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    Clinical Trial Results:
    A randomized, open-label, multicentric phase II trial of PEMBROLIZUMAB (Ketruda®) with chemotherapy versus chemotherapy alone (standard of care) as neo adjuvant treatment of ovarian cancer not amenable to front line debulking surgery.

    Summary
    EudraCT number
    		 2016-004163-39
    Trial protocol
    		 FR  
    Global end of trial date
    02 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Sep 2024
    First version publication date
    27 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    OV126b
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ARCAGY-GINECO
    Sponsor organisation address
    8 rue Lamennais , Paris, France, 75008
    Public contact
    France Binet, ARCAGY-GINECO, neopembrov-study@arcagy.org
    Scientific contact
    France Binet, ARCAGY-GINECO, neopembrov-study@arcagy.org
    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
    27 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of neoadjuvant pembrolizumab and chemo-therapy or chemotherapy alone measured by the complete resection rate after interval debulking surgery. Complete resection will be defined as the removal of all macroscopic residual tumor (Com-plete Cytoreduction score = 0).
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The trial was conducted in agreement with the International Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP). As this clinical study will be carried out in France only, the study was conducted in accordance with the “Code de la Santé Publique” and data collection and recording was done in accordance with the “Méthodologie de Référence MR-001” of the Commission Nationale Informatique et Libertés. Written informed consent (ICF) were obtained from each participant after the study protocol was explained to them and before any study-specific procedures were performed.
    Background therapy
    		 In ovarian carcinoma patients, the anti-PD1 compound nivolumab has been reported to achieve 3 objectives responses out of 13 (23%) heavily pre-treated patients (Hamanishi J, ASCO 2014). Response was prolonged over 1 year in 2 out of the 3 responders (Hamanishi J, ASCO 2015). Similarly, the anti-PD1 pembrozilumab achieved 3 confirmed responses (11.5% [(95% CI, 2.4-30.2]) in 26 patients treated in a phase IB study and 3 additional patients had a tumor reduction of at least 30%. Most common AEs were fatigue (42.3%), anemia (30.8%), and decreased appetite (30.8%). Drugrelated AEs occurred in 69.2% of pts (grade ≥ 3, 1/26 pts) (Varga A et al, 2015). Kryczek et al compared the PD-1 expression level at the surface of intra-tumoral CD4+ FOXP3+ Tregs among many cancer types. Interestingly, the higher level of PD-1 expression (around 20%) was found on Tregs of ovarian cancers whereas it was much lower (<10%) in other cancer types (Colon cancer, Hepatic cancer, Melanoma, Pancreatic carcinoma, Renal cell carcinoma) (Arkadiusz et al 2014). PD-L1 expression has also been detected in ovarian cancer tissue analysis by Immuno-histochemistry staining and its level of expression has been correlated to a bad outcome of patients (Kryczek et al 2009). Together with the aforementioned data on immune infiltration, these results provide rationale for a therapeutic PD-1/PD-L1 pathway blockade in ovarian cancer. In the published trials on such compounds, addition of pembrolizumab to chemotherapy or using alone has been shown to improve the response rates with a median time to response at 8 weeks (Hamanishi et al 2007, Weber et al 2014).
    Evidence for comparator
    		 Ovarian cancer (OC) is the fifth most common cause of death from cancer in women (Gatta et al 2011). Currently, the five-year survival is close to 80-90% for stage I of 50-60% for stage II, 30% for stage III and 10% for stage IV. The 5-years survival, all stages combined, is approximately 45%. Ovarian cancer is often asymptomatic in its early stages and the majority of epithelial ovarian cancers remain clinically undetected until patients have developed late-stage disease (Cannistra 2004). The standard procedure for initial diagnosis recommends the realization of laparoscopy first for all suspicious advanced ovarian carcinoma. This procedure should be able to confirm histological diagnosis and to describe all abdominal extension of the disease. For advanced stages, complete primary cyto-reductive surgery followed by 6 cycles of chemotherapy based remains the standard of care as first treatment in ovarian cancer. It is part of a large surgery including total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, lymphadenectomy and removal of all peritoneal carcinomatosis (Vergote et al 2010). Complete resection of all macroscopic disease at primary debulking surgery has been shown to be the single most important independent prognostic factor in advanced ovarian carcinoma (Du Bois Cancer 2009), and this was confirmed for interval debulking surgery (IDS) after neo adjuvant chemotherapy in the EORTC-GCG study (Vergote et al., 2010). These results suggest that neo-adjuvant chemotherapy followed by surgical cytoreduction is an acceptable management strategy for patients with advanced ovarian cancer and is more and more frequently used in Europe in OC patients with high burden of tumor (2012 French national guidelines Saint Paul de Vence & ESMO guidelines). Due to these confirmed results, the rate of patients receiving neo adjuvant chemotherapy increased over time compared to up front surgery (E Stoeckle et al 2014 and Luyk EJSO 2012).
    Actual start date of recruitment
    03 Apr 2017
    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
    France: 91
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    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)
    51
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited between 26/02/2018 and 17/04/2019

    Pre-assignment
    Screening details
    		 102 patients were eligible in which 11 were excluded, 91 were enrolled and treated (30 in Arm A-Paclitaxel/Carboplatin and 61 in Arm B-Paclitaxel/Carboplatin + Pembrolizumab)

    Period 1
    Period 1 title
    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 - Paclitaxel/Carboplatin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin and paclitaxel should be taken on day 1 of each 3 weeks cycle at the dose of AUC 5 or 6 in a 15–60-minute intravenous infusion and 175 mg/m² in a 3-hour intravenous infusion respectively. One cycle is D1 to D21 and D1C2 = D22C1. Pre-medication should be implemented according to local practices. Premedication with corticosteroids is allowed.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin and paclitaxel should be taken on day 1 of each 3 weeks cycle at the dose of AUC 5 or 6 in a 15–60-minute intravenous infusion and 175 mg/m² in a 3-hour intravenous infusion respectively. One cycle is D1 to D21 and D1C2 = D22C1. Pre-medication should be implemented according to local practices. Premedication with corticosteroids is allowed.

