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    Clinical Trial Results:
    An open label phase II study to evaluate the efficacy and safety of PDR001 in patients with advanced or metastatic, well-differentiated, non-functional neuroendocrine tumors of pancreatic, gastrointestinal (GI), or thoracic origin or poorly-differentiated gastroenteropancreatic euroendocrine carcinoma (GEP-NEC), that have progressed on prior treatment

    Summary
    EudraCT number
    		 2016-002522-36
    Trial protocol
    		 SE   GB   DE   ES   AT   NL   BE   FR   IT  
    Global end of trial date
    13 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2021
    First version publication date
    01 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CPDR001E2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02955069
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the antitumor activity of spartalizumab as a single agent in the well-differentiated NET and poorly-differentiated GEP-NEC groups (overall response rate).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Aug 2014
    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
    Germany: 7
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Japan: 9
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Italy: 26
    Worldwide total number of subjects
    116
    EEA total number of subjects
    62
    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)
    79
    From 65 to 84 years
    36
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place in 35 investigative sites in 12 countries from 14 Feb 2017 to 04 Apr 2018

    Pre-assignment
    Screening details
    		 A total of 149 participants were screened. Those participants who met the eligibility criteria entered the treatment period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Well-differentiated NET
    Arm description
    		 Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was supplied as 100 mg powder for solution for infusion. Spartalizumab was administered intravenously at a dose of 400 mg once every 4 weeks (Q4W), given as a 30-minute infusion on Day 1 of every Cycle (Each cycle was 28 days)

    Arm title
    		 Poorly-differentiated GEP-NEC
    Arm description
    		 Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was supplied as 100 mg powder for solution for infusion. Spartalizumab was administered intravenously at a dose of 400 mg once every 4 weeks (Q4W), given as a 30-minute infusion on Day 1 of every Cycle (Each cycle was 28 days)

    Number of subjects in period 1
    		Well-differentiated NET Poorly-differentiated GEP-NEC
    Started
    95
    21
    Full Analysis Set (FAS)
    95
    21
    Safety set
    95
    21
    Pharmacokinetic analysis set (PAS)
    94
    18
    Immunogenicity (IG) prevalence set
    94
    21
    IG incidence set
    84
    17
    Completed
    0
    0
    Not completed
    95
    21
         Adverse event, serious fatal
    7
    3
         Physician decision
    10
    2
         Adverse event, non-fatal
    7
    2
         Study terminated by sponsor
    4
    -
         Subject/Guardian decision
    3
    1
         Progressive disease
    64
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Well-differentiated NET
    Reporting group description
    		 Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.

    Reporting group title
    Poorly-differentiated GEP-NEC
    Reporting group description
    		 Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.

    Reporting group values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC Total
    Number of subjects
    		 95 21 116
    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)
    		 63 16 79
        From 65-84 years
    		 31 5 36
        85 years and over
    		 1 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.4 ( 11.21 ) 57.4 ( 8.56 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 43 4 47
        Male
    		 52 17 69
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 59 16 75
        Black
    		 4 0 4
        Asian
    		 7 3 10
        Native American
    		 1 0 1
        Black or African American
    		 2 0 2
        White
    		 15 1 16
        Unknown
    		 3 1 4
        Other
    		 3 0 3
        Missing
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Well-differentiated NET
    Reporting group description
    		 Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.

    Reporting group title
    Poorly-differentiated GEP-NEC
    Reporting group description
    		 Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.

    Primary: Overall response rate (ORR) by RECIST 1.1 and as per Blinded Independent Central Review (BIRC).

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    End point title
    		 Overall response rate (ORR) by RECIST 1.1 and as per Blinded Independent Central Review (BIRC). [1]
    End point description
    ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to BIRC radiological assessment by RECIST 1.1. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Primary
    End point timeframe
    From baseline up to approximately 1.5 years
    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: no statistical analysis
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: Percentage of participants
        number (confidence interval 95%)
    7.4 (3.0 to 14.6)
    4.8 (0.1 to 23.8)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) by RECIST 1.1 and as per BIRC

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    End point title
    		 Duration of response (DOR) by RECIST 1.1 and as per BIRC
    End point description
    DOR is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression by RECIST 1.1 and as per BIRC or death due to underlying cancer. For DOR analysis, participants continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    From the date of first documented response (CR or PR) until the first documented disease progression or death, whichever comes first, assessed up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    7
    1
    Units: Days
        median (full range (min-max))
    250 (49 to 288)
    270 (270 to 270)
    No statistical analyses for this end point

