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    Clinical Trial Results:
    OPEN, NON CONTROLLED, PARALLEL COHORTS, MULTICENTER, PHASE 2A STUDY FOR THE EVALUATION OF THE ANTITUMOR ACTIVITY OF GM102 SINGLE AGENT AND IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC COLORECTAL CANCER

    Summary
    EudraCT number
    		 2018-000627-13
    Trial protocol
    		 CZ   BE  
    Global end of trial date
    10 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2022
    First version publication date
    02 Feb 2022
    Other versions
    Summary report(s)
    		 C201 Summary of clinical results final

    Trial information

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    Trial identification
    Sponsor protocol code
    C201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03799731
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GAMAMABS Pharma
    Sponsor organisation address
    1 Place Pierre Potier, Toulouse, France, 31106
    Public contact
    Chantal KREZEL, Gamamabs Pharma, 33 184198016, ckrezel@gamamabs.fr
    Scientific contact
    Jean-François Prost, Gamamabs Pharma, 33 184198016, jfprost@gamamabs.fr
    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
    02 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the anti-tumor activity of GM102 single agent and in combination with trifluridine/tipiracil in locally advanced and metastatic colorectal cancers (CRC).
    Protection of trial subjects
    Patients were followed up in dedicated oncology centers through regular visits. A Trial Steering Committee (TSC) analyzed, qualified murlentamab activity and toxicities and provided recommendations on the IMP (Investigational Medicinal Product, consisting of murlentamab or murlentamab + trifluridine/tipiracil) continuation on a regular basis until study completion. A careful observation of patients was made from the beginning up to 1 hour after each murlentamab infusion. Blood pressure and heart rate monitoring by a qualified nurse or physician was measured just before and just after murlentamab infusion, so that immediate action can be taken in response to symptoms of an adverse reaction Concomitant medications should be kept to a minimum during the study , if they are considered as necessary for the patient's welfare and are unlikely to interfere with the IMP, they may be given at the discretion of the investigator: *Palliative radiotherapy with sponsor, assessment done case by case *Supportive treatment as medically indicated for the patient’s well-being may be prescribed at the investigator’s discretion
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    04 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 40
    Country: Number of subjects enrolled
    Czechia: 25
    Worldwide total number of subjects
    65
    EEA total number of subjects
    65
    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)
    41
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From Jul-2018 to Mar-2020, 73 patients were screened in the 5 sites participating in the study and 65 (89.0%) patients were enrolled. Overall, 81.8% of the enrolled patients completed 2 cycles (time point for primary endpoint criteria analysis). All patients discontinued the treatment during the study (the main reason was progression).

    Pre-assignment
    Screening details
    		 Adult patients with histologically-confirmed metastatic or locally advanced colorectal adenocarcinoma, having failed the previous line of treatment and having received at least two systemic chemotherapy regimens for metastatic colorectal cancer, with at least one of the tumor sites amenable to core needle biopsy; at least one measurable lesion.

    Period 1
    Period 1 title
    Screening period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Screening
    Arm description
    		 73 patients were screened for the study and 65 were included as 8 patients did not meet inclusion/ exclusion criteria
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Screening
    Started
    65
    Completed
    65
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort I
    Arm description
    		 GM102 single agent in refractory patients, having exhausted all therapeutic options. Murlentamab is a humanized glyco-engineered IgG1 antibody targeting AMHRII, administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Murlentamab
    Investigational medicinal product code
    GM102
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Murlentamab is administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle Murlentamab is diluted in 250 mL NaCl 0.9% polyolefin bags according to the patient weight

    Arm title
    		 Cohort II
    Arm description
    		 Murlentamab in combination with trifluridine/tipiracil In patient candidates to receive single agent trifluridine/tipiracil, after at least two lines of treatment for the advanced or metastatic disease. Murlentamab is administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle Trifluridine/tipiracil is administered orally at the dose of 35mg/m²/dose twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Murlentamab
    Investigational medicinal product code
    GM102
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Murlentamab is a humanized glyco-engineered IgG1 antibody targeting AMHRII, administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle The packaging (including perfusion set + unit boxes) is individualised patient-by-patient. The unit boxes were sent to the centres at 2-8°C with probes in bulk boxes containing the number of unit boxes. Each murlentamab unit box contains: - One 20 mL vial containing 150 mg of murlentamab - Instructions for dilution in Sodium Chloride 0,9% Each perfusion set (shipped at room temperature) contains: NaCl (NaCl 0.9%) 250 mL bags and tubing. Murlentamab IS diluted in 250 mL NaCl 0.9% polyolefin bags according to the patient weight

    Investigational medicinal product name
    Trifluridine/tipiracil
    Investigational medicinal product code
    Trifluridine/tipiracil
    Other name
    Lonsurf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trifluridine/tipiracil is administered orally at the dose of 35mg/m²/dose twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle (according to patient’s body surface area) in combination with murlentamab. Trifluridine/tipiracil is delivered to the patient for one cycle at a time (10 days of treatment each time). The patient returned to the pharmacy unused tablets and empty packs at Day 8 of each cycle and at Day 15 of each cycle for accountability before being given the treatment for the next cycle. Tablets of 15 mg/6.14 mg or 20/8.19 mg are used in the study

    Arm title
    		 Cohort II expansion
    Arm description
    		 Murlentamab in combination with trifluridine/tipiracil in patient candidates to receive single agent trifluridine/tipiracil, after at least two lines of treatment for the advanced or metastatic disease.Murlentamab is administered intravenously over a period of 1 hour at the recommended dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle after a loading dose of 10 mg/kg weekly during 28-day cycle 1. Trifluridine/tipiracil is administered orally at the dose of 35mg/m²/dose twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Murlentamab
    Investigational medicinal product code
    GM102
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Murlentamab is administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle after a loading dose of 10 mg/kg weekly during 28-day cycle 1. Murlentamab is diluted in 250 mL NaCl 0.9% polyolefin bags according to the patient weight