    Arm title
    		 Arm B - Paclitaxel/Carboplatin with Pembrolizumab
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin and paclitaxel should be taken on day 1 of each 3 weeks cycle at the dose of AUC 5 or 6 in a 15–60-minute intravenous infusion and 175 mg/m² in a 3-hour intravenous infusion respectively. One cycle is D1 to D21 and D1C2 = D22C1. Pre-medication should be implemented according to local practices. Premedication with corticosteroids is allowed.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin and paclitaxel should be taken on day 1 of each 3 weeks cycle at the dose of AUC 5 or 6 in a 15–60-minute intravenous infusion and 175 mg/m² in a 3-hour intravenous infusion respectively. One cycle is D1 to D21 and D1C2 = D22C1. Pre-medication should be implemented according to local practices. Premedication with corticosteroids is allowed.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    For randomized patients in Arm B without bevacizumab, Pembrolizumab 200 mg will be administered as 30-minute IV infusion every 3 weeks. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). For randomized patients in Arm B with bevacizumab, pembrolizumab was administered first, followed by bevacizumab, with a minimum of 5 minutes between dosing. The initial dose of bevacizumab was delivered over 90 (±15) minutes. If the first infusion is tolerated without infusion-associated adverse events (fever and/or chills), the second infusion may be delivered over 60 (±10) minutes.

    Number of subjects in period 1
    		Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab
    Started
    30
    61
    Completed
    30
    61

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm A - Paclitaxel/Carboplatin
    Reporting group description
    		 -

    Reporting group title
    Arm B - Paclitaxel/Carboplatin with Pembrolizumab
    Reporting group description
    		 -

