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The purpose of this study was to evaluate the maximum tolerated dose (MTD) and pharmacokinetics (PK) of Avelumab monotherapy in Chinese subjects.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Experimental |
| |
| Avelumab 10 mg/kg Q2W | Experimental |
| |
| Avelumab 20 mg/kg Q2W | Experimental |
| |
| Avelumab 10 mg/kg QW | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 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. | Day 1 to Day 21 |
| Area Under the Serum Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Avelumab | 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. | 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 |
| Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Avelumab | 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. | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research site | Guangzhou | Guangzhou | China | |||
| Research site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35354274 | Result | Wu YL, Cheng Y, Chen H, Tu H, Xu C, Wang Z, Liu Y, Xin Y, Lou H, Wang W, Chin K, Li D, Zhao D, Gao Y, Xu W, Pan H. Phase I/Ib dose-escalation study of avelumab in Chinese patients with advanced solid tumors. Future Oncol. 2022 Jun;18(17):2053-2062. doi: 10.2217/fon-2021-1342. Epub 2022 Mar 31. |
| Label | URL |
|---|---|
| Trial Awareness and Transparency website | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety analysis set (SAF) included all participants who have received at least 1 dose of Avelumab.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | 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. | 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. | Posted | Count of Participants | Participants | Day 1 to Day 21 |
Time from first study treatment up to 139 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | MedDRA Version 23.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA Version 23.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Communication Center | Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@emdgroup.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 17, 2019 | Jul 6, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 13, 2019 | Jul 4, 2023 | SAP_001.pdf |
| ID | Term |
|---|---|
| C000609138 | avelumab |
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Subsequent cohorts of subjects treated at different dose levels in this study.
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| Avelumab 10 mg/kg Q2W | Drug | Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg 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 | Drug | Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg 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 | Drug | Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg 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 |
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. |
| 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 |
| Terminal Elimination Rate Constant (Lambda z) of Avelumab | Lambda z was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method. | 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 |
| Maximum Observed Serum Concentration (Cmax) of Avelumab | Cmax was obtained directly from the serum concentration versus time curve. | 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 |
| Last Quantifiable Serum Concentration (Clast) of Avelumab | Clast is the last measurable serum concentration of Avelumab. | 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 |
| Serum Trough Concentration Levels (Ctrough) of Avelumab | Ctrough is defined as the concentration observed immediately before next dosing. | Day 1: within 2 hours prior to 1 hour infusion |
| Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab | The time to reach the maximum observed serum concentration (tmax) was obtained directly from the concentration versus time curve. | 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 |
| Apparent Terminal Half Life (t1/2) of Avelumab | 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. | 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 |
| Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of Avelumab | 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). | 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 |
| Dose Normalized Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau/Dose) of Avelumab | 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. | 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 |
| Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Avelumab | Cmax/Dose was defined as maximum observed serum concentration divided by dose. | 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 |
| Time from first study treatment up to 139 weeks |
| Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA) | Serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of antidrug antibodies (ADA). Number of participants with ADA positive results for Avelumab were reported. | Time from first study treatment up to 139 weeks |
| Changchun |
| Jilin |
| China |
| Research site | Hangzhou | Zhejiang | China |
| Medical Information Location Map - Med Info Contacts | View source |
| 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
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|
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| Secondary | 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) | 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. | SAF included all participants who have received at least 1 dose of Avelumab. | Posted | Count of Participants | Participants | Time from first study treatment up to 139 weeks |
|
|
|
| Secondary | Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA) | 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. | Immunogenicity Analysis Set included all participants who have any dose of avelumab and who have at least one valid ADA result. | Posted | Count of Participants | Participants | Time from first study treatment up to 139 weeks |
|
|
|
| Primary | Area Under the Serum Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Avelumab | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram*hour per milliliter (mcg*h/mL) | 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 |
|
|
|
| Primary | Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Avelumab | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | mcg*h/mL | 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 |
|
|
|
| Primary | Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | mcg*h/mL | 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 |
|
|
|
| Primary | Terminal Elimination Rate Constant (Lambda z) of Avelumab | Lambda z was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | 1/hour | 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 |
|
|
|
| Primary | Maximum Observed Serum Concentration (Cmax) of Avelumab | Cmax was obtained directly from the serum concentration versus time curve. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per milliliter (mcg/mL) | 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 |
|
|
|
| Primary | Last Quantifiable Serum Concentration (Clast) of Avelumab | Clast is the last measurable serum concentration of Avelumab. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | mcg/mL | 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 |
|
|
|
| Primary | Serum Trough Concentration Levels (Ctrough) of Avelumab | Ctrough is defined as the concentration observed immediately before next dosing. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | mcg/mL | Day 1: within 2 hours prior to 1 hour infusion |
|
|
