Clinical Trial Results:
A Randomized, Double-Blind, Adaptive, Phase II/III Study of GSK3359609 in Combination With Pembrolizumab and 5FU-Platinum Chemotherapy Versus Placebo in Combination With Pembrolizumab Plus 5FU-Platinum Chemotherapy for First-Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Summary
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EudraCT number |
2019-003981-42 |
Trial protocol |
FR SE DK DE BE GB HU PL GR IT RO |
Global end of trial date |
19 Sep 2023
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Results information
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Results version number |
v2(current) |
This version publication date |
03 Oct 2024
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First version publication date |
13 May 2022
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Other versions |
v1 |
Version creation reason |
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 |
209227
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04428333 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
GlaxoSmithKline
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Sponsor organisation address |
Rue de l’Institut 89, Rixensart, Belgium, B-1330
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Public contact |
GSK Response Center, GlaxoSmithKline, 044 2089-904466, GSKClinicalSupportHD@gsk.com
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Scientific contact |
GSK Response Center, GlaxoSmithKline, 044 2089-904466, GSKClinicalSupportHD@gsk.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 Apr 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 |
19 Sep 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 |
To evaluate if the addition of GSK3359609 to pembrolizumab in combination with 5FU-platinum based chemotherapy improves the efficacy of the pembrolizumab combination with 5FU-platinum based chemotherapy in participants with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
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Protection of trial subjects |
Not Applicable
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Aug 2020
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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 |
Argentina: 5
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Country: Number of subjects enrolled |
Australia: 11
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Brazil: 5
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Country: Number of subjects enrolled |
Canada: 10
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Country: Number of subjects enrolled |
Denmark: 1
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Country: Number of subjects enrolled |
France: 9
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Ireland: 6
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Country: Number of subjects enrolled |
Italy: 9
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Country: Number of subjects enrolled |
Japan: 2
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Country: Number of subjects enrolled |
Korea, Republic of: 12
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Country: Number of subjects enrolled |
Poland: 13
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Country: Number of subjects enrolled |
Romania: 12
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Country: Number of subjects enrolled |
Russian Federation: 4
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Country: Number of subjects enrolled |
Spain: 7
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
United States: 3
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Worldwide total number of subjects |
117
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EEA total number of subjects |
61
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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) |
77
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From 65 to 84 years |
40
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment in the study stopped post interim safety/efficacy data review after a pre-specified futility analysis of the 209229 trial. Participants discontinued feladilimab/placebo, but treatment with pembrolizumab + chemotherapy continued until disease progression, death or unacceptable toxicity. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
1 subject was incorrectly re-randomized into the study twice & was given a new subject ID. However, the subject was considered only once for the analyses. An additional subject was randomized after the data cut off for primary posting and received only pembrolizumab. Therefore, this subject is included in safety analysis for LSLV posting | ||||||||||||||||||||||||
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 |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy | ||||||||||||||||||||||||
Arm description |
Participants were administered feladilimab (humanized anti- ICOS immunoglobulin G4 [IgG4] monoclonal antibody [mAb]) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an intravenous (IV) infusion along with 5 Fluorouracil (FU)- platinum chemotherapy (cisplatin OR carboplatin) every 3 weeks (Q3W). | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Feladilimab+ Pembrolizumab+ Platinum chemotherapy (cisplatin/carboplatin)+ Fluorouracil (5FU)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants were administered feladilimab first followed by pembrolizumab and thereafter 5FU-platinum chemotherapy intravenously
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Arm title
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Placebo + Pembrolizumab + 5-FU-platinum chemotherapy | ||||||||||||||||||||||||
Arm description |
Participants were administered placebo and pembrolizumab as an IV infusion along with 5 FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo+ Pembrolizumab+ Platinum chemotherapy (cisplatin/carboplatin)+ Fluorouracil (5FU)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants were administered placebo first followed by pembrolizumab and thereafter 5FU-platinum chemotherapy intravenously
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Baseline characteristics reporting groups
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Reporting group title |
Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
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Reporting group description |
Participants were administered feladilimab (humanized anti- ICOS immunoglobulin G4 [IgG4] monoclonal antibody [mAb]) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an intravenous (IV) infusion along with 5 Fluorouracil (FU)- platinum chemotherapy (cisplatin OR carboplatin) every 3 weeks (Q3W). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo + Pembrolizumab + 5-FU-platinum chemotherapy
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Reporting group description |
Participants were administered placebo and pembrolizumab as an IV infusion along with 5 FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
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Reporting group description |
Participants were administered feladilimab (humanized anti- ICOS immunoglobulin G4 [IgG4] monoclonal antibody [mAb]) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an intravenous (IV) infusion along with 5 Fluorouracil (FU)- platinum chemotherapy (cisplatin OR carboplatin) every 3 weeks (Q3W). | ||
Reporting group title |
Placebo + Pembrolizumab + 5-FU-platinum chemotherapy
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Reporting group description |
Participants were administered placebo and pembrolizumab as an IV infusion along with 5 FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W. | ||
Subject analysis set title |
Feladilimab + pembrolizumab + chemotherapy mITT
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
All randomized participants whether or not randomized intervention was administered, excluding those who were first dosed or randomized after the date of DIL requesting immediate discontinuation of feladilimab/placebo. This analysis set was based on the study intervention to which the participants were randomized.