    Investigational medicinal product name
    Trifluridine/tipiracil
    Investigational medicinal product code
    Trifluridine/tipiracil
    Other name
    Lonsurf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trifluridine/tipiracil is administered orally at the dose of 35mg/m²/dose twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle (according to patient’s body surface area) in combination with murlentamab. Trifluridine/tipiracil is delivered to the patient for one cycle at a time (10 days of treatment each time). The patient returned to the pharmacy unused tablets and empty packs at Day 8 of each cycle and at Day 15 of each cycle for accountability before being given the treatment for the next cycle. Tablets of 15 mg/6.14 mg or 20/8.19 mg are used in the study

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 has been defined as screening period and is corresponding to the six weeks preceding the first infusion of IMP where all the inclusion/ exclusion criteria were checked. Baseline is planned at Cycle 1 Day 1 just before the administration of Murlentamab (see the flowchart of the study: appendix 1 of the protocol )
    Number of subjects in period 2
    		Cohort I Cohort II Cohort II expansion
    Started
    21
    18
    26
    Completed
    13
    13
    21
    Not completed
    8
    5
    5
         Two first cycles not completed
    7
    4
    1
         No baseline radiological assessment
    -
    -
    1
         No post baseline radiological assessment
    1
    1
    3
    Period 3
    Period 3 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Overall safety population
    Arm description
    		 Patients who received at least one dose of IMP. The exact number can't be entered in this item, nevertheless all the patients belonging to the safety population set have a follow-up visit (65 patients)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Overall safety population
    Started
    47
    Completed
    47

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort I
    Reporting group description
    		 GM102 single agent in refractory patients, having exhausted all therapeutic options. Murlentamab is a humanized glyco-engineered IgG1 antibody targeting AMHRII, administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle

    Reporting group title
    Cohort II
    Reporting group description
    		 Murlentamab in combination with trifluridine/tipiracil In patient candidates to receive single agent trifluridine/tipiracil, after at least two lines of treatment for the advanced or metastatic disease. Murlentamab is administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle Trifluridine/tipiracil is administered orally at the dose of 35mg/m²/dose twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle

    Reporting group title
    Cohort II expansion
    Reporting group description
    		 Murlentamab in combination with trifluridine/tipiracil in patient candidates to receive single agent trifluridine/tipiracil, after at least two lines of treatment for the advanced or metastatic disease.Murlentamab is administered intravenously over a period of 1 hour at the recommended dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle after a loading dose of 10 mg/kg weekly during 28-day cycle 1. Trifluridine/tipiracil is administered orally at the dose of 35mg/m²/dose twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle

