Clinical Trial Results:
A Phase II, Open-Label, Multicenter Trial to Investigate the Clinical Activity and Safety of Avelumab (MSB0010718C) in Subjects With Merkel Cell Carcinoma
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Summary
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EudraCT number |
2014-000445-79 |
Trial protocol |
IT DE AT ES |
Global end of trial date |
03 May 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Mar 2024
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First version publication date |
06 Mar 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
EMR100070-003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02155647 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Merck Healthcare KGaA, Darmstadt Germany
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Sponsor organisation address |
Frankfurter Strasse 250, Darmstadt, Germany, 64293
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Public contact |
Communication Centre, Merck Healthcare KGaA, Darmstadt Germany, +49 6151725200, service@merckgroup.com
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Scientific contact |
Communication Centre, Merck Healthcare KGaA, Darmstadt Germany, +49 6151725200, service@merckgroup.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 May 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
03 May 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main purpose of this trial was to evaluate the efficacy and safety of avelumab in subjects with metastatic Merkel cell carcinoma (MCC).
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Protection of trial subjects |
Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Jul 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 14
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Country: Number of subjects enrolled |
Switzerland: 1
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Country: Number of subjects enrolled |
Germany: 25
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
France: 46
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Country: Number of subjects enrolled |
Italy: 29
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Country: Number of subjects enrolled |
Japan: 6
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Country: Number of subjects enrolled |
United States: 80
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Worldwide total number of subjects |
204
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EEA total number of subjects |
103
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
44
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From 65 to 84 years |
143
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85 years and over |
17
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Recruitment
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Recruitment details |
- | |||||||||
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Pre-assignment
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Screening details |
A total of 88 subjects were enrolled in Part A of the study and a total of 116 subjects were enrolled in Part B of the study. Subjects enrolled in Part A were not eligible for enrollment in Part B. | |||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Part A: Avelumab | |||||||||
Arm description |
Subjects with metastatic Merkel cell carcinoma (MCC) after failing first-line chemotherapy received Avelumab at a dose of 10 milligram per kilogram (mg/kg) as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Avelumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects with MCC after failing first-line chemotherapy received Avelumab at a dose of 10 mg/kg as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs.
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Arm title
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Part B: Avelumab | |||||||||
Arm description |
Subjects received Avelumab as first-line treatment for metastatic or distally recurrent MCC at a dose of 10 mg/kg as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Avelumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received Avelumab as first-line treatment for metastatic or distally recurrent MCC at a dose of 10 mg/kg as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs.
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Baseline characteristics reporting groups
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Reporting group title |
Part A: Avelumab
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Reporting group description |
Subjects with metastatic Merkel cell carcinoma (MCC) after failing first-line chemotherapy received Avelumab at a dose of 10 milligram per kilogram (mg/kg) as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part B: Avelumab
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Reporting group description |
Subjects received Avelumab as first-line treatment for metastatic or distally recurrent MCC at a dose of 10 mg/kg as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Part A: Avelumab
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Reporting group description |
Subjects with metastatic Merkel cell carcinoma (MCC) after failing first-line chemotherapy received Avelumab at a dose of 10 milligram per kilogram (mg/kg) as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs. | ||
Reporting group title |
Part B: Avelumab
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Reporting group description |
Subjects received Avelumab as first-line treatment for metastatic or distally recurrent MCC at a dose of 10 mg/kg as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs. | ||
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End point title |
Part A: Number of Subjects with Confirmed Best Overall Response (BOR) as per Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 [1] [2] | ||||||||||||||||||
End point description |
Confirmed BOR was determined according to RECIST 1.1 and as adjudicated by an Independent Endpoint Review Committee (IERC) and defined as best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression/recurrence (taking smallest measurement recorded since start of treatment as reference). CR:Disappearance of all evidence of target/non-target lesions. PR:At least 30%reduction from baseline in sum of longest diameter (SLD) of all lesions. SD:Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD:at least 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions. Intent-to-Treat analysis set included all subject who received at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
Up to 113 weeks
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was planned to be reported for Part A only. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Part B: Durable Response Rate (DRR) [3] [4] | ||||||||
End point description |
Durable response is defined as an objective response (confirmed complete response [CR] or confirmed Partial response [PR]) according to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1, determined by the Independent Endpoint Review Committee (IERC), with a duration of at least 6 months. The DRR was determined as the percentage of participants with an objective response in terms of CR or PR according to RECIST 1.1, as determined by the IERC, with a duration of at least 6 months. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Full analysis set (FAS) included all subjects who received at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
Up to 161 weeks
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive summary statistics was planned to be reported for this endpoint. [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Part A: Duration of Response According to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 [5] | ||||||||