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Subject analysis set title |
Placebo + pembrolizumab + chemotherapy mITT
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
All randomized participants whether or not randomized intervention was administered, excluding those who were first dosed or randomized after the date of DIL requesting immediate discontinuation of feladilimab/placebo. This analysis set was based on the study intervention to which the participants were randomized.
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Subject analysis set title |
Feladilimab + pembrolizumab + chemotherapy Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized participants who took at least 1 dose of study intervention. Participants were assigned to the actual study intervention group of feladilimab+pembrolizumab if the participants received any dose of feladilimab. Participants were analyzed according to the actual study intervention received.
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Subject analysis set title |
Placebo + pembrolizumab + chemotherapy Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized participants who took at least 1 dose of study intervention. Participants were assigned to the actual study intervention group of feladilimab+pembrolizumab if the participants received any dose of feladilimab. Participants were analyzed according to the actual study intervention received.
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End point title |
Overall Survival (OS) in mITT population | ||||||||||||
End point description |
OS was defined as the time from the date of randomization until the date of death due to any cause. Kaplan-Meier estimate for the median OS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. All randomized participants whether or not randomized intervention was administered, excluding those who were first dosed or randomized after the date of DIL requesting immediate discontinuation of feladilimab /placebo were included in the mITT population. 99999 = The median was not reached at the time of data cut off and the upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
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End point type |
Primary
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End point timeframe |
Up to approximately 7 months
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and Human Papilloma Virus (HPV) status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
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Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
[1] | ||||||||||||
P-value |
= 0.74 [2] | ||||||||||||
Method |
Stratified Cox proportional hazard model | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
2.16
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
23.87 | ||||||||||||
Notes [1] - Other [2] - Nominal p-value was calculated based on the one sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx). |
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End point title |
OS in programmed death receptor-ligand 1 (PD-L1) combined positive score (CPS) ≥1 population | ||||||||||||
End point description |
OS was defined as the time from the date of randomization until the date of death due to any cause. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Kaplan-Meier estimate for the median OS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method in PD-L1 CPS ≥1 subjects from mITT population. 99999 = The median was not reached at the time of data cut off and the upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
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End point type |
Primary
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End point timeframe |
Up to approximately 7 months
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
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Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
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Number of subjects included in analysis |
101
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Analysis specification |
Pre-specified
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Analysis type |
[3] | ||||||||||||
P-value |
= 0.74 [4] | ||||||||||||
Method |
Stratified Cox proportional hazard model | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
2.16
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
23.87 | ||||||||||||
Notes [3] - Other [4] - Nominal p-value was calculated based on the one sided log-rank test, stratified by stratified by PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx). |
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End point title |
Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 in mITT population | ||||||||||||
End point description |
PFS per RECIST version (v)1.1 was defined as the time from the date of randomization to the date of first documented disease progression or death due to any cause, whichever occurs first. Kaplan-Meier estimate for the median PFS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. All participants in the mITT population were analyzed.
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End point type |
Primary
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End point timeframe |
Up to approximately 7 months
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
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Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
[5] | ||||||||||||
P-value |
= 0.284 [6] | ||||||||||||
Method |
Stratified Cox proportional hazard model | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.7
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
2.43 | ||||||||||||
Notes [5] - Other [6] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx). |
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End point title |
PFS per RECIST v1.1 in the PD-L1 CPS ≥1 population | ||||||||||||
End point description |
PFS per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 was defined as the time from the date of randomization to the date of first documented disease progression or death due to any cause, whichever occurs first. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants in the mITT population with PD-L1 CPS ≥1 is presented here. Kaplan-Meier estimate for the median PFS are presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method.