    Reporting group values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab Total
    Number of subjects
    		 30 61 91
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 18 33 51
        From 65-84 years
    		 12 28 40
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 61.5 (40 to 79) 63 (42 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 30 61 91
    ECOG
    Units: Subjects
        00
    		 14 29 43
        01
    		 15 32 47
        02
    		 1 0 1
    ECG
    Units: Subjects
        Normal
    		 26 49 75
        Abnormal NCS
    		 3 10 13
        NA
    		 1 2 3
    Germline BRCA mutation
    Units: Subjects
        No
    		 16 31 47
        Yes
    		 14 30 44
    Somatic BRCA mutation
    Units: Subjects
        No
    		 12 17 29
        Yes
    		 18 44 62
    BRCA
    Units: Subjects
        No
    		 24 41 65
        Yes
    		 3 13 16
        NA
    		 3 7 10
    Medical Review - Primary site
    Units: Subjects
        Ovary
    		 30 54 84
        Peritoneal
    		 0 7 7
    Medical Review - Adenocarcinoma type
    Units: Subjects
        Serous High Grade (a)
    		 28 60 88
        Serous Low Grade (b)
    		 1 0 1
        Clear cell
    		 1 0 1
        Undifferentiated
    		 0 1 1
    Medical Review - FIGO
    Units: Subjects
        II
    		 1 0 1
        IIIC
    		 22 47 69
        IV
    		 7 14 21
    If stage IV, localization of the visceral disease
    Units: Subjects
        Pleura
    		 1 4 5
        Liver
    		 1 4 5
        Lungs
    		 1 1 2
        Lymph node outside of the abdominal cavity
    		 5 4 9
        Mediastin
    		 0 1 1
        Pleural Effusion
    		 0 1 1
        Unknown
    		 0 1 1
        NA
    		 22 45 67
    Immune or allergic disease
    Units: Subjects
        Allergic rhinitis
    		 1 1 2
        Asthma
    		 1 1 2
        Basedow disease
    		 0 1 1
        Diabetes 2
    		 2 1 3
        Hypothyroidism 2
    		 2 5 7
        Other
    		 4 11 15
        NA
    		 20 41 61
    At least one sign and symptom of adverse events at baseline
    Units: Subjects
        No
    		 19 40 59
        Yes
    		 11 21 32
    List of adverse events at baseline
    Units: Subjects
        Anaemia
    		 0 2 2
        Hypothyroidism
    		 0 1 1
        Gastrointestinal disorders
    		 8 12 20
        General disorders and administration site conditio
    		 0 2 2
        Hepatobiliary disorders
    		 1 1 2
        Urinary tract infection
    		 1 0 1
        Investigations
    		 2 1 3
        Metabolism and nutrition disorders
    		 1 3 4
        Anxiety
    		 0 1 1
        Respiratory, thoracic and mediastinal
    		 1 2 3
        Vascular disorders
    		 2 1 3
        Gamma-glutamyl transferase Increased
    		 1 1 2
        Hypertension
    		 0 1 1
        Abdominal pain
    		 1 0 1
        Hydronephrosis
    		 1 0 1
        NA
    		 11 33 44
    Abnormal and Clinically Significant laboratory examination at inclusion: Hematology
    Units: Subjects
        Hemoglobin
    		 1 1 2
        Lymphocytes
    		 0 0 0
        Monocytes
    		 0 0 0
        Neutrophils
    		 0 0 0
        Platelets
    		 0 0 0
        White blood cells
    		 0 0 0
        NA
    		 29 60 89
    Abnormal and Clinically Significant laboratory examination at inclusion: Biochemistery
    Units: Subjects
        Albumin
    		 0 2 2
        Alkaline phosphatase
    		 1 1 2
        ALT/SGPT
    		 1 0 1
        AST/SGOT
    		 1 0 1
        Creatinine
    		 0 0 0
        Creatinine clearance
    		 1 0 1
        LDH
    		 0 2 2
        Total bilirubin
    		 0 0 0
        NA
    		 26 56 82
    Abnormal and Clinically Significant laboratory examination at inclusion: Hormonology
    Units: Subjects
        FREE T3
    		 0 0 0
        FREE T4
    		 0 0 0
        TSH
    		 0 1 1
        NA
    		 30 60 90
    Abnormal and Clinically Significant laboratory examination at inclusion: Urine Protein analysis
    Units: Subjects
        Negative
    		 18 35 53
        Trace
    		 3 7 10
        T+1
    		 4 6 10
        T+2
    		 1 0 1
        NA
    		 4 13 17
    Initial surgery : Type of approach
    Units: Subjects
        Laparotomy
    		 1 7 8
        Laparoscopy-Laparoscopic assisted
    		 29 53 82
        Biopsy
    		 0 1 1
    Initial surgery : Type of procedure
    Units: Subjects
        Primary Surgical Staging
    		 1 0 1
        Diagnostic procedure-biopsies
    		 29 61 90
    Initial surgery : Residual disease
    Units: Subjects
        Not applicable
    		 27 59 86
        CC3: residue > 2.5 cm
    		 3 1 4
        CC0 : No macroscopic
    		 0 1 1
    Reason for initial non resecability : Patient's status
    Units: Subjects
        Poor performance status
    		 2 1 3
        Denutrition
    		 0 1 1
        Venous thrombosis
    		 0 1 1
        NA
    		 28 58 86
    Fagotti Score
    Units: Subjects
        08
    		 2 1 3
        04
    		 0 1 1
        NA
    		 28 59 87
    Reason for initial non resecability : Other reason
    Units: Subjects
        Non resecable disease
    		 14 29 43
        PCI + Non resecable disease
    		 9 24 33
        No expert center
    		 1 2 3
        Patient's status + Non resecable disease
    		 1 2 3
        Fagotti score + Non resecable disease
    		 0 2 2
        Fagotti score + PCI + Non resecable disease
    		 2 0 2
        PCI
    		 1 1 2
        No identified reason
    		 1 0 1
        Progressive disease
    		 0 1 1
        Patient's status + PCI + Non resecable disease
    		 1 0 1
    Primary reason for end of treatment: Platinum
    Units: Subjects
        Completed as per protocol
    		 27 53 80
        Disease progression as per RECIST V1.1 criteria
    		 1 4 5
        Adverse event
    		 1 1 2
        Symptomatic deterioration
    		 1 0 1
        Death
    		 0 1 1
        Chip during IDS
    		 0 1 1
        Investigator decision
    		 0 1 1
    Primary reason for end of treatment: Bevacizumab
    Units: Subjects
        Completed as per protocol
    		 9 20 29
        Disease progression as per RECIST V1.1 criteria
    		 14 22 36
        Adverse event
    		 4 10 14
        Symptomatic deterioration
    		 1 0 1
        Breast cancer
    		 1 0 1
        Disease progression
    		 0 1 1
        Not applicable
    		 0 4 4
        Treatment not given
    		 0 1 1
        Patient died before adjuvant phase
    		 0 1 1
        Patient decision
    		 0 1 1
        NA
    		 1 1 2
    Primary reason for end of treatment: Pembrolizumab
    Units: Subjects
        Completed as per protocol
    		 0 21 21
        Disease progression as per RECIST V1.1 criteria
    		 0 23 23
        Adverse event
    		 0 14 14
        Death
    		 0 1 1
        Disease progression
    		 0 1 1
        Chip during IDS
    		 0 1 1
        NA
    		 30 0 30
    Interval debulking surgery
    Units: Subjects
        No
    		 1 3 4
        Yes
    		 29 58 87
    Interval debulking surgery : Type of approach
    Units: Subjects
        Laparotomy
    		 24 49 73
        Laparoscopy-Laparoscopic assisted
    		 2 1 3
        Coelioscopy
    		 3 7 10
        NA
    		 1 4 5
    Interval debulking surgery : Type of procedure
    Units: Subjects
        Interval debulking surgery after NACT
    		 24 56 80
        Restaging after previous surgery
    		 2 0 2
        2ry Debulking
    		 3 2 5
        NA
    		 1 3 4
    Reason for non-complete resecability during interval debulking surgery
    Units: Subjects
        Patient's status
    		 1 1 2
        Fagotti score of 7
    		 0 1 1
        Alteration of general state
    		 1 0 1
        Insufficiant response
    		 1 0 1
        No response
    		 0 1 1
        Stable disease
    		 0 1 1
        Stable disease or Insufficiant response
    		 0 1 1
        Non resecable disease
    		 7 13 20
        NA
    		 20 43 63
    Localization of non resecable disease during interval debulking surgery
    Units: Subjects
        Mesenteric involvement
    		 1 6 7
        Massive omentum involvemen
    		 1 4 5
        Massive diaphragmatic dome
    		 4 4 8
        Hepatic hilum involvement
    		 1 1 2
        Diffuse digestive involvement
    		 2 7 9
        Massive ascites
    		 0 1 1
        Diffuse peritoneal carcinomatosis
    		 7 8 15
        Stage IV
    		 2 3 5
        Pleural involvement
    		 1 1 2
        Infracentimetric residuals
    		 0 1 1
        Stomach
    		 0 1 1
        NA
    		 11 24 35
    Weight
    Units: kilogram(s)
        median (full range (min-max))
    		 62.5 (42.5 to 98) 63 (44 to 125) -
    Height
    Units: centimetre
        median (full range (min-max))
    		 162 (146 to 169) 162 (150 to 171) -
    Systolic Blood Pressure
    Units: Millimetre of mercury
        median (full range (min-max))
    		 120.5 (108 to 165) 129 (92 to 183) -
    Diastolic Blood Pressure
    Units: Millimetre of mercury
        median (full range (min-max))
    		 76.50 (52 to 88) 78 (55 to 103) -
    CA125
    Units: U/ml
        median (full range (min-max))
    		 542.00 (18 to 3493) 632.00 (21 to 8911) -
    PCI score
    Units: number
        median (full range (min-max))
    		 25 (18 to 36) 24 (7 to 39) -
    Number of chemotherapy cycles in Neoadjuvant phase: Carboplatin
    Units: Number
        median (full range (min-max))
    		 4 (2 to 6) 4 (1 to 8) -
    Number of chemotherapy cycles in Neoadjuvant phase: Paclitaxel
    Units: Number
        median (full range (min-max))
    		 4 (1 to 6) 4 (1 to 8) -
    Number of chemotherapy cycles in Neoadjuvant phase: Pembrolizumab
    Units: Number
        median (full range (min-max))
    		 0 (0 to 0) 4 (1 to 8) -
    Number of chemotherapy cycles in adjuvant phase: Carboplatin
    Units: number
        median (full range (min-max))
    		 3 (0 to 6) 3 (0 to 5) -
    Number of chemotherapy cycles in adjuvant phase: Paclitaxel
    Units: number
        median (full range (min-max))
    		 3 (0 to 6) 3 (0 to 5) -
    Number of chemotherapy cycles in adjuvant phase: Pembrolizumab
    Units: number
        median (full range (min-max))
    		 0 (0 to 0) 15 (0 to 24) -
    Interval debulking surgery : Time from randomization to surgery
    Units: month
        median (full range (min-max))
    		 3.25 (2.60 to 7.42) 3.19 (2.37 to 7.33) -
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The analysis was performed on the ITT population (N=91). Intention-to-treat (ITT) population is defined as all patients randomized in the trial, regardless of whether they actually received treatment. The population will be described according to randomization.

