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    Clinical Trial Results:
    A randomized parallel group phase III trial of OSE 2101 as 2nd or 3rd line compared with standard treatment (docetaxel or pemetrexed) in HLA-A2 positive patients with locally advanced (IIIB) unsuitable for radiotherapy or metastatic (IV) Non-Small-Cell Lung Cancer. (OSE2101C301)

    Summary
    EudraCT number
    		 2015-003183-36
    Trial protocol
    		 CZ   HU   DE   ES   PL   SI   IT  
    Global end of trial date
    15 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Sep 2023
    First version publication date
    26 Nov 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0OSE2101C301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02654587
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    OSE Immunotherapeutics
    Sponsor organisation address
    22, boulevard Benoni Goullin, Nantes, France, 44200
    Public contact
    Clinical Development, OSE Immunotherapeutics, +33 143 29 78 57, contact@ose-immuno.com
    Scientific contact
    Clinical Development, OSE Immunotherapeutics, +33 143 29 78 57, contact@ose-immuno.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Step 1 (phase II) 2:1 randomized non-comparative one stage Fleming phase II Primary objective To evaluate the overall survival (OS) rate at 12 months in HLA-A2 positive patients with locally advanced (IIIB) or metastatic (IV) NSCLC as 2nd or 3rd line therapy after failure of checkpoint-inhibitor regimens. Step 2 (conditional phase III) comparative randomized phase III Primary objective To demonstrate that OSE2101 is superior to control treatment with respect to overall survival (OS) in HLA-A2 positive patients with locally advanced (IIIB) or metastatic (IV) NSCLC as 2nd or 3rd line therapy after failure of checkpoint-inhibitor regimens.
    Protection of trial subjects
    Patients were completely free to refuse to enter the study or to withdraw from it at any time for any reason. Patients with recognized immunodeficiency disease including human immunodeficiency virus (HIV) infection and other cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects who have hereditary, congenital or acquired immunodeficiencies, patients with auto-immune disease, with the exception of type I diabetes or treated hypothyroidism, and patients with severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, were excluded from the study. Female patients had to be surgically sterile or be postmenopausal, or had to agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. Male patients sexually active with a woman of childbearing potential had to be surgically sterile or had to agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. Pregnant and breastfeeding women were also excluded from the trial.
    Background therapy
    		 Patients in Arm B required premedication as per product information. Unless started earlier for other reasons, the premedication started before day 1 of each cycle (i.e. day 1 of each cycle will be injection day for chemotherapy). - Patients in Arm B with docetaxel: Patients were required to take dexamethasone, 8 mg orally, twice daily, the day before, the day of and the day after docetaxel dosing. Intramuscular or intraperitoneal administration of dexamethasone with the same total dose as oral dexamethasone, or equivalent corticosteroids, were allowed per country regulations. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities. - Patients in Arm B with Pemetrexed Patients were required to take folic acid, 350-1000 µg orally daily beginning approximately 1 to 2 weeks before the first dose of pemetrexed and continuing daily until 3 weeks after the last dose of pemetrexed. Vitamin B12, 1000 µg, was injected intramuscularly approximately 1 to 2 weeks before the first dose of pemetrexed and was repeated approximately every 9 weeks until discontinuation. Patients were also be required to take dexamethasone, 4 mg orally, twice daily, the day before, the day of and the day after pemetrexed dosing. Intramuscular or intraperitoneal administration of dexamethasone with the same total dose as oral dexamethasone was allowed per country regulations.
    Evidence for comparator
    		 Reference therapy was available and approved alike in the US and Europe as the trial extent needed to reach these 2 regions and thus only docetaxel and pemetrexed meet this criterion. Docetaxel was reference therapy in squamous cancer and pemetrexed was reference therapy in non-squamous NSCLC, due to having a better safety profile combined with proven efficacy in this indication.
    Actual start date of recruitment
    12 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    France: 82
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    219
    EEA total number of subjects
    189
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    108
    From 65 to 84 years
    110
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 First Patient First Visit: February 12, 2016 Last Patient Last Visit: January 15, 2021 The study was discontinued on April 1st, 2020 because of the COVID-19 pandemic at the recommendations of the IDMC and Steering Committee when 219 patients had been enrolled.

    Pre-assignment
    Screening details
    		 Pre-screening: HLA-A2 testing (using PCR methods) can be done at any time before inclusion (a specific consent form is available). Screening: 1 to 35 days before treatment administration.