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End point type |
Secondary
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End point timeframe |
Up to approximately 7 months
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
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Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
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Number of subjects included in analysis |
101
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Analysis specification |
Pre-specified
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Analysis type |
[7] | ||||||||||||
P-value |
= 0.284 [8] | ||||||||||||
Method |
Stratified Cox proportional hazard model | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.7
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
2.43 | ||||||||||||
Notes [7] - Other [8] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx). |
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End point title |
Overall Response Rate (ORR) per RECIST v1.1 in mITT population | ||||||||||||
End point description |
ORR per RECIST v1.1 was defined as the proportion of the participants who have a complete response (CR) or partial response (PR) as the best overall response per RECIST v1.1 based upon investigator assessment. As a randomized double-blind study in which primary endpoints are OS and PFS, the confirmation of CR and PR was not required. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. All participants in the mITT population were analyzed.
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End point type |
Secondary
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End point timeframe |
Up to approximately 7 months
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The comparison between treatment groups was based on the stratified Miettinen & Nurminen method with strata weighting by sample size and a single treatment covariate. Stratification factors included PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
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Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
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Method |
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Parameter type |
Difference in Percentage | ||||||||||||
Point estimate |
-4.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-20.8 | ||||||||||||
upper limit |
11.3 |
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End point title |
Milestone OS rate at 12, 24 and 36 months in PD-L1 CPS ≥1 population | ||||||||||||
End point description |
Milestone OS rate at 12, 24, and 36 months was not evaluated. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells.
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End point type |
Secondary
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End point timeframe |
Months 12, 24 and 36
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Notes [9] - No participant had follow-up duration exceeding 12 months. [10] - No participant had follow-up duration exceeding 12 months. |
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No statistical analyses for this end point |
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End point title |
Milestone OS rate at 12, 24 and 36 months in mITT population | ||||||||||||
End point description |
Milestone OS rate at 12, 24, and 36 months was not evaluated.
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End point type |
Secondary
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End point timeframe |
Months 12, 24 and 36
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Notes [11] - No participant had follow-up duration exceeding 12 months. [12] - No participant had follow-up duration exceeding 12 months. |
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No statistical analyses for this end point |
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End point title |
Disease Control Rate (DCR) per RECIST v1.1 in mITT population | ||||||||||||
End point description |
DCR per RECIST v1.1 based upon investigator assessment, was defined as the percentage of participants with a best overall response of CR or PR at any time plus stable disease (SD) meeting the minimum time of 15 weeks. A status of SD≥15 weeks will be assigned if the follow-up disease assessment has met the SD criteria at least once after the date of randomization at a minimum of 14 weeks (98 days) considering a one-week visit window. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. All participants in the mITT population were analysed.