    Subject analysis sets values
    		 ITT population
    Number of subjects
    91
    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)
    51
        From 65-84 years
    40
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    ECOG
    Units: Subjects
        00
        01
        02
    ECG
    Units: Subjects
        Normal
    75
        Abnormal NCS
    13
        NA
    3
    Germline BRCA mutation
    Units: Subjects
        No
        Yes
    Somatic BRCA mutation
    Units: Subjects
        No
        Yes
    BRCA
    Units: Subjects
        No
        Yes
        NA
    Medical Review - Primary site
    Units: Subjects
        Ovary
        Peritoneal
    Medical Review - Adenocarcinoma type
    Units: Subjects
        Serous High Grade (a)
        Serous Low Grade (b)
        Clear cell
        Undifferentiated
    Medical Review - FIGO
    Units: Subjects
        II
        IIIC
        IV
    If stage IV, localization of the visceral disease
    Units: Subjects
        Pleura
    5
        Liver
    5
        Lungs
    2
        Lymph node outside of the abdominal cavity
    9
        Mediastin
    1
        Pleural Effusion
    1
        Unknown
    1
        NA
    67
    Immune or allergic disease
    Units: Subjects
        Allergic rhinitis
        Asthma
        Basedow disease
        Diabetes 2
        Hypothyroidism 2
        Other
        NA
    At least one sign and symptom of adverse events at baseline
    Units: Subjects
        No
        Yes
    List of adverse events at baseline
    Units: Subjects
        Anaemia
        Hypothyroidism
        Gastrointestinal disorders
        General disorders and administration site conditio
        Hepatobiliary disorders
        Urinary tract infection
        Investigations
        Metabolism and nutrition disorders
        Anxiety
        Respiratory, thoracic and mediastinal
        Vascular disorders
        Gamma-glutamyl transferase Increased
        Hypertension
        Abdominal pain
        Hydronephrosis
        NA
    Abnormal and Clinically Significant laboratory examination at inclusion: Hematology
    Units: Subjects
        Hemoglobin
        Lymphocytes
        Monocytes
        Neutrophils
        Platelets
        White blood cells
        NA
    Abnormal and Clinically Significant laboratory examination at inclusion: Biochemistery
    Units: Subjects
        Albumin
        Alkaline phosphatase
        ALT/SGPT
        AST/SGOT
        Creatinine
        Creatinine clearance
        LDH
        Total bilirubin
        NA
    Abnormal and Clinically Significant laboratory examination at inclusion: Hormonology
    Units: Subjects
        FREE T3
    0
        FREE T4
    0
        TSH
    1
        NA
    90
    Abnormal and Clinically Significant laboratory examination at inclusion: Urine Protein analysis
    Units: Subjects
        Negative
        Trace
        T+1
        T+2
        NA
    Initial surgery : Type of approach
    Units: Subjects
        Laparotomy
    8
        Laparoscopy-Laparoscopic assisted
    82
        Biopsy
    1
    Initial surgery : Type of procedure
    Units: Subjects
        Primary Surgical Staging
        Diagnostic procedure-biopsies
    Initial surgery : Residual disease
    Units: Subjects
        Not applicable
        CC3: residue > 2.5 cm
        CC0 : No macroscopic
    Reason for initial non resecability : Patient's status
    Units: Subjects
        Poor performance status
        Denutrition
        Venous thrombosis
        NA
    Fagotti Score
    Units: Subjects
        08
        04
        NA
    Reason for initial non resecability : Other reason
    Units: Subjects
        Non resecable disease
        PCI + Non resecable disease
        No expert center
        Patient's status + Non resecable disease
        Fagotti score + Non resecable disease
        Fagotti score + PCI + Non resecable disease
        PCI
        No identified reason
        Progressive disease
        Patient's status + PCI + Non resecable disease
    Primary reason for end of treatment: Platinum
    Units: Subjects
        Completed as per protocol
        Disease progression as per RECIST V1.1 criteria
        Adverse event
        Symptomatic deterioration
        Death
        Chip during IDS
        Investigator decision
    Primary reason for end of treatment: Bevacizumab
    Units: Subjects
        Completed as per protocol
    29
        Disease progression as per RECIST V1.1 criteria
    36
        Adverse event
    14
        Symptomatic deterioration
    1
        Breast cancer
    1
        Disease progression
    1
        Not applicable
    4
        Treatment not given
    1
        Patient died before adjuvant phase
    1
        Patient decision
    1
        NA
    2
    Primary reason for end of treatment: Pembrolizumab
    Units: Subjects
        Completed as per protocol
    21
        Disease progression as per RECIST V1.1 criteria
    23
        Adverse event
    14
        Death
    1
        Disease progression
    1
        Chip during IDS
    1
        NA
    30
    Interval debulking surgery
    Units: Subjects
        No
        Yes
    Interval debulking surgery : Type of approach
    Units: Subjects
        Laparotomy
        Laparoscopy-Laparoscopic assisted
        Coelioscopy
        NA
    Interval debulking surgery : Type of procedure
    Units: Subjects
        Interval debulking surgery after NACT
        Restaging after previous surgery
        2ry Debulking
        NA
    Reason for non-complete resecability during interval debulking surgery
    Units: Subjects
        Patient's status
        Fagotti score of 7
        Alteration of general state
        Insufficiant response
        No response
        Stable disease
        Stable disease or Insufficiant response
        Non resecable disease
        NA
    Localization of non resecable disease during interval debulking surgery
    Units: Subjects
        Mesenteric involvement
        Massive omentum involvemen
        Massive diaphragmatic dome
        Hepatic hilum involvement
        Diffuse digestive involvement
        Massive ascites
        Diffuse peritoneal carcinomatosis
        Stage IV
        Pleural involvement
        Infracentimetric residuals
        Stomach
        NA
    Weight
    Units: kilogram(s)
        median (full range (min-max))
    Height
    Units: centimetre
        median (full range (min-max))
    Systolic Blood Pressure
    Units: Millimetre of mercury
        median (full range (min-max))
    Diastolic Blood Pressure
    Units: Millimetre of mercury
        median (full range (min-max))
    77 (52 to 103)
    CA125
    Units: U/ml
        median (full range (min-max))
    562.60 (18 to 8911)
    PCI score
    Units: number
        median (full range (min-max))
    Number of chemotherapy cycles in Neoadjuvant phase: Carboplatin
    Units: Number
        median (full range (min-max))
    Number of chemotherapy cycles in Neoadjuvant phase: Paclitaxel
    Units: Number
        median (full range (min-max))
    Number of chemotherapy cycles in Neoadjuvant phase: Pembrolizumab
    Units: Number
        median (full range (min-max))
    Number of chemotherapy cycles in adjuvant phase: Carboplatin
    Units: number
        median (full range (min-max))
    Number of chemotherapy cycles in adjuvant phase: Paclitaxel
    Units: number
        median (full range (min-max))
    Number of chemotherapy cycles in adjuvant phase: Pembrolizumab
    Units: number
        median (full range (min-max))
    Interval debulking surgery : Time from randomization to surgery
    Units: month
        median (full range (min-max))
    3.22 (2.37 to 7.42)