End point description |
The duration of response as determined from IERC tumor assessment was calculated for each subject with a confirmed response (CR or PR) as the time from first observation of response until first observation of documented disease progression or death when death occurs within 12 weeks of the last tumor assessment, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Results were calculated based on Kaplan-Meier estimates. Intent-to-Treat analysis set included all subjects who received at least 1 dose of study treatment. Here "Number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to 325 weeks
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| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to reported for Part A only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Part A: Number of Subjects with Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) [6] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The laboratory measurements included hematology, liver function and blood chemistry. Number of subjects with clinically significant abnormalities with Grade greater than or equals to (>=) 3 in laboratory values reported as TEAEs were reported. Clinically Significance was decided by investigator. Safety analysis set included all subjects who received at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
Up to 325 weeks
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| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Part A: Number of Subjects with Treatment-Related (TR) Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Serious TEAEs and Treatment-Related TEAEs leading to Death [7] | ||||||||||||
End point description |
Related Adverse events (AE) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE) as adverse events with relationship to study treatment reported by the investigator. 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. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs. Related TEAEs are defined as events with a relationship of missing, unknown, or yes. Safety analysis set included all subjects who received at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
Up to 325 weeks
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| Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Part A: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 [8] | ||||||||
End point description |
The PFS time (based on IERC tumor assessments), according to the RECIST 1.1, was defined as the time from first administration of study treatment until first observation of PD or death when death occurred within 12 weeks of the last tumor assessment or first administration of study treatment (whichever was later). PFS time (in months) was defined as: (date of PD or death – date of the first dose of study treatment + 1)/30.4375 (months). PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance
of 1 or more new lesions and unequivocal progression of non-target lesions Intent-to-Treat analysis set included all subjects who received at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
Up to 325 weeks
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| Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to reported for Part A only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Part A: Number of Subjects with Clinically Significant Abnormalities in Vital Signs Reported as Treatment Emergent Adverse Events (TEAEs) [9] | ||||||||||||||||||||||||||||
End point description |
Vital signs including body temperature, body weight, respiratory rate, heart rate (after 5-minute rest), and arterial blood pressure (after 5-minute rest) were evaluated. Number of subjects with clinically significant abnormalities in Vital Signs reported as TEAEs. Clinically Significance was decided by investigator. Safety analysis set included all subjects who received at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
Up to 325 weeks
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| Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Part A: Number of Subjects with Clinically Significant Abnormalities in Electrocardiogram (ECG) [10] | ||||||||||||||||||||||
End point description |
A 12-lead ECG was recorded after the subject has been in a supine position breathing quietly for 5 minutes. The ECG results was used to evaluate the heart rate, atrial ventricular conduction, PR interval, QRS, QTcF and QTcB. Number of subjects with clinical significant abnormalities in ECG parameter reported here. Clinically Significance was decided by investigator. Safety analysis set included all subjects who received at least 1 dose of study treatment. Here "Number of subjects analyzed" signifies those who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to 325 weeks
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| Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Part A: Interim Analysis: Overall Survival (OS) Time [11] | ||||||||
End point description |
The OS time was defined as the time from first administration of trial treatment until death. The OS time was analyzed using the Kaplan-Meier method. Intent-to-Treat analysis set included all subjects who received at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
Up to 87 weeks (Data reported are per pre-specified interim analysis with a data cut-off date of 3 Mar 2016)
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| Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to reported for Part A only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Part A: Final Analysis: Overall Survival (OS) Time [12] | ||||||||
End point description |
The OS time was defined as the time from first administration of trial treatment until death. The OS time was analyzed using the Kaplan-Meier method. Intent-to-Treat analysis set included all subjects who received at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
Time from first administration of trial treatment until death (Up to 325 weeks)
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| Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to reported for Part A only. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Part A: Subject's Response Status According to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 at 6 and 12 months [13] | ||||||||||||||||
End point description |
The response status at 6 and 12 months after start of trial treatment according to RECIST 1.1 (as determined by the IERC) was determined. A subject was considered to be in response at the given timepoint (6 or 12 months after the start of the subject's treatment) if the subject had a documented response (PR or CR) prior to that timepoint, and neither died nor experienced disease progression according to the RECIST 1.1 nor was lost to follow-up up to the given timepoint. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Percentage of subjects in response and not in response according to RECIST1.1 at 6 and 12 months were reported. Intent-to-Treat analysis set included all subjects who received at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
At Month 6 and 12
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| Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Part A: Serum Concentration at End of Infusion (CEOI) of Avelumab [14] | ||||||||||||||||||||||
End point description |
Serum concentration at end of infusion (CEOI) of Avelumab is reported. Pharmacokinetic analysis set consists of all subjects who received at least 1 dose of avelumab, and provide at least 1 measurable post-dose concentration. Here "n" signifies those subjects who were evaluable at specified timepoints.
