Clinical Trial Results:
A Phase IIa, single-arm, multicenter study to investigate the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in participants with advanced squamous non-small-cell lung cancer
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Summary
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EudraCT number |
2018-001529-24 |
Trial protocol |
HU ES |
Global end of trial date |
27 May 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
29 May 2022
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First version publication date |
29 May 2022
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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 |
MS201944-0170
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03717155 | ||
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 Center, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151 72 5200, service@merckgroup.com
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Scientific contact |
Communication Center, 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 |
27 May 2021
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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 |
27 May 2021
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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 objective of the study was to investigate the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in subjects with treatment-naïve advanced non-small-cell lung cancer (NSCLC).
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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 |
30 Oct 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Spain: 15
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Country: Number of subjects enrolled |
Hungary: 11
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Country: Number of subjects enrolled |
Serbia: 17
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Worldwide total number of subjects |
43
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EEA total number of subjects |
26
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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) |
20
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From 65 to 84 years |
23
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85 years and over |
0
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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 43 subjects were enrolled in this study at different sites in Hungary, Serbia and Spain. | ||||||
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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 |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Avelumab and Cetuximab | ||||||
Arm description |
Subjects received 800 milligrams Avelumab, 1250 milligrams per square meter (mg/m^2) gemcitabine on Day 1 and Day 8, cisplatin at a dose of 75 mg/m^2 on Day 1 along with 250 mg/m2 body surface area Cetuximab on Day 1 and 500 mg/m2 body surface area on Day 8 of each cycle as intravenous (IV) infusions up to maximum of 4 cycles (each cycle is of 3 weeks) until disease progression or unacceptable toxicities. In case of cisplatin toxicities, subjects were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles. Subsequently subjects were administered with avelumab and cetuximab as IV infusion at the dose of 800 mg and 500 mg/m^2 respectively, every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities. | ||||||
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 |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received avelumab intravenous infusions at a dose of 800 milligram (mg) on Day 1 and Day 8 of each 3-week cycle for the first 4 cycles. Thereafter, administered every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities.
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Investigational medicinal product name |
Cetuximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received cetuximab intravenous infusions at a dose of 250 milligram per meter square (mg/m^2) body surface area on Day 1 and 500 mg/m^2 body surface area on Day 8 of first 4 cycles of concurrent chemotherapy. Thereafter, administered given at a dose of 500 mg/m^2 intravenous every 2 weeks in the Maintenance phase, until disease progression or unacceptable toxicities.
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Investigational medicinal product name |
Gemcitabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received gemcitabine intravenous infusions at a dose of 1250 mg/m^2 body surface area on Day 1 and Day 8 in 3-week cycles up to a maximum of 4 cycles, until disease progression or unacceptable toxicities.
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Investigational medicinal product name |
Cisplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received cisplatin intravenous infusions at a dose of 75 mg/m^2 body surface area on Day 1 of 3-week cycles up to a maximum of 4 cycles, until disease progression or unacceptable toxicities.
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Investigational medicinal product name |
Carboplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
In case of cisplatin toxicities, subjects were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles.
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Baseline characteristics reporting groups
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Reporting group title |
Avelumab and Cetuximab
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Reporting group description |
Subjects received 800 milligrams Avelumab, 1250 milligrams per square meter (mg/m^2) gemcitabine on Day 1 and Day 8, cisplatin at a dose of 75 mg/m^2 on Day 1 along with 250 mg/m2 body surface area Cetuximab on Day 1 and 500 mg/m2 body surface area on Day 8 of each cycle as intravenous (IV) infusions up to maximum of 4 cycles (each cycle is of 3 weeks) until disease progression or unacceptable toxicities. In case of cisplatin toxicities, subjects were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles. Subsequently subjects were administered with avelumab and cetuximab as IV infusion at the dose of 800 mg and 500 mg/m^2 respectively, every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Avelumab and Cetuximab
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Reporting group description |
Subjects received 800 milligrams Avelumab, 1250 milligrams per square meter (mg/m^2) gemcitabine on Day 1 and Day 8, cisplatin at a dose of 75 mg/m^2 on Day 1 along with 250 mg/m2 body surface area Cetuximab on Day 1 and 500 mg/m2 body surface area on Day 8 of each cycle as intravenous (IV) infusions up to maximum of 4 cycles (each cycle is of 3 weeks) until disease progression or unacceptable toxicities. In case of cisplatin toxicities, subjects were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles. Subsequently subjects were administered with avelumab and cetuximab as IV infusion at the dose of 800 mg and 500 mg/m^2 respectively, every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities. | ||
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End point title |
Percentage of Subjects With Confirmed Best Objective Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Assessed by Investigator [1] | ||||||||
End point description |
Confirmed BOR was defined as the percentage of subjects who achieved confirmed CR or PR, according to RECIST version 1.1 assessed by Investigator.CR: Disappearance of all evidence of target & non-target lesions. PR: At least 30% reduction from baseline in SLD of all lesions. SD= Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: At least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline or appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Full analysis set includes all subjects who received at least one non-zero dose of any study treatment. Full analysis set includes all subjects who received at least one non-zero dose of any study treatment.