    End points

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    End points reporting groups
    Reporting group title
    Arm A - Paclitaxel/Carboplatin
    Reporting group description
    		 -

    Reporting group title
    Arm B - Paclitaxel/Carboplatin with Pembrolizumab
    Reporting group description
    		 -

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The analysis was performed on the ITT population (N=91). Intention-to-treat (ITT) population is defined as all patients randomized in the trial, regardless of whether they actually received treatment. The population will be described according to randomization.

    Primary: Rate of complete debulking

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    End point title
    		 Rate of complete debulking
    End point description
    According to the hypothesis, 33 successes over 54 evaluable patients were expected in arm B treated with pembrolizumab (P0=50%, P1=70%). According to our results, the resection was complete (CC0) for 45 patients (73.8%) in arm B treated with pembrolizumab and thus were considered in success. In conclusion, treatment with neoadjuvant pembrolizumab and chemotherapy showed efficacy in this study.
    End point type
    Primary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        Complete debulking (1)
    21
    45
    66
        NA
    9
    16
    25
    Statistical analysis title
    		 Descriptive statistics
    Statistical analysis description
    No statistical test will be performed in this study.
    Comparison groups
    Arm A - Paclitaxel/Carboplatin v Arm B - Paclitaxel/Carboplatin with Pembrolizumab
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05
    Method
    		 Descriptive analysis
    Confidence interval
    Notes
    [1] - Descriptive statistics

    Primary: CCI according to central review

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    End point title
    		 CCI according to central review
    End point description
    End point type
    Primary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        CC0 : No macroscopic
    21
    45
    66
        CC1: <= 0.25 cm
    0
    2
    2
        CC3: residue > 2.5 cm
    8
    11
    19
        NA
    1
    3
    4
    Statistical analysis title
    		 Descriptive statistics
    Comparison groups
    Arm B - Paclitaxel/Carboplatin with Pembrolizumab v Arm A - Paclitaxel/Carboplatin
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.05
    Method
    		 Descriptive analysis
    Confidence interval
    Notes
    [2] - Descriptive statistics

    Primary: Rate of complete debulking – Sensitivity analysis

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    End point title
    		 Rate of complete debulking – Sensitivity analysis
    End point description
    End point type
    Primary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        Complete debulking (2)
    17
    41
    58
        NA
    13
    20
    33
    Statistical analysis title
    		 Descriptive statistics
    Comparison groups
    Arm B - Paclitaxel/Carboplatin with Pembrolizumab v Arm A - Paclitaxel/Carboplatin
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.05
    Method
    		 Descriptive analysis
    Confidence interval
    Notes
    [3] - Descriptive statistics

    Secondary: PCI score : Response at IDS compared to baseline PCI

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    End point title
    		 PCI score : Response at IDS compared to baseline PCI
    End point description
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        No
    4
    11
    15
        Yes
    23
    44
    67
        NA
    3
    6
    9
    No statistical analyses for this end point

    Secondary: PCI score (sugarbaker index)

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    End point title
    		 PCI score (sugarbaker index)
    End point description
    Overall, 81.7% of patients had a response at Interval Debluking Surgery (IDS) compared to baseline as Peritoneal Cancer Index (PCI), in which the mean change in PCI score was -9.99 (9.00) for 80 patients. This decrease in PCI score estimated better prognosis after IDS.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: number
    arithmetic mean (standard deviation)
        PCI score at baseline
    21.48 ( 7.87 )
    20.41 ( 9.45 )
    20.74 ( 8.95 )
        PCI score before IDS
    11.64 ( 8.25 )
    9.71 ( 9.17 )
    10.36 ( 8.87 )
    No statistical analyses for this end point

    Secondary: Overall rate response (ORR)

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    End point title
    		 Overall rate response (ORR)
    End point description
    At the end of neoadjuvant period, 4 patients (5%) had a complete response, 58 patients (65%) had partial response, 25 patients (28%) were in stable disease, and 2 patients (2%) were in progression. In addition, two patients didn’t have tumor assessment. They have started 2 and 1 cycles of treatment respectively and stopped it due to an adverse event. Regarding overall response rate at the end of neo-adjuvant phase, 18 patients (62.1%) in arm A showed CR or PR response compared to 44 patients (73.3%) in arm B.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        ORR at the end of neo-adjuvant phase
    18
    44
    62
        NA
    12
    17
    29
    No statistical analyses for this end point

    Secondary: Overall rate response (ORR) : Tumor response observed

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    End point title
    		 Overall rate response (ORR) : Tumor response observed
    End point description
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        Complete response
    2
    2
    4
        Partial response
    16
    42
    58
        Stable disease
    11
    14
    25
        Progressive disease
    0
    2
    2
        NA
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Best response to the global strategy assessed by RECIST

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    End point title
    		 Best response to the global strategy assessed by RECIST
    End point description
    According to RECIST 1.1 criteria, 37 complete responses (61.7%) and 17 partial responses (28.3%) were observed in arm B compared to 14 CR (48.3%) and 10 PR (34.5%) responses in arm A.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        Complete response
    14
    37
    51
        Partial response
    10
    17
    27
        Stable disease
    5
    6
    11
        Progressive disease
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Best response before IDS assessed by CA125