    Reporting group values
    		 Cohort I Cohort II Cohort II expansion Total
    Number of subjects
    		 21 18 26 65
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 11 13 17 41
        From 65-84 years
    		 10 5 9 24
        85 years and over
    		 0 0 0 0
    Age continuous
    The median age was similar between cohorts: approximately 63 in Cohort I, 59 in Initial Cohort II and Cohort II expansion, respectively
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 63 (56 to 70) 59 (52 to 66) 59 (52 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 8 7 12 27
        Male
    		 13 11 14 38
    ECOG performance status
    Units: Subjects
        Grade 0
    		 6 6 13 25
        Grade 1
    		 15 12 13 40
    CRC primary disease
    Location of the tumor was mainly reported in the colon in the Cohort I and Cohort II expansion: 16 patients (76.2%) and 19 patients (73.1%), respectively. In Initial Cohort II, the location was balanced between colon and rectum
    Units: Subjects
        Colon ascending
    		 3 3 5 11
        Colon descending
    		 1 0 2 3
        Colon hepatic flexure
    		 4 2 2 8
        Colon sigmoid
    		 6 4 9 19
        Colon splenic flexure
    		 1 0 0 1
        Colon transverse
    		 1 0 1 2
        Rectum
    		 5 9 7 21
    Primary tumor differentiation
    Primary tumor was mainly reported as moderately differentiated in all cohorts: 15 patients in Cohort I (75.0%), 10 patients in Cohort II (76.9%) and 15 patients in Cohort II expansion (75.0%), respectively
    Units: Subjects
        Highly differentiated
    		 5 1 1 7
        Low Differentiation Or Undifferentiated Disease
    		 0 2 4 6
        Moderately differentiated
    		 15 10 15 40
        Undetermined
    		 1 5 6 12
    CRC molecular characteristics KRAS
    Mutations when analyzed were mainly reported in KRAS: 13 patients in Cohort I (61.9%), 12 patients in Cohort II (66.7%) and 16 patients in Cohort II expansion (64.0%), respectively
    Units: Subjects
        Not done
    		 0 0 1 1
        If done, mutated
    		 13 12 16 41
        If done, not mutated
    		 8 6 9 23
    Primary surgery
    The majority of the patients benefited from surgery in the time course of their disease (18 patients in Cohort I [85.7%], 15 patients in Initial Cohort II [83.3%] and 22 patients in Cohort II expansion [84.6%], respectively)
    Units: Subjects
        No
    		 3 3 4 10
        Yes
    		 18 15 22 55
    Resection if primary surgery
    Resection was mainly considered as “R0” for most of the patients (n=26, 83.9%) ranging from 62.5% to 100%.
    Units: Subjects
        No resection
    		 3 3 4 10
        If resection, R0
    		 11 5 10 26
        If resection, R1
    		 0 1 0 1
        If resection, R2
    		 0 2 2 4
        If resection, missing value
    		 7 7 10 24
    Time to onset
    Patients included in Initial Cohort II or Cohort II expansion presented mainly synchronous disease when patients included in the Cohort I presented mainly metachronous disease.
    Units: Subjects
        Metachronous disease
    		 13 7 9 29
        Synchronous disease
    		 8 11 17 36
    First location of metastases
    Seven patients (33.3%) of Cohort I, eight patients (44.4%) in Initial Cohort II and eight patients (30.8%) in Cohort II expansion presented at least two metastases. Moreover, one patient (4.8%) in Cohort I, two patients (11.1%) in Initial Cohort II and one patient (3.8%) in Cohort II expansion presented at least three metastasis, respectively. Metastases locations were reported in the liver, peritoneum or in lung, bones, lymph nodes, and ovaries. None of the patients presented brain metastasis
    Units: Subjects
        Liver
    		 13 14 12 39
        Peritoneum
    		 2 1 3 6
        Other
    		 6 3 11 20
    Previous anti-cancer treatment
    All patients had received at least one previous anticancer treatment. Roughly, one half of the patients in the Cohort I (52%) and II expansion (46%) had received at least one previous neoadjuvant and/or adjuvant anti-cancer treatment. The disease at treatment start was mainly located in the colon or rectum in Cohort I (81.8%) and Initial Cohort II (63.6%) when it was mostly metastatic (63.6%) in the Cohort II expansion
    Units: Subjects
        At least 1 prev neoadj and/or adj, local cancer
    		 9 7 4 20
        At least 1 prev neoadj and/or adj, metastat cancer
    		 2 4 7 13
        No previous neoadjuvant and/or adjuvant
    		 10 7 15 32
    Time since diagnosis
    Median time since diagnosis ranged from 2.22 years (Min ; Max: 0.9 ; 7.7) in Cohort II to 3.78 years (Min ; Max: 1.3 ; 9.0) in Cohort I
    Units: Number of years
        median (full range (min-max))
    		 3.78 (1.3 to 9) 2.22 (0.9 to 7.7) 3.02 (0.9 to 7.9) -
    Time from primary diagnosis to first metastases
    Units: Number of months
        median (full range (min-max))
    		 2.5 (0 to 43.2) 0.13 (-1.1 to 26.9) 0.23 (-0.5 to 35.4) -
    Time since first metastases
    Units: Number of months
        median (full range (min-max))
    		 34.07 (11.1 to 100) 22.23 (10.9 to 73.9) 30.55 (10.3 to 80.7) -
    Number of lines of anti cancer treatment
    All patients had received at least one previous metastatic line of treatment. The median number of lines received was higher in Cohort I (4.00, ranged from 1 to 7) as compared to Initial Cohort II and Cohort II expansion that were similar (2.00 vs 2.50, respectively? ranged one to four cohort II and one to six cohort II expansion). Overall, 90.5% (n=19) and 66.7% (n=14) of the patients included in Cohort I, 16.7% (n=3) and 11.1% (n=2) in the Initial Cohort II and 50.0% (n=13) and 30.8% (n=8) of the patients in the Cohort II had received at least three or four lines of metastatic treatment, res
    Units: NUMBER
        median (full range (min-max))
    		 4 (2 to 7) 2 (1 to 4) 2.5 (1 to 6) -
    Time between last previous anti-cancer treatment and first infusion of murlentamab
    The median time between last previous anti-cancer treatment and first infusion of murlentamab was of 5.29 months (Min ; Max: 2.1 ; 22.1) in Cohort I, 4.44 months (Min ; Max: 2.1 ; 46.7) in Initial Cohort II and 7.54 months (Min ; Max: 2.1 ; 43.4) in Cohort II expansion. The treatment given to the patients in all cohorts included mainly: Fluorouracil, Irinotecan, Oxaliplatin and Bevacizumab
    Units: month
        median (full range (min-max))
    		 5.29 (2.1 to 22.1) 4.44 (2.1 to 46.7) 7.54 (2.1 to 43.4) -

    End points

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    End points reporting groups
    Reporting group title
    Screening
    Reporting group description
    		 73 patients were screened for the study and 65 were included as 8 patients did not meet inclusion/ exclusion criteria
    Reporting group title
    Cohort I
    Reporting group description
    		 GM102 single agent in refractory patients, having exhausted all therapeutic options. Murlentamab is a humanized glyco-engineered IgG1 antibody targeting AMHRII, administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle

    Reporting group title
    Cohort II
    Reporting group description
    		 Murlentamab in combination with trifluridine/tipiracil In patient candidates to receive single agent trifluridine/tipiracil, after at least two lines of treatment for the advanced or metastatic disease. Murlentamab is administered intravenously over a period of 1 hour at the dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle Trifluridine/tipiracil is administered orally at the dose of 35mg/m²/dose twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle

    Reporting group title
    Cohort II expansion
    Reporting group description
    		 Murlentamab in combination with trifluridine/tipiracil in patient candidates to receive single agent trifluridine/tipiracil, after at least two lines of treatment for the advanced or metastatic disease.Murlentamab is administered intravenously over a period of 1 hour at the recommended dose of 7 mg/kg weekly at Days 1, Day 8, Day 15 and Day 21 of each 28-day cycle after a loading dose of 10 mg/kg weekly during 28-day cycle 1. Trifluridine/tipiracil is administered orally at the dose of 35mg/m²/dose twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle
    Reporting group title
    Overall safety population
    Reporting group description
    		 Patients who received at least one dose of IMP. The exact number can't be entered in this item, nevertheless all the patients belonging to the safety population set have a follow-up visit (65 patients)

    Subject analysis set title
    Cohort I AMHRII<20%
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    AMHRII expression determined by IHC on baseline biopsy Efficacy Evaluable patients

    Subject analysis set title
    Cohort I AMHRII≥20%
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    AMHRII expression determined by IHC on baseline biopsy Efficacy Evaluable patients

    Subject analysis set title
    Cohort II AMHRII<20%
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    AMHRII expression determined by IHC on baseline biopsy Efficacy Evaluable patients

    Subject analysis set title
    Cohort II AMHRII≥20%
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    AMHRII expression determined by IHC on baseline biopsy Efficacy Evaluable patients