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End point type |
Secondary
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End point timeframe |
Up to approximately 7 months
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The comparison between treatment groups was based on the stratified Miettinen & Nurminen method with strata weighting by sample size and a single treatment covariate. Stratification factors included PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
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||||||||||||
Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in Percentage | ||||||||||||
Point estimate |
-4.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-22.2 | ||||||||||||
upper limit |
13.1 |
|
|||||||||||||
End point title |
ORR per RECIST v1.1 in PD-L1 CPS ≥1 population | ||||||||||||
End point description |
ORR per RECIST v1.1 was defined as the proportion of the participants who have a CR or PR as the best overall response per RECIST v1.1 based upon investigator assessment. As a randomized double-blind study in which primary endpoints are OS and PFS, the confirmation of CR and PR was not required. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants in the mITT population with PD-L1 CPS ≥1 are presented here.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The comparison between treatment groups was based on the stratified Miettinen & Nurminen method with strata weighting by sample size and a single treatment covariate. Stratification factors included PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
|
||||||||||||
Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
|
||||||||||||
Number of subjects included in analysis |
101
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in Percentage | ||||||||||||
Point estimate |
-5.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-21.4 | ||||||||||||
upper limit |
11.3 |
|
|||||||||||||
End point title |
Duration of Response (DoR) per RECIST v1.1 in mITT population | ||||||||||||
End point description |
DoR per RECIST v1.1 is defined as the time from first documented evidence of CR or PR until first documented disease progression per RECIST v1.1 based upon investigator assessment or death due to any cause, whichever occurs first, among participants who demonstrated CR or PR as the best overall response per RECIST v1.1. Kaplan-Meier estimate for the median DoR is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with a best overall response of CR or PR in mITT population are presented. 99999 = The median was not reached at the time of data cut off, the lower and upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
DCR per RECIST v1.1 in PD-L1 CPS ≥1 population | ||||||||||||
End point description |
DCR per RECIST v1.1 based upon investigator assessment, was defined as the percentage of participants with a best overall response of CR or PR at any time plus SD meeting the minimum time of 15 weeks. A status of SD≥15 weeks will be assigned if the follow-up disease assessment has met the SD criteria at least once after the date of randomization at a minimum of 14 weeks (98 days) considering a one-week visit window. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants in the mITT population with PD-L1 CPS ≥1 are presented here.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The comparison between treatment groups was based on the stratified Miettinen & Nurminen method with strata weighting by sample size and a single treatment covariate. Stratification factors included PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
|
||||||||||||
Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
|
||||||||||||
Number of subjects included in analysis |
101
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
Method |
|||||||||||||
Parameter type |
Difference in Percentage | ||||||||||||
Point estimate |
-5.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-22.8 | ||||||||||||
upper limit |
13.3 |
|
|||||||||||||
End point title |
DoR per RECIST v1.1 in PD-L1 CPS ≥1 population | ||||||||||||
End point description |
DoR per RECIST v1.1 is defined as the time from first documented evidence of CR or PR until first documented disease progression per RECIST v1.1 based upon investigator assessment or death due to any cause, whichever occurs first, among participants who demonstrated CR or PR as the best overall response per RECIST v1.1. Kaplan-Meier estimate for the median DoR is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with a best overall response of CR or PR in mITT population with PD-L1 CPS ≥1 are presented. 99999 = The median was not reached at the time of data cut off, the lower and upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants with adverse Events of Special Interest (AESI) in safety population | |||||||||
End point description |
AESI was defined as events of potential immunologic etiology, including immune-related (ir) AEs. Safety Population. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 37.2 months
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants with AEs in PD-L1 CPS ≥1 population | |||||||||
End point description |
An AE was defined as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant’s participation in the research, whether or not considered related to the participant’s participation in the research in PD-L1 CPS ≥1 participants from safety population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with PD-L1 CPS ≥1 in the safety population are presented. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 37.2 months
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants with Adverse Events (AEs) in safety population | |||||||||
End point description |
An AE was defined as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant’s participation in the research, whether or not considered related to the participant’s participation in the research. Safety Population: All randomized participants who took at least 1 dose of study intervention. Participants were analyzed according to the actual study intervention received. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 37.2 months
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants with Serious Adverse Events (SAEs) in safety population | |||||||||
End point description |
A SAE was defined as any untoward medical occurrence that, at any dose, results in death, was life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, was a congenital anomaly/birth defect and other situations according to medical or scientific judgement. Safety Population. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 37.2 months
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Severity of AEs in safety population | ||||||||||||||||||||||||
End point description |
Severity of each AE was reported during the study and was assigned a grade according to the National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE). AEs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. Safety Population. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Up to approximately 37.2 months