    Pre-assignment period milestones
    Number of subjects started
    		 312 [1]
    Number of subjects completed
    		 219

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Not eligible (did not receive ICI as prior therapy: 93
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: No data were analysed for patients who were not eigible.
    Period 1
    Period 1 title
    Treatment period step 1 & 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - OSE2101
    Arm description
    		 OSE2101: Day 1 each 21-day cycle for 6 cycles, then every 8 weeks for the remainder of year one and, finally every 12 weeks beyond year one.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OSE2101
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients randomized to OSE2101 received 1 mL of OSE2101 administered subcutaneously on Day 1 every three weeks for six cycles, then every eight weeks for the remainder of year one and, finally every twelve weeks beyond year one until unequivocal RECIST 1.1-defined disease progression as determined by the investigator, unacceptable toxicity, or consent withdrawal.

    Arm title
    		 Arm B - docetaxel or pemetrexed
    Arm description
    		 Docetaxel (patients with squamous cancer) or pemetrexed (patients with non-squamous NSCLC): Day 1 each 21-day cycle (i.e. every 3 weeks)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Patients randomized to docetaxel received standard approved NSCLC dose: 75 mg/m2 in 1 hour infusion every 3 weeks. Docetaxel was prepared as per the manufacturer’s recommendations. Patients were also be required to take dexamethasone, 8 mg orally, twice daily, the day before, the day of and the day after docetaxel dosing. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities at the discretion of the investigator.

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Patients randomized to pemetrexed received standard approved NSCLC dose: 500 mg/m2 in 10-minute infusion every 3 weeks. Pemetrexed was prepared as per the manufacturer’s recommendations. Patients were also be required to take folic acid, 350-1000 µg orally daily beginning approximately 1 to 2 weeks before the first dose of pemetrexed and continuing daily until 3 weeks after the last dose of pemetrexed. Vitamin B12, 1000 µg, was injected intramuscularly approximately 1 to 2 weeks before the first dose of pemetrexed and was repeated approximately every 9 weeks until discontinuation. Patients were also be required to take dexamethasone, 4 mg orally, twice daily, the day before, the day of and the day after pemetrexed dosing.

    Number of subjects in period 1
    		Arm A - OSE2101 Arm B - docetaxel or pemetrexed
    Started
    139
    80
    Completed
    2
    1
    Not completed
    137
    79
         Adverse event, serious fatal
    5
    6
         Consent withdrawn by subject
    1
    2
         Disease progression
    109
    49
         Adverse event, non-fatal
    17
    14
         Other
    4
    2
         Not treated
    1
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - OSE2101
    Reporting group description
    		 OSE2101: Day 1 each 21-day cycle for 6 cycles, then every 8 weeks for the remainder of year one and, finally every 12 weeks beyond year one.

    Reporting group title
    Arm B - docetaxel or pemetrexed
    Reporting group description
    		 Docetaxel (patients with squamous cancer) or pemetrexed (patients with non-squamous NSCLC): Day 1 each 21-day cycle (i.e. every 3 weeks)

    Reporting group values
    		 Arm A - OSE2101 Arm B - docetaxel or pemetrexed Total
    Number of subjects
    		 139 80 219
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.3 ( 8.77 ) 63.6 ( 7.89 ) -
    Gender categorical
    Units: Subjects
        Female
    		 40 24 64
        Male
    		 99 56 155

    End points

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    End points reporting groups
    Reporting group title
    Arm A - OSE2101
    Reporting group description
    		 OSE2101: Day 1 each 21-day cycle for 6 cycles, then every 8 weeks for the remainder of year one and, finally every 12 weeks beyond year one.

    Reporting group title
    Arm B - docetaxel or pemetrexed
    Reporting group description
    		 Docetaxel (patients with squamous cancer) or pemetrexed (patients with non-squamous NSCLC): Day 1 each 21-day cycle (i.e. every 3 weeks)

    Subject analysis set title
    Patients of Interest
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Population of Interest (PoI) was defined as patients with secondary resistance to ICI monotherapy administered as last line.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This analysis set included all patients included who were randomized and received at least one dose of randomized study treatment. Patients will be analyzed in the group according to the treatment they received. All safety data analyses were analyzed using the safety set.