    Subject analysis set title
    modified Intent To Treat
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Intention-To Treat (ITT) set is defined as all patients who receive at least one administration of any study drug (murlentamab for Cohort I and murlentamab and/or trifluridine/tipiracil for Cohort II

    Subject analysis set title
    Efficacy Evaluable set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Efficacy Evaluable Patient (EEP) set is defined as all ITT patients with radiological baseline assessment and at least one radiological post-baseline assessment and who completed the first two cycles (8 weeks) of treatment

    Subject analysis set title
    Per Protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol (PP) set consists of all evaluable patients who do not violate the terms of the protocol in a way that would affect the study outcome significantly. All decisions to exclude patients from the PP population were made before locking the database

    Subject analysis set title
    Pharmacokinetics set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetics (PK) set is defined as all patients who received at least one dose of any study drug (murlentamab for Cohort I and murlentamab and/or trifluridine/tipiracil for Cohort II), and who had at least one evaluable PK blood sample for murlentamab

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set (SS) was defined for safety analysis: it consists of all patients who receive at least one infusion of murlentamab. Both cohorts were evaluated separately for safety

    Primary: Overall Tumor Response Rate (ORR)

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    End point title
    		 Overall Tumor Response Rate (ORR) [1]
    End point description
    Overall Tumor Response Rate (ORR) defined as the proportion of evaluable patients who achieved partial or complete response (RECIST criteria version 1.1) from the end of cycle 2 and subsequently confirmed at least 4 weeks after. Reporting per arms only for the EEP set. The co-primary endpoint was not met in Cohort I as no patient achieved either an ORR or a PFS at 6 months. In the second Cohort overall, the ORR criteria was not met as only one patient achieved a partial response.
    End point type
    Primary
    End point timeframe
    From the end of cycle 2
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were done in this study: quantitative data summarized by : number of data available, number of missing data, mean, standard deviation, first quartile (Q1), median, third quartile (Q3), minimum and maximum; qualitative data summarized by : number of data available, number of missing data, frequency and percentage for each modality. The percentages were based on the number of data available. All CIs provided computed at 95%; level of significance set at 5% (two-sided)
    End point values
    		 Cohort I Cohort II Cohort II expansion
    Number of subjects analysed
    13
    13
    21
    Units: number of patients responders
    number (not applicable)
        investigator assessment Yes
    0
    0
    1
        investigator assessment No
    13
    13
    20
        IRC assessment Yes
    0
    0
    1
        IRC assessment No
    13
    13
    20
    Attachments
    		 ORR and PFS at 6 months
    No statistical analyses for this end point

    Primary: Progression free survival (PFS) at 6 months

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    End point title
    		 Progression free survival (PFS) at 6 months [2]
    End point description
    The Progression Free Survival (PFS) at 6 months, defined as the proportion of patients without documented progression or death due to any cause. Reporting per arms only for EEP set The co-primary endpoint was not met in Cohort I as no patient achieved either an ORR or a PFS at 6 months. In the second cohort overall, the PFS endpoints was met as 9 out 34 patients were free from progression at 6 months according to Investigators’ judgment in the EEP set.
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were done in this study: quantitative data summarized by : number of data available, number of missing data, mean, standard deviation, first quartile (Q1), median, third quartile (Q3), minimum and maximum; qualitative data summarized by : number of data available, number of missing data, frequency and percentage for each modality. The percentages were based on the number of data available. All CIs provided computed at 95%; level of significance set at 5% (two-sided)
    End point values
    		 Cohort I Cohort II Cohort II expansion
    Number of subjects analysed
    13
    13
    21
    Units: number of patients without progression
    number (not applicable)
        investigator assessment Yes
    0
    4
    5
        investigator assessment No
    13
    9
    16
        IRC assessment Yes
    0
    3
    7
        IRC assessment No
    13
    10
    14
    Attachments
    		 ORR and PFS at 6 months
    No statistical analyses for this end point

    Secondary: Overall Tumor Response Rate (ORR) iRECIST

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    End point title
    		 Overall Tumor Response Rate (ORR) iRECIST
    End point description
    Immune Objective Response Rate (iORR) iORR per iRECIST criteria includes the notion of unconfirmed (iUPD) and confirmed progressive disease (iCPD). In case of unconfirmed progression (i.e. IUPD), IMP treatment can be pursued if patient is clinically stable. Patient will be re-assessed at least 4 weeks later and no longer that 8 weeks later for response to treatment (iCR, iPR or iCPD) according to tumor evaluation calculated from baseline tumor target lesions, without taking the previous unconfirmed progression into account. reporting per cohorts only for EEP set.
    End point type
    Secondary
    End point timeframe
    ORR is also assessed according to iRECIST criteria from the end of cycle 2
    End point values
    		 Cohort I Cohort II Cohort II expansion
    Number of subjects analysed
    13
    13
    21
    Units: number of patients responders
    number (not applicable)
        investigator assessment yes
    0
    0
    1
        investigator assessment no
    13
    13
    20
        IRC assessment yes
    0
    0
    1
        IRC assessment no
    13
    13
    20
    Attachments
    		 iORR-Secondary endpoint
    No statistical analyses for this end point

    Secondary: Clinical benefit rate (CBR)

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    End point title
    		 Clinical benefit rate (CBR)
    End point description
    Clinical benefit rate (CBR) at each tumor evaluation (number and % of non-progressors, i.e. CR+PR+SD) using RECIST and iRECIST criteria. Proportion of patients who are non-progressors (radiologically and clinically, including responders and stabilized patients, using RECIST 1.1 and iRECIST criteria) from the first administration of murlentamab (cohort I) or murlentamab + trifluridine/tipiracil (Cohort II) at 8 (+/- 10 days, end of cycle 2) and 16 (+/- 15 days, end of cycle 4) weeks. Overall, only one patient in Cohort II expansion achieved a partial response . In addition, patients in Cohort II overall were more likely to achieve a stable disease than patient included in Cohort I: five patients (38.5%) in Cohort I, nine patients (69.2%) in Cohort II and 15 patients (71.4%) in Cohort II expansion, respectively.
    End point type
    Secondary
    End point timeframe
    End of cycle 2: 8 weeks and end of cycle 4 (16 weeks)
    End point values
    		 Cohort I Cohort II Cohort II expansion
    Number of subjects analysed
    13
    13
    21
    Units: number of patients non progressors
    number (not applicable)
        at 8 weeks yes
    0
    2
    0
        at 8 weeks no
    13
    11
    21
        at 16 weeks yes
    0
    2
    0
        at 16 weeks no
    13
    11
    21
    Attachments
    		 CBR- Secondary endpoint
    No statistical analyses for this end point