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End point type |
Secondary
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End point timeframe |
Day 1, 43, 85, 169, 253, 337 and 421
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| Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Part A: Number of Subjects with Positive Treatment Emergent Anti-Avelumab Antibodies [15] | ||||||
End point description |
Serum samples were analyzed by a validated electrochemiluminesce immunoassay to detect the presence of anti-avelumab antibodies. Samples that screened positive were subsequently tested in a confirmatory assay. Those confirmed positive were titered for a quasi-quantitative result. Number of subjects with positive treatment emergent anti-Avelumab antibodies were reported. Subjects not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent. Safety analysis set included all participants who received at least 1 dose of study treatment. Here "Number of subjects analyzed" signifies those who were evaluable for this outcome measure.
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End point type |
Secondary
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End point timeframe |
Up to 80 weeks
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| Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||
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End point title |
Part A: Minimum Serum Post-dose (Ctrough) Concentration of Aveluamb [16] | ||||||||||||||||||||||||||||||||
End point description |
Minimum serum post-dose (Ctrough) concentration of avelumab was reported. Pharmacokinetic analysis set consists of all subjects who received at least 1 dose of avelumab, and provide at least 1 measurable post-dose concentration. Here "n" signifies those subjects who were evaluable at specified timepoints and "9999" signifies that standard deviation was not calculable for n = 1.
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End point type |
Secondary
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End point timeframe |
Day 15, 29, 43, 57, 71, 85, 99, 169, 211, 253, 337 and 421
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| Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part A only. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
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End point title |
Part B: Final Analysis: Overall Survival (OS) Time [17] | ||||||||
End point description |
The OS time was defined as the time from first administration of study treatment until the date of death. OS was calculated using following formula = (date of death – date of the first dose of study treatment + 1)/30.4375 (months). Full Analysis Set included all subjects who received at least 1 dose of study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Time from first administration of trial treatment until death (Up to 396 weeks)
|
||||||||
| Notes [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
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|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Part B: Interim Analysis: Overall Survival (OS) Time [18] | ||||||||
End point description |
The OS time was defined as the time from first administration of study treatment until the date of death. OS was calculated using following formula = (date of death – date of the first dose of study treatment + 1)/30.4375 (months). Full Analysis Set included all subjects who received at least 1 dose of study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 161 weeks (Data reported are per pre-specified interim analysis with a data cut-off date of 2 May 2019)
|
||||||||
| Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
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|
|||||||||
| No statistical analyses for this end point | |||||||||
|
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End point title |
Part B: Number of Subjects with Confirmed Best Overall Response (BOR) as per Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 [19] | ||||||||||||||||||
End point description |
Confirmed BOR was determined according to RECIST 1.1 and as adjudicated by an Independent Endpoint Review Committee (IERC) and defined as best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression/recurrence (taking smallest measurement recorded since start of treatment as reference). CR:Disappearance of all evidence of target/non-target lesions. PR:At least 30%reduction from baseline in sum of longest diameter (SLD) of all lesions. SD:Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD:at least 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions. Full Analysis Set included all subjects who received at least 1 dose of study treatment.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Up to 396 weeks
|
||||||||||||||||||
| Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to reported for Part B only. |
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|
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| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||
End point title |
Part B: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 [20] | ||||||||
End point description |
The PFS time (based on IERC tumor assessments), according to the RECIST 1.1, was defined as the time from first administration of study treatment until first observation of PD or death when death occurred within 12 weeks of the last tumor assessment or first administration of study treatment (whichever was later). PFS time (in months) was defined as: (date of PD or death – date of the first dose of study treatment + 1)/30.4375 (months). PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Full Analysis Set included all subjects who received at least 1 dose of study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 396 weeks
|
||||||||
| Notes [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Part B: Duration of Response According to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 [21] | ||||||||
End point description |