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    End point title
    		 Best response before IDS assessed by CA125
    End point description
    According to CA-125 evaluation, 31 normalized responses (50.8%) and 22 non-normalized responses (36.1%) were observed in arm B before IDS compared to 15 normalized responses (50.0%) and 10 non-normalized responses (33.3%) responses in arm A.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        Response and normalized
    15
    31
    46
        Response without normalized
    10
    22
    32
        Normalized
    1
    1
    2
        No response or PD
    2
    2
    4
        Normal baseline CA-125
    1
    4
    5
        NE (no baseline and/or post-baseline sample)
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Best response to the global strategy assessed by CA125

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    End point title
    		 Best response to the global strategy assessed by CA125
    End point description
    Regarding best response to global strategy, 46 normalized responses (75.4%) and 7 non-normalized responses (11.5%) were observed in arm B compared to 22 normalized responses (73.3%) and 3 non-normalized responses (10.0%) responses in arm A.
    End point type
    Secondary
    End point timeframe
    Overal period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        Response and normalized
    22
    46
    68
        Response without normalized
    3
    7
    10
        Normalized
    1
    1
    2
        No response or PD
    2
    2
    4
        Normal baseline CA-125
    1
    4
    5
        NE (no baseline and/or post-baseline sample)
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) according to RECIST or symptomatic deterioration

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    End point title
    		 Progression-free survival (PFS) according to RECIST or symptomatic deterioration
    End point description
    Disease progression according to RECIST or death occurred in 20 patients (66.7%) in arm A compared to 34 patients (55.7%) in arm B treated with pembrolizumab.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        No
    11
    29
    40
        Yes
    19
    32
    51
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) according to RECIST or symptomatic deterioration or death

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    End point title
    		 Progression-free survival (PFS) according to RECIST or symptomatic deterioration or death
    End point description
    As shown in Figure 6, median PFS was 20.8 months (95%CI [15.0-24.5]) in arm A compared to 19.3 months [17.0; 23.4] in arm B treated with pembrolizumab.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        No
    10
    27
    37
        Yes
    20
    34
    54
    Attachments
    		 Figure 6. Progression free survival (PFS)
    No statistical analyses for this end point

    Secondary: Overall survival (OS): Death

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    End point title
    		 Overall survival (OS): Death
    End point description
    The follow-up of alive patients is at median of 22 months (min: 6.8, max: 32.5). At the time of the analysis, 19 deaths were notified, 6 (20%) in arm A and 13 (21.3%) in arm B treated with pembrolizumab. Median were not estimable both arms: arm A (95% CI 22.9) and arm B (95% CI 25.2) as illustrated in Figure 7.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        No
    24
    48
    72
        Yes
    6
    13
    19
    Attachments
    		 Figure 7. Overall survival (OS)
    No statistical analyses for this end point

    Secondary: Overall survival (OS): Cause of death

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    End point title
    		 Overall survival (OS): Cause of death
    End point description
    Moreover, 14 patients died of progression, 1 of acute leukemia, 1 of neurological complications, 1 of peritonitis after debulking surgery and 1 without reason mentioned.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin with Pembrolizumab ITT population
    Number of subjects analysed
    30
    61
    91
    Units: Patients
        Disease progression
    4
    10
    14
        Discovery of acute leukemia
    1
    0
    1
        Neurological complications
    0
    1
    1
        Peritonitis after debulking
    0
    1
    1
        Unknown
    1
    1
    2
        NA
    24
    48
    72
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Arm A - Paclitaxel/Carboplatin
    Reporting group description
    		 -