    Secondary: Disease Control Rate by RECIST 1.1 and as per BIRC

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    End point title
    		 Disease Control Rate by RECIST 1.1 and as per BIRC
    End point description
    Disease control rate is defined as the proportion of patients with best overall response of CR, PR or stable disease (SD) according to RECIST 1.1 criteria and as per BIRC. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: Percentage of participants
        number (confidence interval 95%)
    64.2 (53.7 to 73.8)
    19.0 (5.4 to 41.9)
    No statistical analyses for this end point

    Secondary: Time to response (TTR) by RECIST 1.1 and as per BIRC

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    End point title
    		 Time to response (TTR) by RECIST 1.1 and as per BIRC
    End point description
    TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed. TTR was evaluated according to RECIST 1.1 and as per BIRC. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    From baseline to the first documented response, assessed up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    7
    1
    Units: Days
        median (full range (min-max))
    110 (52 to 218)
    53 (53 to 53)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) by RECIST 1.1 and as per BIRC

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    End point title
    		 Progression-free survival (PFS) by RECIST 1.1 and as per BIRC
    End point description
    PFS is defined as the time from the date of first dose to the date of the first documented radiological progression or death due to any cause. PFS was evaluated according to RECIST 1.1 and as per BIRC. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown.
    End point type
    Secondary
    End point timeframe
    From baseline until the date of the first documented radiological progression or death due to any cause, whichever comes first, assessed up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: Months
        median (confidence interval 95%)
    3.8 (3.6 to 5.5)
    1.8 (1.5 to 2.0)
    No statistical analyses for this end point

    Secondary: Immune related Overall Response Rate (irORR) by irRECIST and as per BIRC

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    End point title
    		 Immune related Overall Response Rate (irORR) by irRECIST and as per BIRC
    End point description
    irORR is the proportion of patients with a best overall response of immune related Complete Response (irCR) or immune related partial response (irPR), according to BIRC assessment by irRECIST. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the total measurable tumor burden (TMTB) compared to baseline and not qualifying for irCR or immune related progressive disease (irPD).
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: Percentage of participants
        number (confidence interval 95%)
    7.4 (3.0 to 14.6)
    4.8 (0.1 to 23.8)
    No statistical analyses for this end point

    Secondary: Immune related Duration of Response (irDoR) by irRECIST and as per BIRC.

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    End point title
    		 Immune related Duration of Response (irDoR) by irRECIST and as per BIRC.
    End point description
    irDOR is defined as the time from first documentation of irCR or irPR until the time of first documentation of progression per irRECIST based on BIRC assessment. Participants continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. An adequate tumour assessment is a tumour assessment with an overall response other than unknown for irRECIST. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR
    End point type
    Secondary
    End point timeframe
    From the date of first documented confirmed response (irCR or irPR) until the first documented progression, assessed up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    7
    1
    Units: Days
        median (full range (min-max))
    228 (49 to 288)
    270 (270 to 270)
    No statistical analyses for this end point

    Secondary: Immune related Time to Response (irTTR) by irRECIST and as per BIRC

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    End point title
    		 Immune related Time to Response (irTTR) by irRECIST and as per BIRC
    End point description
    irTTR is defined as the time between date of start of treatment until first documented response (confirmed irCR or irPR) by irRECIST and as per BIRC. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR.
    End point type
    Secondary
    End point timeframe
    From baseline to the first documented response, assessed up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    7
    1
    Units: Days
        median (full range (min-max))
    110 (52 to 218)
    53 (53 to 53)
    No statistical analyses for this end point

    Secondary: Immune related Disease Control Rate (irDCR) by irRECIST and as per BIRC

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    End point title
    		 Immune related Disease Control Rate (irDCR) by irRECIST and as per BIRC
    End point description
    irDCR is defined as the proportion of patients with a best overall response of irCR or irPR or immune related stable disease (irSD) according to irRECIST and as per BIRC. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR. irSD: Neither a sufficient shrinkage to qualify for irPR or irCR, nor an increase in lesions, or a clear and unequivocal progression of existing nontarget or new non-measurable lesions that would qualify for irPD.
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: Percentage of participants
        number (confidence interval 95%)
    66.3 (55.9 to 75.7)
    19.0 (5.4 to 41.9)
    No statistical analyses for this end point

    Secondary: Immune related Progression Free Survival (irPFS) by irRECIST and as per BIRC