    Primary: Overall Survival (OS) in ITT

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    End point title
    		 Overall Survival (OS) in ITT
    End point description
    To demonstrate that OSE2101 was superior to control treatment with respect to OS in HLA-A2 positive patients with advanced NSCLC as 2nd or 3rd line therapy after failure of checkpoint-inhibitor regimens in the primary population consisting of the Population of Interest (PoI) defined as patients with secondary resistance to ICI monotherapy administered as last line. A sensitivity analysis was to be done in all randomized patients. OS was summarized using the Kaplan-Meier method and displayed graphically.
    End point type
    Primary
    End point timeframe
    OS was defined as time from randomization to death, expressed in months, and was censored at the analysis cut-off date (15JAN2021).
    End point values
    		 Arm A - OSE2101 Arm B - docetaxel or pemetrexed
    Number of subjects analysed
    139
    80
    Units: months
        median (confidence interval 95%)
    8.80 (7.622 to 10.842)
    8.34 (6.472 to 9.791)
    Attachments
    		 Kaplan-Meier Plot of Overall Survival
    Statistical analysis title
    		 Hazard Ratio Cox Regression
    Statistical analysis description
    A 2-sided log-rank test stratified for the randomization stratification factors was used to compare OS between the two treatment arms. The Cox regression model, stratified for the same stratification factors, was fitted, and the estimated hazard ratio and 2-sided 95% confidence interval was provided. The hazard ratio, as estimated in this Cox regression model, was provided with its 2-sided 95% CI.
    Comparison groups
    Arm B - docetaxel or pemetrexed v Arm A - OSE2101
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.19

    Primary: Overall survival (OS) in PoI

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    End point title
    		 Overall survival (OS) in PoI
    End point description
    To demonstrate that OSE2101 was superior to control treatment with respect to OS in HLA-A2 positive patients with advanced NSCLC as 2nd or 3rd line therapy after failure of checkpoint-inhibitor regimens in the primary population consisting of the Population of Interest (PoI) defined as patients with secondary resistance to ICI monotherapy administered as last line.
    End point type
    Primary
    End point timeframe
    OS was defined as time from randomization to death, expressed in months, and was censored at the analysis cut-off date (15JAN2021).
    End point values
    		 Arm A - OSE2101 Arm B - docetaxel or pemetrexed
    Number of subjects analysed
    80 [1]
    38 [2]
    Units: months
        median (confidence interval 95%)
    11.07 (8.575 to 13.503)
    7.47 (4.731 to 10.283)
    Attachments
    		 Kaplan-Meier Plot of Overall Survival in PoI
    Notes
    [1] - Only Patients of Interest
    [2] - Only Patients of Interest
    Statistical analysis title
    		 Hazard Ratio Cox Regression
    Statistical analysis description
    A 2-sided log-rank test stratified for the randomization stratification factors was used to compare OS between the two treatment arms. The Cox regression model, stratified for the same stratification factors, was fitted, and the estimated hazard ratio and 2-sided 95% confidence interval was provided.
    Comparison groups
    Arm A - OSE2101 v Arm B - docetaxel or pemetrexed
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.587
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.377
         upper limit
    		 0.913

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time that the subject/patient provided informed consent through the study treatment period until the last injection and including 28 calendar days after the final administration of the investigational medicinal product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    OSE2101
    Reporting group description
    		 Patient who had received OSE2101

    Reporting group title
    SoC (Doc/Pem)
    Reporting group description
    		 Patients treated with comparator (Docetaxel or Pemetrexed)