    Reporting group title
    Arm B - Paclitaxel/Carboplatin + Pembrolizumab
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin + Pembrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 30 (36.67%)
    27 / 61 (44.26%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE LEUKAEMIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PANCREATIC CARCINOMA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENOUS THROMBOSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    EVENTRATION REPAIR
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMA CLOSURE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMPAIRED HEALING
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORGANISING PNEUMONIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONGESTIVE CARDIOMYOPATHY
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HEADACHE
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHOCELE
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE BONE MARROW APLASIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOCYTOSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAL FISTULA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATOCELLULAR INJURY
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLANGITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS BULLOUS
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYTHEMA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROTEINURIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THYROIDITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    INFECTED LYMPHOCELE
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SEPSIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL ABSCESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERINEPHRIC ABSCESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A - Paclitaxel/Carboplatin Arm B - Paclitaxel/Carboplatin + Pembrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    61 / 61 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE LEUKAEMIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    PANCREATIC CARCINOMA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SEBORRHOEIC KERATOSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    6 / 30 (20.00%)
    16 / 61 (26.23%)
         occurrences all number
    6
    16
    HOT FLUSH
         subjects affected / exposed
    5 / 30 (16.67%)
    3 / 61 (4.92%)
         occurrences all number
    5
    3
    VENOUS THROMBOSIS
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    LYMPHOEDEMA
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    PHLEBITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    ANGIOPATHY
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    HYPOTENSION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PELVIC VENOUS THROMBOSIS
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    VENOUS THROMBOSIS LIMB
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    TOOTH EXTRACTION
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    EVENTRATION REPAIR
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    STOMA CLOSURE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    TRANSFUSION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    19 / 30 (63.33%)
    42 / 61 (68.85%)
         occurrences all number
    19
    42
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    1 / 30 (3.33%)
    9 / 61 (14.75%)
         occurrences all number
    1
    9
    FATIGUE
         subjects affected / exposed
    5 / 30 (16.67%)
    4 / 61 (6.56%)
         occurrences all number
    5
    4
    OEDEMA PERIPHERAL
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 61 (4.92%)
         occurrences all number
    4
    3
    IMPAIRED HEALING
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 61 (4.92%)
         occurrences all number
    0
    3
    PYREXIA
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    ILL-DEFINED DISORDER
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    PAIN
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    XEROSIS
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    ADVERSE DRUG REACTION
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    CATHETER SITE INFLAMMATION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    CATHETER SITE OEDEMA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    CATHETER SITE PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    CATHETER SITE RASH
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    CHEST PAIN
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    DYSPLASIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    FEELING COLD
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    INFLAMMATION
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    MEDICAL DEVICE PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    NODULE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    SENSE OF OPPRESSION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 30 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    4
    HYPERSENSITIVITY
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    SARCOIDOSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    VULVOVAGINAL DRYNESS
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 61 (1.64%)
         occurrences all number
    4
    1
    METRORRHAGIA
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    VAGINAL DISCHARGE
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    CYSTOCELE
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    OEDEMA GENITAL
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PELVIC DISCOMFORT
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PELVIC PAIN
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PRURITUS GENITAL
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    EPISTAXIS
         subjects affected / exposed
    6 / 30 (20.00%)
    15 / 61 (24.59%)
         occurrences all number
    6
    15
    COUGH
         subjects affected / exposed
    1 / 30 (3.33%)
    8 / 61 (13.11%)
         occurrences all number
    1
    8
    DYSPNOEA
         subjects affected / exposed
    3 / 30 (10.00%)
    14 / 61 (22.95%)
         occurrences all number
    3
    14
    PULMONARY EMBOLISM
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 61 (8.20%)
         occurrences all number
    2
    5
    RHINORRHOEA
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    HAEMOPTYSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    NASAL DRYNESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    ORGANISING PNEUMONIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PLEURAL DISORDER
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PNEUMONITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    RESPIRATORY DISORDER
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    RHINITIS ALLERGIC
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    2 / 30 (6.67%)
    7 / 61 (11.48%)
         occurrences all number
    2
    7
    INSOMNIA
         subjects affected / exposed
    4 / 30 (13.33%)
    4 / 61 (6.56%)
         occurrences all number
    4
    4
    DEPRESSION
         subjects affected / exposed
    0 / 30 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    4
    MAJOR DEPRESSION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SLEEP DISORDER
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    5 / 30 (16.67%)
    0 / 61 (0.00%)
         occurrences all number
    5
    0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    BLOOD THYROID STIMULATING HORMONE DECREASED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    BLOOD THYROID STIMULATING HORMONE INCREASED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    LYMPHOCYTE COUNT INCREASED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    THYROID FUNCTION TEST ABNORMAL
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    WEIGHT INCREASED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    PROCEDURAL PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    BURN OESOPHAGEAL
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    FALL
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    TOOTH FRACTURE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    CONGESTIVE CARDIOMYOPATHY
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SINUS BRADYCARDIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    TACHYCARDIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    12 / 30 (40.00%)
    27 / 61 (44.26%)
         occurrences all number
    12
    27
    HEADACHE
         subjects affected / exposed
    7 / 30 (23.33%)
    13 / 61 (21.31%)
         occurrences all number
    7
    13
    PARAESTHESIA
         subjects affected / exposed
    3 / 30 (10.00%)
    11 / 61 (18.03%)
         occurrences all number
    3
    11
    DYSGEUSIA
         subjects affected / exposed
    4 / 30 (13.33%)
    7 / 61 (11.48%)
         occurrences all number
    4
    7
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 30 (3.33%)
    5 / 61 (8.20%)
         occurrences all number
    1
    5
    NEUROTOXICITY
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 61 (4.92%)
         occurrences all number
    1
    3
    SCIATICA
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 61 (4.92%)
         occurrences all number
    0
    3
    DIZZINESS
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    NEURALGIA
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    ANOSMIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    DYSAESTHESIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    EPILEPSY
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    HYPOAESTHESIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    MEMORY IMPAIRMENT
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    MONOPLEGIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    17 / 30 (56.67%)
    33 / 61 (54.10%)
         occurrences all number
    17
    33
    NEUTROPENIA
         subjects affected / exposed
    12 / 30 (40.00%)
    24 / 61 (39.34%)
         occurrences all number
    12
    24
    THROMBOCYTOPENIA
         subjects affected / exposed
    8 / 30 (26.67%)
    18 / 61 (29.51%)
         occurrences all number
    8
    18
    LEUKOPENIA
         subjects affected / exposed
    6 / 30 (20.00%)
    6 / 61 (9.84%)
         occurrences all number
    6
    6
    LYMPHOPENIA
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    EOSINOPHILIA
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    LYMPHOCELE
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    FEBRILE BONE MARROW APLASIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    LEUKOCYTOSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    TINNITUS
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    DEAFNESS BILATERAL
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    VERTIGO
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Eye disorders
    DRY EYE
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 61 (3.28%)
         occurrences all number
    2
    2
    EYELID OEDEMA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    LACRIMATION INCREASED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    VISUAL ACUITY REDUCED
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    XEROPHTHALMIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    NAUSEA
         subjects affected / exposed
    12 / 30 (40.00%)
    33 / 61 (54.10%)
         occurrences all number
    12
    33
    ABDOMINAL PAIN
         subjects affected / exposed
    12 / 30 (40.00%)
    25 / 61 (40.98%)
         occurrences all number
    12
    25
    CONSTIPATION
         subjects affected / exposed
    11 / 30 (36.67%)
    25 / 61 (40.98%)
         occurrences all number
    11
    25
    DIARRHOEA
         subjects affected / exposed
    11 / 30 (36.67%)
    23 / 61 (37.70%)
         occurrences all number
    11
    23
    VOMITING
         subjects affected / exposed
    6 / 30 (20.00%)
    12 / 61 (19.67%)
         occurrences all number
    6
    12
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    6 / 30 (20.00%)