    Secondary: Tumor Growth Rate (TGR)

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    End point title
    		 Tumor Growth Rate (TGR)
    End point description
    Tumor Growth Rate (TGR) pre and under treatment (at the first tumor evaluation under treatment).TGR curves (pretreatment and after completion of 2 cycles, at the first on-treatment CT scan) was calculated and displayed for each patient. Tumor growth rate was evaluable in the EEP set in the majority of the patient of the Cohort I and Cohort II (11 patients, 84.6% in both cohorts). On the contrary, TGR evaluation was only available in six patients (28.6%) of the Cohort II expansion which limits the impact of the analysis in this cohort. Nevertheless, among these patients, all but three patients included in Cohort II (patients 04-05, 01-06 and 02-01) and two patients included in Cohort I (patients 01-03 and 01-11) reported a negative percentage of variation in the TGR.
    End point type
    Secondary
    End point timeframe
    End of cycle 2 (8 weeks)
    End point values
    		 Cohort I Cohort II Cohort II expansion
    Number of subjects analysed
    11
    10
    6
    Units: percent
        median (full range (min-max))
    -33.19 (-122 to 118.2)
    -58.76 (-224.8 to 744.6)
    -101.7 (-108.3 to -11.9)
    Attachments
    		 TGR-Secondary endpoint
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    PFS is defined (proportion of patients) as the time elapsed from the date of 1st infusion to the date of documented progression or death due to any cause, whichever occurs first. Patients without documented progression are censored at the date of last response assessment that is stable disease or better. After 2 months, only 1 patient (7.7%), 6 patients (46.2%) and 11 patients (52.4%) are still considered as non-progressors in the Cohort I, Cohort II and II expansion, respectively. After 10 months, 1 patient (7.7%) and 2 patients (9.5%) are still at risk in Cohort II and II expansion, respectively. When considering AMHRII membrane expression, no modification was observed in Cohort I while in Cohort II overall patients presenting AMHRII membrane expression ≥20% presented a higher PFS than those with AMHRII membrane expression <20% according to RECIST criteria with median [95% CI] PFS of 1.77 months [1.71 - 1.87] vs 3.55 months [2.04 - 6.90], respectively
    End point type
    Secondary
    End point timeframe
    Up to the progression date
    End point values
    		 Cohort I AMHRII<20% Cohort I AMHRII≥20% Cohort II AMHRII<20% Cohort II AMHRII≥20%
    Number of subjects analysed
    6
    3
    17
    13
    Units: number of patients who progressed
    number (not applicable)
        At 2 months
    6
    3
    14
    2
        At 4 months
    6
    3
    15
    9
        At 6 months
    6
    3
    15
    9
        At 8 months
    6
    3
    17
    11
        At 10 months
    6
    3
    17
    11
        At 12 months
    6
    3
    17
    13
        At 14 months
    6
    3
    17
    13
    Attachments
    		 PFS-secondary endpoint
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time elapsed from the date of first infusion to the date of death whatever the cause. OS will be primarily analyzed on the ITT set. Patients without documentation of death at the time of analysis will be censored at the date last known to be alive. By the time of the analysis, after 36 months follow-up for the EEP, all patients (100%) in the Cohort I, 92.3% patients in initial Cohort II (12 events, 1 censor), and 71.4% of the patients of Cohort II expansion (15 events, 6 censors) had died. When considering AMHRII membrane expression, patients in Cohort II with expression ≥20% tended to have a longer OS than those with an AMHRII expression <20% with a Median [95% CI] OS of 9.00 months [3.68 - 11.47] vs 11.76 months [7.13 - 22.37], respectively (p-value for Logrank test is 0.2129). On the contrary, the loading dose in Cohort II overall did not show any impact on OS (p-value for Logrank test is 0.4345).
    End point type
    Secondary
    End point timeframe
    Up to the death or the analysis cut-off date
    End point values
    		 Cohort I AMHRII<20% Cohort I AMHRII≥20% Cohort II AMHRII<20% Cohort II AMHRII≥20%
    Number of subjects analysed
    6
    3
    17
    13
    Units: number of dead patients
    number (not applicable)
        at 2 months
    0
    0
    0
    0
        at 4 months
    2
    0
    5
    0
        at 6 months
    3
    2
    6
    2
        at 8 months
    4
    2
    7
    4
        at 10 months
    4
    3
    9
    5
        at 12 months
    5
    3
    13
    7
        at 14 months
    5
    3
    13
    9
        at 16 months
    5
    3
    13
    9
        at 18 months
    5
    3
    13
    9
        at 20 months
    5
    3
    13
    9
        at 22 months
    6
    3
    14
    9
        at 24 months
    6
    3
    14
    10
        at 26 months
    6
    3
    14
    10
        at 28 months
    6
    3
    14
    10
        at 30 months
    6
    3
    14
    10
        at 32 months
    6
    3
    14
    10
        at 34 months
    6
    3
    14
    10
        at 36 months
    6
    3
    14
    10
    Attachments
    		 OS-Secondary endpoint
    No statistical analyses for this end point