    Serious adverse events
    		 OSE2101 SoC (Doc/Pem)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 138 (34.06%)
    33 / 74 (44.59%)
         number of deaths (all causes)
    10
    11
         number of deaths resulting from adverse events
    10
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    3 / 138 (2.17%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Metastases to central nervous system
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic syndrome0
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 138 (2.90%)
    5 / 74 (6.76%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Influenza like illness
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 138 (1.45%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    6 / 138 (4.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    12 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Giant cell arteritis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchial obstruction
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 138 (2.17%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Haemoptysis
         subjects affected / exposed
    1 / 138 (0.72%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 138 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Wheezing
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 138 (0.00%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 138 (0.72%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 138 (0.72%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 138 (1.45%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 138 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 138 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 138 (1.45%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 138 (1.45%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 138 (1.45%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 OSE2101 SoC (Doc/Pem)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    131 / 138 (94.93%)
    74 / 74 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 138 (2.90%)
    4 / 74 (5.41%)
         occurrences all number
    5
    5
    General disorders and administration site conditions
    Injection site induration
         subjects affected / exposed
    16 / 138 (11.59%)
    0 / 74 (0.00%)
         occurrences all number
    17
    0
    Injection site pain
         subjects affected / exposed
    10 / 138 (7.25%)
    0 / 74 (0.00%)
         occurrences all number
    14
    0
    Injection site reaction
         subjects affected / exposed
    13 / 138 (9.42%)
    0 / 74 (0.00%)
         occurrences all number
    15
    0
    Asthenia
         subjects affected / exposed
    32 / 138 (23.19%)
    32 / 74 (43.24%)
         occurrences all number
    36
    67
    Chest pain
         subjects affected / exposed
    13 / 138 (9.42%)
    2 / 74 (2.70%)
         occurrences all number
    13
    2
    Chills
         subjects affected / exposed
    9 / 138 (6.52%)
    0 / 74 (0.00%)
         occurrences all number
    10
    0
    Fatigue
         subjects affected / exposed
    13 / 138 (9.42%)
    12 / 74 (16.22%)
         occurrences all number
    13
    15
    General physical health deterioration
         subjects affected / exposed
    4 / 138 (2.90%)
    6 / 74 (8.11%)
         occurrences all number
    4
    6
    Oedema
         subjects affected / exposed
    2 / 138 (1.45%)
    4 / 74 (5.41%)
         occurrences all number
    2
    4
    Oedema peripheral
         subjects affected / exposed
    7 / 138 (5.07%)
    7 / 74 (9.46%)
         occurrences all number
    8
    9
    Pain
         subjects affected / exposed
    7 / 138 (5.07%)
    5 / 74 (6.76%)
         occurrences all number
    8
    11
    Pyrexia
         subjects affected / exposed
    26 / 138 (18.84%)
    10 / 74 (13.51%)
         occurrences all number
    37
    11
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    10 / 138 (7.25%)
    0 / 74 (0.00%)
         occurrences all number
    21
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 138 (9.42%)
    8 / 74 (10.81%)
         occurrences all number
    17
    10
    Dyspoea
         subjects affected / exposed
    22 / 138 (15.94%)
    16 / 74 (21.62%)
         occurrences all number
    27
    20
    Haemoptysis
         subjects affected / exposed
    6 / 138 (4.35%)
    5 / 74 (6.76%)
         occurrences all number
    8
    5
    Investigations
    Weight decreased
         subjects affected / exposed
    6 / 138 (4.35%)
    8 / 74 (10.81%)
         occurrences all number
    6
    8
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 138 (2.17%)
    4 / 74 (5.41%)
         occurrences all number
    3
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 138 (5.07%)
    2 / 74 (2.70%)
         occurrences all number
    16
    2
    Neuropathy peripheral
         subjects affected / exposed
    0 / 138 (0.00%)
    7 / 74 (9.46%)
         occurrences all number
    0
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 138 (6.52%)
    14 / 74 (18.92%)
         occurrences all number
    11
    15
    Febrile neutropenia
         subjects affected / exposed
    0 / 138 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    4
    Leukopenia
         subjects affected / exposed
    0 / 138 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    5
    Neutropenia
         subjects affected / exposed
    1 / 138 (0.72%)
    14 / 74 (18.92%)
         occurrences all number
    1
    15
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 138 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 138 (5.07%)
    1 / 74 (1.35%)
         occurrences all number
    8
    1
    Constipation
         subjects affected / exposed
    9 / 138 (6.52%)
    11 / 74 (14.86%)
         occurrences all number
    10
    13
    Diarrhoea
         subjects affected / exposed
    12 / 138 (8.70%)