The duration of response as determined from IERC tumor assessment was calculated for each subject with a confirmed response (CR or PR) as the time from first observation of response until first observation of documented disease progression or death when death occurs within 12 weeks of the last tumor assessment, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Full Analysis Set included all subjects who received at least 1 dose of study treatment. Here "Number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 396 weeks
|
||||||||
| Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Part B: Number of Subjects with Treatment-Related (TR) Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Serious TEAEs and Treatment-Related TEAEs leading to Death [22] | ||||||||||||
End point description |
Related Adverse events (AE) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE) as adverse events with relationship to study treatment reported by the investigator. 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. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs. Related TEAEs are defined as events with a relationship of missing, unknown, or yes. Full Analysis Set included all subjects who received at least 1 dose of study treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to 396 weeks
|
||||||||||||
| Notes [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||
End point title |
Part B: Number of Subjects with Positive Treatment Emergent Anti-Avelumab Antibodies [23] | ||||||
End point description |
Serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of antidrug antibodies (ADA). Samples that screened positive were subsequently tested in a confirmatory assay. Those that confirmed positive were titered for a quasi-quantitative result. Number of subjects with positive treatment emergent anti-Avelumab antibodies were reported. Subjects not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent. Full Analysis Set included all subjects who received at least 1 dose of study treatment. Here "Number of subjects analyzed" signifies those participants who were evaluable for this endpoint.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Up to 161 weeks
|
||||||
| Notes [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||||||
End point title |
Part B: Subject's Response Status According to RECIST 1.1 at 6 and 12 months [24] | ||||||||||||||||
End point description |
The response status at 6 and 12 months after start of trial treatment according to RECIST 1.1 (as determined by the IERC) was determined. A subject was considered to be in response at the given timepoint (6 or 12 months after the start of the subject's treatment) if the subject had a documented response (PR or CR) prior to that timepoint, and neither died nor experienced disease progression according to the RECIST 1.1 nor was lost to follow-up up to the given timepoint. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Percentage of subjects in response and not in response according to RECIST1.1 at 6 and 12 months were reported. Full Analysis Set included all subjects who received at least 1 dose of study treatment.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Month 6 and 12
|
||||||||||||||||
| Notes [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
|||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||
|
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End point title |
Part B: Serum Concentration at End of Infusion (CEOI) of Avelumab [25] | ||||||||||||||
End point description |
Serum concentration at end of infusion (CEOI) of Avelumab is reported. PK Analysis Set included all subjects who received at least 1 dose of avelumab, and provided at least 1 measurable post-dose concentration. Here "n" signifies those subjects who were evaluable at specified time-point for this endpoint.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
At Day 1, 43 and 169
|
||||||||||||||
| Notes [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
|||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Part B: Minimum Serum Post-dose (Ctrough) Concentration of Aveluamb [26] | ||||||||||||||||||||||||||||||||
End point description |
Minimum serum post-dose (Ctrough) concentration of avelumab was reported. PK Analysis Set included all subjects who received at least 1 dose of avelumab, and provided at least 1 measurable post-dose concentration. Here "n" signifies those subjects who were evaluable at specified time-point for this endpoint.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Day 15, Day 29, Day 43, Day 85, Day 127, Day 169, Day 253, Day 337, Day 421, Day 505, Day 589, Day 673
|
||||||||||||||||||||||||||||||||
| Notes [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was planned to be reported for Part B only. |
|||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
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Adverse events information
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Timeframe for reporting adverse events |
Part A: Up to 325 weeks; Part B: Up to 396 weeks
|
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Adverse event reporting additional description |
Adverse events were reported as per MedDRA v21.1 for Part A arm and MedDRA v22.0 for Part B.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.122.0
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Reporting groups
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Reporting group title |
Part B: Avelumab
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Reporting group description |
Participants received Avelumab as first-line treatment for metastatic or distally recurrent MCC at a dose of 10 mg/kg as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part A: Avelumab
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Reporting group description |
Participants with metastatic Merkel cell carcinoma (MCC) after failing first-line chemotherapy received Avelumab at a dose of 10 milligram per kilogram (mg/kg) as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Apr 2014 |
• Changed the frequency of electrocardiogram monitoring in the study.
• Clarified that contraceptive use (Inclusion Criterion #9) is required for 30 days prior to first study drug administration through 60 days after the stopping study participation if the risk of conception exists (ie, females subjects of childbearing potential and male subjects).