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants with AESIs in PD-L1 CPS ≥1 population | |||||||||
End point description |
AESI was defined as events of potential immunologic etiology, including irAEs in PD-L1 CPS ≥1 participants from safety population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with PD-L1 CPS ≥1 in the safety population are presented. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 37.2 months
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants with SAEs in PD-L1 CPS ≥1 population | |||||||||
End point description |
A SAE was defined as any untoward medical occurrence that, at any dose, results in death, was life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, was a congenital anomaly/birth defect and other situations according to medical or scientific judgement in PD-L1 CPS ≥1 participants from safety population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with PD-L1 CPS ≥1 in the safety population are presented. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 37.2 months
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Severity of SAEs in safety population | ||||||||||||
End point description |
Severity of each SAE was reported during the study and was assigned a grade according to the NCI-CTCAE. SAEs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. Data of participants experiencing SAEs of Grade >= 3 have been presented. Safety Population. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 37.2 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Severity of AESIs in safety population | ||||||||||||
End point description |
Severity of each AESI was reported during the study and was assigned a grade according to the NCI-CTCAE. AESIs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. Data of participants experiencing AESIs of Grade >= 3 has been presented. Data of participants experiencing AESIs of Grade >= 3 have been presented. Safety Population. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 37.2 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Severity of AESI in PD-L1 CPS ≥1 population | ||||||||||||
End point description |
Severity for each AESI was reported during the study and assigned a grade according to the NCI-CTCAE v5.0. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with PD-L1 CPS ≥1 in the safety population experiencing AESIs of Grade ≥3 have been presented. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 37.2 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Severity of AEs in PD-L1 CPS ≥1 population | ||||||||||||
End point description |
Severity for each AE was reported during the study and assigned a grade according to the NCI-CTCAE v5.0. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with PD-L1 CPS ≥1 in the safety population experiencing AEs of Grade ≥3 have been presented. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 37.2 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Severity of SAEs in PD-L1 CPS ≥1 population | ||||||||||||
End point description |
Severity for each SAE was reported during the study and assigned a grade according to the NCI-CTCAE v5.0. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with PD-L1 CPS ≥1 in the safety population experiencing SAEs of Grade ≥3 have been presented. An additional participant was randomized after the data cut off and received pembrolizumab. Therefore, participant was included in safety analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 37.2 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of participants with dose modifications in safety population | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of participants with dose modifications (including dose interruptions, dose delays, dose reductions and treatment discontinuations) were reported by each interventional component. All participants in the safety population were analyzed. 99999 = The numbers are reported per component and dose reductions were not permitted for feladilimab/placebo/pembrolizumab. The data presented is based on the primary data cut-off.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of participants with dose modifications in PD-L1 CPS ≥1 population | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of participants with dose modifications (i.e. interruptions, discontinuations) in the PD-L1 CPS ≥1 population was reported. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. 99999 = The numbers are reported per component and dose reductions were not permitted for feladilimab/placebo/pembrolizumab. The data presented is based on the primary data cut-off.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Time to deterioration in pain in mITT population | ||||||||||||
End point description |
TTD in pain is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the European Organization for Research and Treatment of Cancer Item Library(EORTC IL51) Questionnaire pain domain, i.e. an increase from baseline of at least 8.33 observed at all subsequent non-missing visits. The EORTC Quality of Life Questionnaire 35-Item Head and Neck Module (QLQ-H&N35) is a head and neck specific module with multi-item scales. The questionnaire scores for each scale and single-item measure are averaged and transformed linearly to present a score ranging from 0–100. A high score represents a high/healthy level of functioning. Kaplan-Meier estimate for the median TTD is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. All participants in the mITT population were analysed. 99999 = The upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
|
||||||||||||
Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
[13] | ||||||||||||
P-value |
= 0.329 [14] | ||||||||||||
Method |
Stratified Cox proportional hazard model | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.85
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.42 | ||||||||||||
upper limit |
1.71 | ||||||||||||
Notes [13] - Other [14] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx). |
|
|||||||||||||
End point title |
Time to deterioration in physical function in mITT population | ||||||||||||
End point description |
TTD in physical function is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the Physical Function (PF) T-score, i.e. a decrease from baseline of at least 2.4 observed at all subsequent non-missing visits, as measured by the Patient-Reported Outcomes Measurement Information System - Physical Function (PROMIS PF 8c). The PROMIS PF 8c is an 8-item fixed length short form derived from the PROMIS Physical Function item bank. It includes a 5-point scale with three sets of response options. Scores on the PROMIS PF 8c are reported on a T score metric (mean = 50 and SD = 10), with higher scores reflecting better physical functioning. All participants in the mITT population were analyzed. 99999 = The upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