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End point type |
Primary
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End point timeframe |
Time from the first dose of study drug until occurrence of PD, death due to any cause (assessed up to 612 days)
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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: Only descriptive summary statistics was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects with Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events (AEs), Treatment-Related Grade >=3 AEs and Immune-related AEs (irAEs) | ||||||||||||||
End point description |
AE was defined as any unfavorable & unintended sign (including an abnormal laboratory finding), symptom, or disease associated with use of study drug, whether or not considered related to study drug or worsening of pre-existing medical condition, whether or not related to study drug. SAE was an AE that resulted in any of the following outcomes: death; life threatening; significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE is defined as AEs starting or worsening after first intake of study drug. TEAEs include both Serious & non-serious TEAEs. irAEs included AEs that matches a preferred term on list of pre-selected MedDRA terms. AEs with relationship to study treatment are reported as Treatment-related AEs. Treatment related AEs with grade 3 or more is also reported. Safety analysis set included all subjects who received at least one non-zero dose of any study treatment.
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End point type |
Secondary
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End point timeframe |
Time from the first dose of study drug assessed up to (941 days)
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Progression-Free Survival (PFS) Time Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | ||||||||
End point description |
Progression free survival (PFS) is defined as the time (in months) from first treatment day to the date of the first documentation of objective progression of disease (PD) according to RECIST version 1.1 assessed by Investigator, or death due to any cause, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Full analysis set includes all subjects who received at least one non-zero dose of any study treatment.
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End point type |
Secondary
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End point timeframe |
Time from the first dose of study drug until occurrence of PD, death due to any cause (assessed up to 737 days)
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of response (DOR) | ||||||||
End point description |
DOR is defined for subjects with confirmed complete response (CR) or partial response (PR), as the time from first documentation of confirmed response to the date of first documentation of progression of disease (PD) according to RECIST version 1.1 (assessed by Investigator) or death due to any cause. Duration of objective response was assessed using Kaplan-Meier analysis. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Full analysis set included all subjects who receive at least one non-zero dose of any study treatment. Here "Overall number of subjects analyzed" signifies those subjects who had confirmed CR or PR.
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End point type |
Secondary
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End point timeframe |
Time from the first dose of study drug until occurrence of PD, death due to any cause (assessed up to 612 days)
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| No statistical analyses for this end point | |||||||||
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End point title |
Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | ||||||||||||||||||||||||||||||||||||||
End point description |
Ceoi is the serum concentration observed immediately at the end of infusion. This was taken directly from the observed Avelumab concentration-time data. Pharmacokinetic (PK) analysis set included all subjects who received at least one dose of avelumab and/or cetuximab, have no important events affecting PK, and provide at least one measurable post-dose concentration. Number of Subjects Analyzed=subjects evaluable for this endpoint & n=subjects evaluated at specified time point.
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End point type |
Secondary
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End point timeframe |
Pre-dose, 2 hours after end of infusion on Day 1, 8, 22 and 29; Pre-dose, 30 minutes after the end of infusion on Day 43, 50, 64, 71; Pre-dose, 3 hours after end of infusion on Day 85, 99, 113, 127, 169, 253, and 337
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
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End point title |
Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | ||||||||||||||||||||||||||||||||||||||
End point description |
Ceoi is the serum concentration observed immediately at the end of infusion. This was taken directly from the observed cetuximab concentration-time data. PK analysis set included all subjects who received at least one dose of avelumab and/or cetuximab, have no important events affecting PK, and provide at least one measurable post-dose concentration. Here, n=subjects evaluated at specified time point.