    Secondary: PD evaluation: AMHRII expression

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    End point title
    		 PD evaluation: AMHRII expression
    End point description
    AMHRII expression by immunostaining (IHC) in archived tumor samples, in the baseline biopsies and in the biopsy performed under murlentamab treatment (after 2 cycles of treatment). AMHRII expression at the tumor cell membrane from patient biopsies was evaluated by Institut Curie before (screening visit) and under treatment (at the end of Cycle 2) and presented in a specific report enclosed ro CSR. Moreover, a listing summarizing AMHRII expression in tumor cells at the cell membrane pre and under treatment for each patient is presented. AMHRII expression determined by IHC on baseline biopsy was available for 16 patients (76.2%) in Cohort I, 18 patients (100%) in Cohort II and 22 patients (84.6%) in Cohort II expansion, respectively. AMHRII membrane expression was ≥20% in four (25.0%) patients in cohort I, seven (38.9%) patients in Initial Cohort II and nine (40.9%) patients in cohort II expansion, respectively
    End point type
    Secondary
    End point timeframe
    Up to the end of cycle 2
    End point values
    		 Cohort I Cohort II Cohort II expansion
    Number of subjects analysed
    9
    13
    17
    Units: Number of patients
    number (not applicable)
        Baseline AMHRII<20%
    6
    8
    9
        Baseline AMHRII≥20%
    3
    5
    8
    No statistical analyses for this end point

    Secondary: Exposure to murlentamab

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    End point title
    		 Exposure to murlentamab
    End point description
    Pharmacokinetic analysis of murlentamab was performed by Eurofins ADME (report enclosed to CSR) on the pharmacokinetics set by cohort (Cohort I, Cohort II, Cohort II expansion, Cohort II overall) and by loading dose (7mg/kg and 10mg/kg) within Cohort II overall. Descriptive statistics (individual data listing of serum concentration) of murlentamab serum concentration (µg/mL) at Day 1 and Day 15 of the first 2 cycles and at end of treatment visit when available, before infusion and 1 hour after the start of murlentamab infusion.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 15 of the first 2 cycles and at end of treatment (EOT) visit (7 days after the last IMP infusion) when available
    End point values
    		 Cohort I Cohort II Cohort II expansion
    Number of subjects analysed
    21
    18
    26
    Units: Number of patients
    number (not applicable)
        Treatment compliance between 90-110% yes
    21
    17
    22
        Treatment compliance between 90-110% no
    0
    1
    4
    Attachments
    		 Exposure of Murlentamab
    No statistical analyses for this end point

    Secondary: Exposure of patients to trifluridine in cohort II

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    End point title
    		 Exposure of patients to trifluridine in cohort II [3]
    End point description
    Exposure of patients to trifluridine in cohort II will be assessed through description of trifluridine plasma concentrations in PK samples in the first 18 patients enrolled in cohort II. Pharmacokinetics’ analysis report was done by Eurofins ADME BIOANALYSES and report is enclosed to CSR. Trifluridine/tipiracil exposure (only for Cohort II) was calculated and analyzed by an external company (Eurofins ADME BIOANALYSES). Descriptive statistics (individual data listing of trifluridine/tipiracil plasma concentration (ng/mL) ) at Day 1 and Day 15 of the first 2 cycles and at end of treatment visit when available, before infusion and 1 hour after the start of murlentamab infusion.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 15 of the first 2 cycles and at end of treatment (EOT) visit (7 days after the last IMP administration) when available
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trifluridine was administered (trifluridine/tipiracil) in combination with Murlentamab in the cohorts II and II expansion. It was decided to measure the concentration of trifluridine only in the cohort II;
    End point values
    		 Cohort II
    Number of subjects analysed
    17
    Units: concentration
    arithmetic mean (standard deviation)
        Cycle 1 Day 15
    137.92 ( 552.01 )
        Cycle 2 Day 1
    0.28591 ( 1.1788 )
        Cycle 2 Day 15
    3.4481 ( 4.059 )
        End of Treatment (EoT)
    5.5751 ( 15.769 )
    Attachments
    		 Exposure to Trifluridine
    No statistical analyses for this end point

    Secondary: Evidence of anti-murlentamab antibodies (ADA)

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    End point title
    		 Evidence of anti-murlentamab antibodies (ADA)
    End point description
    Evidence of anti-murlentamab antibodies (ADA) at screening, at the beginning of every even cycle (pre-dose), and at the end of treatment visit.Anti-murlentamab antibodies results (Positive / Negative) will be described at Screening visit, at Day 1 of each performed cycle and at end of treatment. At screening, one patient (4.8%) in Cohort I, two patients (11.1%) Cohort II and one patient (3.8%) Cohort II expansion presented anti-murlentamab antibodies at screening. Subsequently, anti-murlentamab antibodies were only found in the same patient of the Cohort II expansion until C10D1. At the end of treatment, anti-murlentamab antibodies were found in one patient in Cohort II (7.7%) and one patient in Cohort II expansion (5.3%); these patients presented already these ADAs at screening.
    End point type
    Secondary
    End point timeframe
    At screening, beginning of even cycles and at the end of study
    End point values
    		 Cohort I Cohort II Cohort II expansion
    Number of subjects analysed
    21
    18
    26
    Units: number of positive or negative
    number (not applicable)
        Screening negative
    20
    16
    25
        Screening positive
    1
    2
    1
        C2D1 negative
    17
    16
    22
        C2D1 positive
    0
    0
    1
        End of treatment negative
    16
    12
    18
        End of treatment positive
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time informed consent is signed until at least 30 days after the last IMP administration. Safety evaluation is performed on safety set and by cohort.
    Adverse event reporting additional description
    Type, frequency, seriousness, severity and relatedness of IMP emergent adverse events (TEAEs) analyzed. 923 AEs were recorded for 64 patients (98.5%). Only the number of patients affected is reported. None SAE related to GM102. The general health deterioration resulting in death in cohort I is related to disease progression and not to murlentamab
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Cohort I
    Reporting group description
    		 Cohort I (GM102 single agent) in refractory patients, having exhausted all therapeutic options; monotherapy, with 15 evaluable patients for efficacy. Murlentamab administered at the recommended dose of 7 mg/kg weekly