    10 / 61 (16.39%)
         occurrences all number
    6
    10
    GINGIVAL BLEEDING
         subjects affected / exposed
    3 / 30 (10.00%)
    6 / 61 (9.84%)
         occurrences all number
    3
    6
    TOOTHACHE
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 61 (8.20%)
         occurrences all number
    2
    5
    DYSPEPSIA
         subjects affected / exposed
    1 / 30 (3.33%)
    5 / 61 (8.20%)
         occurrences all number
    1
    5
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 61 (4.92%)
         occurrences all number
    2
    3
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 61 (6.56%)
         occurrences all number
    1
    4
    COLITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    4
    HAEMORRHOIDS
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    ASCITES
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    GASTRITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    GASTROINTESTINAL DISORDER
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    STOMATITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    ABDOMINAL HERNIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    ABDOMINAL RIGIDITY
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    ANAL FISTULA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    APHTHOUS ULCER
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    APTYALISM
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    DENTAL CYST
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    DYSPHAGIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    EPIGASTRIC DISCOMFORT
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    FAECALOMA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    GASTROINTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    IMPAIRED GASTRIC EMPTYING
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    INTRA-ABDOMINAL FLUID COLLECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    MESENTERIC ARTERY THROMBOSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    NONINFECTIVE GINGIVITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    OESOPHAGEAL PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    OESOPHAGITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    PERIODONTAL DISEASE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    RECTAL DISCHARGE
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    RECTAL OBSTRUCTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SENSITIVITY OF TEETH
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    SUBILEUS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    HEPATOCELLULAR INJURY
         subjects affected / exposed
    1 / 30 (3.33%)
    5 / 61 (8.20%)
         occurrences all number
    1
    5
    CHOLESTASIS
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    AUTOIMMUNE HEPATITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    CHOLANGITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    10 / 30 (33.33%)
    18 / 61 (29.51%)
         occurrences all number
    10
    18
    RASH
         subjects affected / exposed
    3 / 30 (10.00%)
    13 / 61 (21.31%)
         occurrences all number
    3
    13
    PRURITUS
         subjects affected / exposed
    3 / 30 (10.00%)
    9 / 61 (14.75%)
         occurrences all number
    3
    9
    ERYTHEMA
         subjects affected / exposed
    0 / 30 (0.00%)
    6 / 61 (9.84%)
         occurrences all number
    0
    6
    DRY SKIN
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 61 (4.92%)
         occurrences all number
    0
    3
    URTICARIA
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    HYPERHIDROSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    NAIL DISORDER
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    RASH PAPULAR
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    RASH PRURITIC
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    SKIN TOXICITY
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    XERODERMA
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    DERMATITIS BULLOUS
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    ECZEMA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    HYPERKERATOSIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    NIGHT SWEATS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PRURIGO
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PRURITUS GENERALISED
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    PURPURA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    RASH MACULAR
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SCAR PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    SKIN REACTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    PROTEINURIA
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 61 (4.92%)
         occurrences all number
    3
    3
    RENAL FAILURE
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 61 (4.92%)
         occurrences all number
    1
    3
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    DYSURIA
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    URINARY INCONTINENCE
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    HAEMATURIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    RENAL COLIC
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    2 / 30 (6.67%)
    17 / 61 (27.87%)
         occurrences all number
    2
    17
    HYPERTHYROIDISM
         subjects affected / exposed
    0 / 30 (0.00%)
    9 / 61 (14.75%)
         occurrences all number
    0
    9
    THYROID DISORDER
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    BASEDOW'S DISEASE
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    THYROIDITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    14 / 30 (46.67%)
    31 / 61 (50.82%)
         occurrences all number
    14
    31
    MYALGIA
         subjects affected / exposed
    2 / 30 (6.67%)
    11 / 61 (18.03%)
         occurrences all number
    2
    11
    PAIN IN EXTREMITY
         subjects affected / exposed
    5 / 30 (16.67%)
    8 / 61 (13.11%)
         occurrences all number
    5
    8
    BACK PAIN
         subjects affected / exposed
    4 / 30 (13.33%)
    7 / 61 (11.48%)
         occurrences all number
    4
    7
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    3 / 30 (10.00%)
    6 / 61 (9.84%)
         occurrences all number
    3
    6
    MUSCLE SPASMS
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 61 (4.92%)
         occurrences all number
    2
    3
    NECK PAIN
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 61 (4.92%)
         occurrences all number
    0
    3
    PAIN IN JAW
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    TENDONITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    ARTHRITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    BONE PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    FLANK PAIN
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    GROIN PAIN
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    JOINT STIFFNESS
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    OSTEONECROSIS OF JAW
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    RHEUMATIC DISORDER
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SJOGREN'S SYNDROME
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    TENDON PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    4 / 30 (13.33%)
    13 / 61 (21.31%)
         occurrences all number
    4
    13
    NASOPHARYNGITIS
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 61 (6.56%)
         occurrences all number
    3
    4
    CYSTITIS
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 61 (4.92%)
         occurrences all number
    2
    3
    GASTROENTERITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 61 (4.92%)
         occurrences all number
    1
    3
    VULVOVAGINAL MYCOTIC INFECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    4
    BRONCHITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    BARTHOLINITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    FUNGAL INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    GINGIVITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    INFECTED LYMPHOCELE
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    ORAL FUNGAL INFECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    PERITONITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    PHARYNGITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    SEPSIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    TOOTH ABSCESS
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    VIRAL INFECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    ABDOMINAL ABSCESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    ABSCESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    BRAIN EMPYEMA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    ENTEROBIASIS
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    EPSTEIN-BARR VIRUS INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    ERYSIPELAS
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    HEPATITIS B REACTIVATION
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    HERPES VIRUS INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    INFECTED DERMAL CYST
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    INFECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    INFLUENZA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    LARYNGITIS
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    LYMPHANGITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PARONYCHIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PERINEPHRIC ABSCESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PERIODONTITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    PNEUMONIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    RHINITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SINUSITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SKIN INFECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    SUBDIAPHRAGMATIC ABSCESS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    TOOTH INFECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    VIRAL RHINITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    VULVITIS
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    WOUND INFECTION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    4 / 30 (13.33%)
    9 / 61 (14.75%)
         occurrences all number
    4
    9
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 30 (0.00%)
    5 / 61 (8.20%)
         occurrences all number
    0
    5
    CELL DEATH
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    HYPERKALAEMIA
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    DEHYDRATION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    ELECTROLYTE IMBALANCE
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    HYPERCREATININAEMIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    HYPERTRIGLYCERIDAEMIA
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    HYPOALBUMINAEMIA
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    IRON DEFICIENCY
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    MALNUTRITION
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    VITAMIN D DEFICIENCY
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2019
    Amendment 1- Version 2.0 Clarification of inclusion criteria, amended management of pembrolizumab adverse event
    03 Jun 2020
    Amendment 2 – Version 3.0 Modification of the primary endpoint, addition of two secondary endpoints and one exploratory criterion

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The main limitation of the trial is the small sample size and the non-comparative statistical design, which does not allow the estimation of pembrolizumab contribution (including its impact on survival) to the treatment regime.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/39013870
    For support, Contact us.
    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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