    22 / 74 (29.73%)
         occurrences all number
    15
    28
    Nausea
         subjects affected / exposed
    20 / 138 (14.49%)
    14 / 74 (18.92%)
         occurrences all number
    23
    17
    Stomatitis
         subjects affected / exposed
    2 / 138 (1.45%)
    4 / 74 (5.41%)
         occurrences all number
    2
    5
    Vomiting
         subjects affected / exposed
    14 / 138 (10.14%)
    11 / 74 (14.86%)
         occurrences all number
    18
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 138 (0.72%)
    21 / 74 (28.38%)
         occurrences all number
    1
    26
    Nail toxicity
         subjects affected / exposed
    0 / 138 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 138 (14.49%)
    6 / 74 (8.11%)
         occurrences all number
    26
    6
    Back pain
         subjects affected / exposed
    14 / 138 (10.14%)
    9 / 74 (12.16%)
         occurrences all number
    17
    9
    Myalgia
         subjects affected / exposed
    7 / 138 (5.07%)
    4 / 74 (5.41%)
         occurrences all number
    8
    5
    Pain in extremity
         subjects affected / exposed
    4 / 138 (2.90%)
    4 / 74 (5.41%)
         occurrences all number
    6
    5
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 138 (0.72%)
    5 / 74 (6.76%)
         occurrences all number
    1
    6
    Pneumonia
         subjects affected / exposed
    2 / 138 (1.45%)
    4 / 74 (5.41%)
         occurrences all number
    2
    4
    Respiratory tract infection
         subjects affected / exposed
    3 / 138 (2.17%)
    5 / 74 (6.76%)
         occurrences all number
    4
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    28 / 138 (20.29%)
    14 / 74 (18.92%)
         occurrences all number
    31
    23
    Hyperglycaemia
         subjects affected / exposed
    1 / 138 (0.72%)
    4 / 74 (5.41%)
         occurrences all number
    1
    5
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 138 (3.62%)
    5 / 74 (6.76%)
         occurrences all number
    5
    5
    Hypokalaemia
         subjects affected / exposed
    1 / 138 (0.72%)
    4 / 74 (5.41%)
         occurrences all number
    2
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2015
    Exclusion criteria n°9 added to exclude patients treated with corticosteroids within 3-weeks before inclusion (except if low dose)
    30 Nov 2015
    Exclusion criteria n°1 modified to exclude patients with Large Cell Carcinoma; Inclusion criterion n°5 clarified to authorize patients as 2nd line after failure of prior platinum-based chemotherapy or as 3rd line after failure of platinum-based chemotherapy then immune checkpoint inhibitor (ICI)
    14 Feb 2017
    Inclusion criterion n°5 modified to authorize patients as 2nd line or 3rd line after failure of platinum-based chemotherapy and/or failure of ICI (sequential or combined with chemo) as ICIs may be used either as 1st or 2nd line therapy; PDL-1 expression on tumor biopsy not further mandatory for inclusion; clarification on inclusion criteria n°9 to authorize only patients with asymptomatic brain metastases.
    21 Dec 2017
    Inclusion criterion n°5 modified to only authorize the subgroup of patients previously treated with ICI and who have progressed after ICI (as 2nd line after ICI + chemotherapy first line or as 3rd line after platinum-based chemotherapy in first line then ICI in second line); Study design modified for a Phase II (Step-1) / Phase III (Step-2) design with a first step Fleming non comparative Phase II design and randomization 2:1; First secondary criterion modified for disease control rate instead of progression-free survival; Clarification on population for analysis for Step-1 and Step-2 (in version 4.1 per request after the voluntary harmonized procedure (VHP) in the European Union) Per IDMC request, the recruitment was temporarily halted from June 2017 to November 2017 before the decision to restart the recruitment only in the subgroup of patients who progressed after ICI was taken based on the IDMC independent analysis of data (safety and death events) reported in the first 131 patients randomized until June 2017; This analysis was blinded from the investigators and the Sponsor.
    29 Mar 2019
    • Implementation of the 8th edition of TNM instead of 7th edition leading to modify the study title with no modification of the target study population; • Inclusion criterion n°7 modified to authorize patient with progression during or within 12 months after the end of ICI as sequential or concomitant platinumbased chemotherapy ± radiation for locally advanced disease (stage III); • Study design modified to to remove the possibility of a sample size reassessment of Step-2 based on the Step-1 Phase II results, o to continue with the 2:1 randomization ratio in Step-2 and, as a consequence, o to increase the number of events in Step-2 from 250 to 278 and to increase accordingly the number of patients, o to not consider for the final analysis the 38 patients with previous ICI treatment randomized before the recruitment hold; • Implementation of NCI CTCAE version 5.0 instead of CTCAE version 4.0 leading to clarifying the definition of cytokine release syndrome (CRS) as well as the management of CRS still per Lee recommendation; • A translational study has been added for patients/sites who agreed, in order to assess immunogenicity before and under treatment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    25 Mar 2020
    On March 25, 2020 due to the COVID-19 pandemic, the Independent Data Monitoring Committee (IDMC) and Steering Committee recommended to discontinue the ATALANTE-1 study, to complete the analysis of Step-1 and to continue the treatment and follow-up of the 219 patients already randomized in Step-2 until the death of remaining patients.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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