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End point type |
Secondary
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End point timeframe |
Pre-dose, 2 hours after end of infusion on Day 1, 8, 22 and 29; Pre-dose, 30 minutes after the end of infusion on Day 43, 50, 64, 71; Pre-dose, 3 hours after end of infusion on Day 85, 99, 113, 127, 169, 253, and 337
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
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End point title |
Serum Trough Concentration Levels (Ctrough) of Avelumab | ||||||||||||||||||||||||||||||||||||
End point description |
Ctrough is the serum concentration observed immediately before next dosing. PK analysis set included all subjects who received at least one dose of avelumab and/or cetuximab, have no important events affecting PK, and provide at least one measurable post-dose concentration. Number of Subjects Analyzed=subjects evaluable for this endpoint and n=subjects evaluated at specified time point.
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End point type |
Secondary
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End point timeframe |
Pre-dose: Day 8, Day 22, Day 29, Day 43, Day 50, Day 64, Day 71, Day 85, Day 99, Day 113, Day 127, Day 169, Day 253 and Day 337
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Serum Trough Concentration Levels (Ctrough) of Cetuximab | ||||||||||||||||||||||||||||||||||||
End point description |
Ctrough is the serum concentration observed immediately before next dosing. PK analysis set included all subjects who received at least one dose of avelumab and/or cetuximab, have no important events affecting PK, and provide at least one measurable post-dose concentration. Number of Subjects Analyzed=subjects evaluable for this endpoint and n=subjects evaluated at specified time point.
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End point type |
Secondary
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End point timeframe |
Pre-dose: Day 8, Day 22, Day 29, Day 43, Day 50, Day 64, Day 71, Day 85, Day 99, Day 113, Day 127, Day 169, Day 253 and Day 337
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Overall Survival (OS) | ||||||||
End point description |
OS is defined as the time from the first treatment day to the date of death due to any cause. Overall survival was assessed using Kaplan-Meier analysis. Full analysis set includes all subjects who received at least one non-zero dose of any study treatment. Here, n=subjects evaluated at specified time point.
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End point type |
Secondary
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End point timeframe |
Time from the first dose of study drug until occurrence of death due to any cause (assessed up to 941 days)
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects with Positive Anti-Drug Antibody (ADA) of Avelumab | ||||||
End point description |
The detection of antibodies to avelumab was performed using a validated immunoassay method with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of avelumab were reported. ADA analysis set included all subjects who received at least 1 dose of avelumab and/or cetuximab and have at least 1 valid ADA result.
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End point type |
Secondary
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End point timeframe |
Pre-dose up to 149 days
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects Positive for Anti-Drug Antibody (ADA) of Cetuximab | ||||||
End point description |
The detection of antibodies to cetuximab was performed using a validated immunoassay method with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of cetuximab were reported. ADA analysis set included all subjects who receive at least 1 dose of avelumab and/or cetuximab and have at least 1 valid ADA result.
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End point type |
Secondary
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End point timeframe |
Pre-dose up to 149 days
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
Time from the first dose of study drug until 941 days.
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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 |
24.0
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Reporting groups
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Reporting group title |
Avelumab and Cetuximab
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Reporting group description |
Subjects received 800 milligrams Avelumab, 1250 milligrams per square meter (mg/m^2) gemcitabine on Day 1 and Day 8, cisplatin at a dose of 75 mg/m^2 on Day 1 along with 250 mg/m2 body surface area Cetuximab on Day 1 and 500 mg/m2 body surface area on Day 8 of each cycle as intravenous (IV) infusions up to maximum of 4 cycles (each cycle is of 3 weeks) until disease progression or unacceptable toxicities. In case of cisplatin toxicities, subjects were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles. Subsequently subjects were administered with avelumab and cetuximab as IV infusion at the dose of 800 mg and 500 mg/m^2 respectively, every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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20 Aug 2019 |
update of inclusion criterion number 1 regarding the
upper age limit. In addition, switch to on-study anticancer therapy with carboplatin will be allowed for participants who cannot tolerate treatment with cisplatin. |
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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 | |||