    Reporting group title
    Cohort II
    Reporting group description
    		 Cohort II (murlentamab in combination with trifluridine/tipiracil) in patient candidates to receive single agent trifluridine/tipiracil, after at least two lines of treatment for the advanced or metastatic disease. Cohort II: combination, with 35-40 evaluable patients for efficacy (cohort II and cohort expansion) The first 18 patients (cohort II) received murlentamab at the recommended dose of 7 mg/kg weekly combined with trifluridine/tipiracil at the dose of 35 mg/m2/dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle

    Reporting group title
    Cohort II expansion
    Reporting group description
    		 Cohort II (murlentamab in combination with trifluridine/tipiracil) in patient candidates to receive single agent trifluridine/tipiracil, after at least two lines of treatment for the advanced or metastatic disease. Cohort II: combination, with 35-40 evaluable patients for efficacy (cohort II and cohort expansion) The additional 25 patients (cohort II expansion)will receive the recommended murlentamab loading dose of 10 mg/kg q1w during the first 28-day cycle combined with trifluridine/tipiracil at the dose of 35 mg/m2/dose administered orally twice daily on Days 1 to 5 and Days 8 to 12. The objective is to reach murlentamab steady state during the first 28-day cycle. During the subsequent 28-day cycles, murlentamab will be administered at the recommended dose of 7 mg/kg weekly, combined with trifluridine/tipiracil at the dose of 35 mg/m2/dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle.