|
||||||||||||
Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
[15] | ||||||||||||
P-value |
= 0.472 [16] | ||||||||||||
Method |
Stratified Cox proportional hazard model | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.96
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.44 | ||||||||||||
upper limit |
2.11 | ||||||||||||
Notes [15] - Other [16] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx). |
|
|||||||||||||
End point title |
Time to deterioration in pain in PD-L1 CPS ≥1 populations | ||||||||||||
End point description |
TTD in pain is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the EORTC IL51 pain domain, i.e. an increase from baseline of at least 8.33 observed at all subsequent non-missing visits. The EORTC QLQ-H&N35 is a head and neck specific module with multi-item scales. The mouth pain, swallowing, speech problems, opening mouth, coughing, feeding tube, and trouble with social eating domains were administered and referred to as the EORTC IL51. The questionnaire scores for each scale and single-item measure are averaged and transformed linearly to present a score ranging from 0–100. A high score represents a high/healthy level of functioning. 99999 = The upper limit of the 95% CI was not calculable from the available data at the time of data cut off. Data for participants with PD-L1 CPS ≥1 in the mITT population are presented.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 7 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
|
||||||||||||
Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
[17] | ||||||||||||
P-value |
= 0.302 [18] | ||||||||||||
Method |
Stratified Cox proportional hazard model | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.82
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.4 | ||||||||||||
upper limit |
1.69 | ||||||||||||
Notes [17] - Other [18] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx). |
|
|||||||||||||
End point title |
Time to deterioration in physical function in PD-L1 CPS ≥1 population | ||||||||||||
End point description |
TTD in physical function is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the PF T-score, i.e. a decrease from baseline of at least 2.4 observed at all subsequent non-missing visits, as measured by the PROMIS PF 8c. The PROMIS PF 8c is an 8-item fixed length short form derived from the PROMIS Physical Function item bank. It includes a 5-point scale with three sets of response options. Scores on the PROMIS PF 8c are reported on a T score metric (mean = 50 and SD = 10), with higher scores reflecting better physical functioning. Data are presented for the PD-L1 CPS ≥1 participants from mITT population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. 99999 = The upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
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End point type |
Secondary
|
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End point timeframe |
Up to approximately 7 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
|
||||||||||||
Comparison groups |
Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
|
||||||||||||
Number of subjects included in analysis |
101
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
[19] | ||||||||||||
P-value |
= 0.335 [20] | ||||||||||||
Method |
Stratified Cox proportional hazard model | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.83
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.36 | ||||||||||||
upper limit |
1.9 | ||||||||||||
Notes [19] - Other [20] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx). |
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Adverse events information
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Timeframe for reporting adverse events |
All cause mortality, non-SAEs and SAEs were collected from Day 1 to up to approximately 37.2 months.
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Adverse event reporting additional description |
Six participants randomized to feladilimab arm, received first dose after the DIL date were re-assigned to placebo arm.1 participant randomized to feladilimab arm, was never dosed and excluded from the safety population. Safety data for participants who continued to receive Pembrolizumab has been updated after study completion.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.0
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Reporting groups
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Reporting group title |
Placebo + Pembrolizumab + 5-FU-platinum chemotherapy
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants were administered placebo and pembrolizumab as an IV infusion along with 5FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
|
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Reporting group description |
Participants were administered feladilimab (humanized anti- ICOS IgG4 mAb) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an IV infusion along with 5 FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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13 Apr 2021 |
Amendment 1: The primary rationale for the amendment was to account for a study design update from a Phase III study to an adaptive Phase II/III study which allows for a proper balance of the risk and benefit of a Phase III expansion decision. Additional updates included were: eligibility criteria to address high risk of bleeds that are a feature inherent to the underlying disease of a population with HNSCC and define unstable medical condition; definition of second course of study treatment that was expanded to include participants who complete 35 cycles of study treatment. |
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30 Jun 2021 |
Amendment 2: A DIL dated 13-April-2021 was issued requiring the stopping of further screening and the discontinuation of the administration of GSK3359609 (feladilimab) or placebo for all participants on INDUCE-4, effective immediately. Further to the DIL, since all participants had the option to remain on pembrolizumab alone plus 5FU-platinum as study therapy, GSK issued a Protocol Clarification Letter (PCL) dated 28-April-2021 to reduce any unnecessary burden of on treatment and follow up assessments (the PCL did not alter any screening assessments). This protocol amendment was a follow up to the PCL, with a primary intent to only update the SoA; other impacted, relevant sections were also updated accordingly. Additionally, updates were made to management guidelines to align with pembrolizumab IB update. |
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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. | |||
Data are reported following the interim analysis decision to stop further accrual into the study and discontinue feladilimab/placebo. The study primary completion analysis results should be interpreted with consideration of the immature data |