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| Primary | Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab | The time to reach the maximum observed serum concentration (tmax) was obtained directly from the concentration versus time curve. | 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. | Posted | Median | Full Range | hours | 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 |
|
|
|
| Primary | Apparent Terminal Half Life (t1/2) of Avelumab | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | 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 |
|
|
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| Primary | Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of Avelumab | 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | (mcg*h/mL)/(mg/kg) | 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 |
|
|
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| Primary | Dose Normalized Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau/Dose) of Avelumab | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | (mcg*h/mL)/(mg/kg) | 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 |
|
|
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| Primary | Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Avelumab | Cmax/Dose was defined as maximum observed serum concentration divided by dose. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | (mcg/mL)/(mg/kg) | 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 |
|
|
|
| 1 |
| 3 |
| 1 |
| 3 |
| 3 |
| 3 |
| EG001 | 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. | 4 | 7 | 3 | 7 | 7 | 7 |
| EG002 | 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. | 6 | 6 | 2 | 6 | 6 | 6 |
| EG003 | 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. | 7 | 8 | 2 | 8 | 8 | 8 |
| Dysphagia | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hepatic failure | Hepatobiliary disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Head injury | Injury, poisoning and procedural complications | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hyperuricemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Apnea | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Bronchostenosis | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Atrioventricular block first degree | Cardiac disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Atrioventricular block second degree | Cardiac disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Bundle branch block right | Cardiac disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Sinus arrhythmia | Cardiac disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Supraventricular tachycardia | Cardiac disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Ventricular extrasystoles | Cardiac disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Autoimmune thyroiditis | Endocrine disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypothyroidism | Endocrine disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Ascites | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Epigastric discomfort | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Lower gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Asthenia | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Chest discomfort | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Chest pain | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Chills | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Feeling cold | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Malaise | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pain | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Swelling face | General disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Gingivitis | Infections and infestations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Herpes zoster | Infections and infestations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Skin infection | Infections and infestations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Infusion related reaction | Injury, poisoning and procedural complications | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Activated partial thromboplastin time prolonged | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Amylase increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Bilirubin conjugated increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood chloride increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood lactate dehydrogenase increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood phosphorus increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood pressure increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood thyroid stimulating hormone decreased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Blood urea increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Electrocardiogram QT prolonged | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Heart rate increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| International normalised ratio increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Low density lipoprotein increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Neutrophil count decreased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Prothrombin time prolonged | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Red blood cells urine positive | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Reticulocyte count increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Urinary sediment present | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Urine output decreased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Weight decreased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Weight increased | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| White blood cells urine positive | Investigations | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Glycopenia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypernatraemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypochloraemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypoproteinaemia | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Lactic acidosis | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Metabolic acidosis | Metabolism and nutrition disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Neck mass | Musculoskeletal and connective tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Tumour pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Aphasia | Nervous system disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Dysuria | Renal and urinary disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Haematuria | Renal and urinary disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Oedema genital | Reproductive system and breast disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pelvic fluid collection | Reproductive system and breast disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Bronchostenosis | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Dry throat | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pulmonary congestion | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Sputum discoloured | Respiratory, thoracic and mediastinal disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Dermatitis bullous | Skin and subcutaneous tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Leukoderma | Skin and subcutaneous tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Night sweats | Skin and subcutaneous tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Vitiligo | Skin and subcutaneous tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Yellow skin | Skin and subcutaneous tissue disorders | MedDRA Version 23.1 | Non-systematic Assessment |
|
| Bedridden | Social circumstances | MedDRA Version 23.1 | Non-systematic Assessment |
|
Not provided
Not provided
| Participants with Treatment Related TEAEs |
|