    Serious adverse events
    		 Cohort I Cohort II Cohort II expansion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    5 / 18 (27.78%)
    4 / 26 (15.38%)
         number of deaths (all causes)
    9
    7
    11
         number of deaths resulting from adverse events
    1
    0
    0
    Nervous system disorders
    Cerebral ischaemia
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
    Additional description: Patient 01-05 SAE“General deterioration” (abdominal pain) leading to the patient’s hospitalization from 27-Sep-2018 to 12-Oct-2018 and then to the patient's death on 30-Oct-2018. SAE not related to the IMPs, but related to the underlying disease.
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
    Additional description: related to trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    5 / 18 (27.78%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
    Additional description: related to trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
    Additional description: One of this event led to trifluridine/tipiracil discontinuation for the patient affected in cohort II expansion. Not related to IMP but to underlying disease
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia, obstructive
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
    Additional description: Not related to IMP but to underlying disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort I Cohort II Cohort II expansion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    18 / 18 (100.00%)
    25 / 26 (96.15%)
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 21 (28.57%)
    4 / 18 (22.22%)
    14 / 26 (53.85%)
         occurrences all number
    6
    4
    14
    Pyrexia
         subjects affected / exposed
    7 / 21 (33.33%)
    0 / 18 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    7
    0
    3
    Oedema peripheral
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 18 (16.67%)
    2 / 26 (7.69%)
         occurrences all number
    4
    3
    2
    Asthenia
         subjects affected / exposed
    5 / 21 (23.81%)
    2 / 18 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    5
    2
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    4 / 26 (15.38%)
         occurrences all number
    0
    0
    4
    Chest pain
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    1
    General physical health deterioration
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 18 (11.11%)
    5 / 26 (19.23%)
         occurrences all number
    3
    2
    5
    Cough
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 18 (16.67%)
    3 / 26 (11.54%)
         occurrences all number
    3
    3
    3
    Epistaxis
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 18 (11.11%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Dry throat
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Rales
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 18 (5.56%)
    3 / 26 (11.54%)
         occurrences all number
    2
    1
    3
    Confusional state
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    White blood cell count decreased
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 18 (11.11%)
    7 / 26 (26.92%)
         occurrences all number
    0
    2
    7
    Blood bilirubin increased
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 18 (16.67%)
    2 / 26 (7.69%)
         occurrences all number
    3
    3
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    5 / 26 (19.23%)
         occurrences all number
    1
    1
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 18 (11.11%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    2
    Alanine aminotransferase increased
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 18 (11.11%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    2
    Neutrophil count decreased
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    2
    Weight decreased
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    1
    Blood creatinine increased
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Body temperature increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 18 (11.11%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 18 (16.67%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    3
    Headache
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    3 / 26 (11.54%)
         occurrences all number
    1
    1
    3
    Dizziness
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 18 (11.11%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    Burning sensation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 21 (23.81%)
    11 / 18 (61.11%)
    14 / 26 (53.85%)
         occurrences all number
    5
    11
    14
    Neutropenia
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    12 / 18 (66.67%)
    18 / 26 (69.23%)
         occurrences all number
    0
    12
    18
    Thrombocytopenia
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    5 / 18 (27.78%)
    4 / 26 (15.38%)
         occurrences all number
    0
    5
    4
    Leukopenia
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 18 (16.67%)
    1 / 26 (3.85%)
         occurrences all number
    0
    3
    1
    Febrile neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    2
    Eye disorders
    Lacrimation increased
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 21 (23.81%)
    12 / 18 (66.67%)
    9 / 26 (34.62%)
         occurrences all number
    5
    12
    9
    Abdominal pain
         subjects affected / exposed
    6 / 21 (28.57%)
    8 / 18 (44.44%)
    6 / 26 (23.08%)
         occurrences all number
    6
    8
    6
    Constipation
         subjects affected / exposed
    6 / 21 (28.57%)
    3 / 18 (16.67%)
    8 / 26 (30.77%)
         occurrences all number
    6
    3
    8
    Diarrhoea
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    5 / 18 (27.78%)
    11 / 26 (42.31%)
         occurrences all number
    0
    5
    11
    Vomiting
         subjects affected / exposed
    3 / 21 (14.29%)
    5 / 18 (27.78%)
    7 / 26 (26.92%)
         occurrences all number
    3
    5
    7
    Stomatitis
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 18 (16.67%)
    2 / 26 (7.69%)
         occurrences all number
    1
    3
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 18 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    2
    2
    1
    Ascites
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 18 (11.11%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    Flatulence
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    2
    Proctalgia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    2
    Small intestinal obstruction
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    2
    Gingival erosion
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Aerophagia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Anal haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Umbilical hernia, obstructive
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Ocular icterus
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    Hepatic cytolysis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Cholangitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 18 (16.67%)
    2 / 26 (7.69%)
         occurrences all number
    0
    3
    2
    Pruritus
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Skin toxicity
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 18 (11.11%)
    3 / 26 (11.54%)
         occurrences all number
    2
    2
    3
    Back pain
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 18 (5.56%)
    2 / 26 (7.69%)
         occurrences all number
    4
    1
    2
    Pain in extremity
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    2
    Muscle spasms
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Flank pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 18 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Bacterial vaginosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal gonococcal infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 21 (23.81%)
    8 / 18 (44.44%)
    10 / 26 (38.46%)
         occurrences all number
    5
    8
    10
    Hypokalaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 18 (16.67%)
    4 / 26 (15.38%)
         occurrences all number
    2
    3
    4
    Hypocalcaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    Hypomagnesaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    Hypoproteinaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    Vitamin D deficiency
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 18 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    Dehydration
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperglycaemia
    Additional description: Observed only in the groups murlentamab+trifluridine/tipiracil
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 18 (5.56%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 18 (5.56%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2018
    Addition of regorafenib in the available therapies for which pateints of cohort II are not considered for (see inclusion criterion 8 below): "Cohort II (combination with trifluridine/tipiracil): patients eligible for trifluridine/tipiracil who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, regorafenib and anti-EGFR agents. Patients must have received at least 2 prior lines of standard chemotherapy for mCRC". Addition of an exclusion criterion: 12. Severe New York Heart Association (NYHA) III and IV heart failure Suppression of to a hospital for the patient deprived of liberty in exclusion criterion 15 "Patient deprived of liberty by a judicial or administrative decision, patient admitted to a hospital, social institution or who is under a measure of legal protection, patient hospitalized without consent or who is in an emergency situation." Increase of monitoring duration after the first infusion of GM102 to 2 hours: "Patients must be closely monitored during infusions of GM102, during two hours at least after the end of the first infusion and then during one hour at least after the end of subsequent infusions. Blood pressure and heart rate monitoring by a qualified nurse or physician should be measured just before and just after GM102 infusion, so that immediate action can be taken in response to symptoms of an adverse reaction" Protocol amended with this first amendment is Protocol version v2.0 of 15-May-2018
    03 Dec 2019
    Protocol C201 was amended to version 3.0 to increase the sample size of cohort II to 25 additional patients to be enrolled, with the objective to obtain at least 35 evaluable patients in cohort II to gather more information on the efficacy of murlentamab plus trifluridine/tipiracil in metastatic pretreated CRC patients. More data on AMHRII expression on tumor cells at baseline and under treatment will be obtained aiming at determining an IHC assay for future trials for patient selection and future analytical validation. First preliminary results of the study on the 39 patients analyzed in both cohorts (cut-off date of April 24, 2019), suggested a longer than expected PFS for murlentamab + trifluridine/tipiracil, especially for patients with marked AMHRII expression. A larger cohort of patients treated with the combination will allow to investigate a potential relationship between the level of AMHRII expression in tumoral cells, the clinical response to treatment and the patient overall outcome (progression-free survival becoming a primary endpoint and overall survival). The hypothesis to demonstrate: 85% of probability that the true number of patients free of progression at 6 months is greater than 15% if 8 out of 35 patients (~30%) are free of progression for trifluridine/tipiracil single agent In addition, the PFS at 6 months was moved from secondary to primary endpoint, an exploratory endpoint was added to investigate the potential relationship between AMHRII IHC expression and response to treatment and patient overall outcome, an exclusion criterion has been added to exclude patients with known allergy to rodents as Murlentamab is produced from a rat myeloma cell line (YB2/0); archived tumoral tissue is available and collected to assess AMHRII expression, relevant biomarkers and tumor microenvironment features at an earlier stage of the disease, in addition to the baseline and under treatment tumor biopsy. Protocol version v3.0 of 06-November-2019
    28 Apr 2020
    Protocol C201, version 3.0 from 6 November 2019,was amended to a version 4.0 in the context of the Covid-19 pandemic and in accordance to the related EMA Guidance (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 1 (20/03/2020)) .The objectives of this amendment are to ensure as a priority the health and safety of trial participants, to allow them to remain in the trial as long they have a benefit, and to preserve the validity of data in order to reach the trial objectives."Substantial amendment” on safety measures related to Covid-19 pandemic with an immediate implementation on all sites as agreed with the study coordinating investigator and the principal investigator of each site.In addition, the principal investigator of each site has to conduct a Covid-19 risk assessment for each patient under study drug in the C201 expansion study, as recommended by the EMA guidance. Recruitment put on hold since 26 patients have been included so far.Patients withdrawn for Covid-19 will be replaced (as we can’t assess the PFS for these patients); recruitment will restart to replace non evaluable patients or patients withdrawn for Covid-19;an exclusion criterion is added: “Patient positive to Covid 19”. If it is not possible to collect the tumoral biopsy at the end of cycle 2, it must be done at the end of cycle 3 or end of cycle 4 or at the end of treatment in case of premature termination whatever the reason; the biopsy under treatment is mandatory in the protocol.The CT-scan is planned to be done at the end of each of pair cycle, every 8-week but if it not done at the planned date, done at the next visit or at the end of the next cycle at the latest. Several visits could be performed by phone.Asymptomatic positive patients to Covid-19 are eligible to continue the study based on investigator's decision;Covid 19 symptomatic patients excluded of the study; Protocol amended is Protocol version v4.0 of 17-April-2020

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

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