• Revised the Exclusion Criterion #4 so that radiotherapy administered to superficial lesions is not allowed if such lesions are considered target lesions in efficacy evaluation or may influence efficacy evaluation of the investigational agent.
• Clarified required premedication and allow for flexibility based on local treatment standards and guideline. |
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06 Jun 2014 |
• Added response status at 6 and 12 months as a secondary objective.
• Changed from the characterization of PK profile (exploratory objective) to the characterization of population PK (secondary objective).
• Updated PK sampling to provide additional post infusion samples for characterization of population PK.
• Clarified the wording of the exploratory objective regarding the immunogenicity of MSB0010718C and change to a secondary objective.
• Added additional immunogenicity sampling in the follow-up period.
• Added a comparison of the TTP on last prior anticancer therapy to PFS time on treatment with MSB0010718C as an exploratory objective.
• Added a further exploratory analysis repeating the analysis of secondary and exploratory objectives that will be conducted 12 months after the accrual of the last subject.
• Added health-related quality of life questionnaires (the EuroQol EQ-5D and Functional Assessment of Cancer Therapy – Melanoma questionnaires) used for a new exploratory objective “To explore the benefits of MSB0010718C as perceived by subjects with metastatic MCC”.
• Aligned the study endpoints with the amended objectives.
• Updated the study procedures and assessments and Schedule of Assessments to align with the added PK sampling and patient reported outcome assessments.
• Clarified discontinuation criteria for therapeutic failure. |
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05 Sep 2014 |
• Added optional subject interviews to the health-related quality of life assessments and added new exploratory endpoint regarding the subjects experience with their disease and treatment as reported in the optional subject interviews.
• Modified language in Inclusion Criterion 3 (histologically proven MCC);
• Added new Inclusion Criterion 4 and allowed for archival biopsy at Screening if fresh or recent biopsy was not feasible;
• Added updated results in the Background Information from previous studies.
• Modified language regarding the collection and storage of tissue samples.
• Modified language regarding pharmacogenetic samples and identity protection.
• Added clarifying language regarding unplanned interim analysis. |
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17 Nov 2014 |
• Added language stipulating that subjects with confirmed CR should stay on treatment for a minimum of 6 months and maximum of 12 months.
• Deleted the 1-year time restriction for re-initiation of treatment for subjects who had confirmed CR and relapse after treatment discontinuation.
• Added an algorithm for the treatment of immune-related AEs.
• Added language stipulating that Grade 3 and 4 diagnostic tests (for example, ECGs, laboratory findings) must be reported as an AE by the Investigator to the Sponsor. |
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22 Dec 2014 |
• Added new safety visits at Week 2, 4, and 6 for blood draws for the analysis of liver enzymes for subjects with liver metastases.
• Modified Inclusion Criterion 7 regarding hepatic function so that all subjects were to have Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) <= 2.5 × Upper limit of normal (ULN).
• Added new Inclusion criterion of estimated life expectancy of 12 weeks. |
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26 Feb 2015 |
• Changed in IMP name from MSB0010718C to avelumab.
• Added tumor shrinkage as exploratory objective and added to endpoints.
• Changed timing of interim analysis.
• Updated safety results.
• Deleted MCV cellular responses from Schedule of Assessments. |
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08 Jan 2016 |
• Designated a “Part A” and “Part B” of the study.
• Designated all subjects who had enrolled in the study prior to Amendment 7 as subjects participating in Part A of the study and updated all sections accordingly – Note, apart from this designation, no changes were made to the language for subjects participating in Part A.
• Added a new cohort of subjects who had not received any prior systemic treatment for metastatic MCC. These subjects were designated as participating in Part B of the study.
• Updated all sections as necessary for the Part A and Part B designations. |
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23 May 2017 |
• To allow for 5-year survival follow-up
• For consistency between Part A and Part B and to ensure complete data collection to evaluate the duration of response in subjects with response regardless of whether they discontinued study drug or not.
• Regular review of safety data by the SMC no longer deemed necessary due to the now well characterized avelumab safety profile.
• Changed the mandatory observation based on the latest avelumab safety information.
• To ensure clarity for Investigators, country reviewers and IRB/IEC reviewers of importance of completion of the trial, even with health authority approvals. |
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25 May 2018 |
• Clarified that survival follow-up for 5 years is for both Parts A and B.
• Added new language regarding continued treatment past initial determination of PD.
• Modified mandatory 2-hour post infusion observation to be based on based upon clinical judgment and presence/severity of prior infusion reactions. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
