study treatment up to 139 weeks	14.3% 1/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Respiratory, thoracic and mediastinal disorders Apnea	0.00% 0/3 • Time from first study treatment up to 139 weeks	14.3% 1/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	0.00% 0/8 • Time from first study treatment up to 139 weeks
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/3 • Time from first study treatment up to 139 weeks	0.00% 0/7 • Time from first study treatment up to 139 weeks	0.00% 0/6 • Time from first study treatment up to 139 weeks	12.5% 1/8 • Time from first study treatment up to 139 weeks

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