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    End point title
    		 Immune related Progression Free Survival (irPFS) by irRECIST and as per BIRC
    End point description
    irPFS is defined as the time from date of start of treatment to the date of event defined as the first documented assessment of immune related progression that is confirmed or death due to any cause. If a patient has not had an event, immune related progression-free survival was censored at the date of last adequate tumor assessment. An adequate tumor assessment is a tumor assessment with overall response other than unknown for irRECIST.
    End point type
    Secondary
    End point timeframe
    From baseline until the date of the first documented immune related progression or death due to any cause, whichever comes first, assessed up to approximately 1.5 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: Months
        median (confidence interval 95%)
    3.8 (3.6 to 5.5)
    1.8 (1.5 to 2.0)
    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 from the start of treatment date to the date of death, due to any cause. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive. Note: 999999 indicates value is not evaluable.
    End point type
    Secondary
    End point timeframe
    From baseline until death due to any cause, assessed up to approx. 3 years
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: Months
        median (confidence interval 95%)
    23.4 (19.2 to 999999)
    6.8 (4.0 to 8.6)
    No statistical analyses for this end point

    Secondary: Changes from baseline in Chromogranin A (CgA) levels

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    End point title
    		 Changes from baseline in Chromogranin A (CgA) levels
    End point description
    Blood samples were collected for assessment of CgA level. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline. Only those participants with evaluable data at the specified time points for this outcome measure were analyzed (represented by n=X / Y in the category titles). Note: 999999 indicates value is not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, day 1 of each cycle from cycle 2 to end of treatment, assessed up to approx. 1.5 years. Cycle=28 days.
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: microgram/liter (ug/L)
    arithmetic mean (standard deviation)
        Cycle 2 Day 1, n= 87 / 14
    874.6 ( 6694.64 )
    6466.9 ( 23760.13 )
        Cycle 3 Day 1, n= 77 / 8
    -1811.7 ( 21413.11 )
    706.5 ( 2294.87 )
        Cycle 4 Day 1, n= 69 / 6
    579.9 ( 13437.06 )
    1544.5 ( 2712.23 )
        Cycle 5 Day 1, n= 53 / 5
    598.2 ( 11724.93 )
    1306.6 ( 3125.84 )
        Cycle 6 Day 1, n= 47 / 3
    1337.6 ( 7106.32 )
    4531.7 ( 8694.65 )
        Cycle 7 Day 1, n= 41 / 2
    -564.5 ( 12643.71 )
    11089.5 ( 17551.10 )
        Cycle 8 Day 1, n= 29 / 2
    3726.0 ( 18813.63 )
    9103.5 ( 14759.44 )
        Cycle 9 Day 1, n= 27 / 1
    22522.2 ( 94054.85 )
    -1342.0 ( 999999 )
        Cycle 10 Day 1, n= 26 / 1
    54301.5 ( 250229.27 )
    -1376.0 ( 999999 )
        Cycle 11 Day 1, n= 21 / 1
    84634.7 ( 344244.60 )
    -1393.0 ( 999999 )
        Cycle 12 Day 1, n= 18 / 1
    8177.6 ( 36820.47 )
    -1362.0 ( 999999 )
        Cycle 13 Day 1, n= 16 / 1
    -379.8 ( 1509.95 )
    -1377.0 ( 999999 )
        Cycle 14 Day 1, n= 15 / 0
    398.3 ( 1866.56 )
    999999 ( 999999 )
        Cycle 15 Day 1, n= 12 / 0
    13.1 ( 1120.60 )
    999999 ( 999999 )
        Cycle 16 Day 1, n= 4 / 0
    -81.0 ( 1583.99 )
    999999 ( 999999 )
        Cycle 17 Day 1, n= 1 / 0
    -176.0 ( 999999 )
    999999 ( 999999 )
        Cycle 18 Day 1, n= 1 / 0
    42.0 ( 999999 )
    999999 ( 999999 )
        End of treatment, n= 34 / 7
    30115.3 ( 131958.16 )
    3899.6 ( 7991.40 )
    No statistical analyses for this end point

    Secondary: Change from baseline in neuron specific enolase (NSE) levels

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    End point title
    		 Change from baseline in neuron specific enolase (NSE) levels
    End point description
    Blood samples were collected for assessment of NSE level. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline. Only those participants with evaluable data at the specified time points for this outcome measure were analyzed (represented by n=X / Y in the category titles). Note: 999999 indicates value is not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, day 1 of each cycle to end of treatment, assessed up to approx. 1.5 years. Cycle=28 days.
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: microgram/liter (ug/L)
    arithmetic mean (standard deviation)
        Cycle 2 Day 1, n= 81 / 13
    0.8 ( 29.71 )
    27.9 ( 40.77 )
        Cycle 3 Day 1, n= 73 / 7
    2.5 ( 29.33 )
    32.6 ( 56.87 )
        Cycle 4 Day 1, n= 66 / 2
    -0.1 ( 14.98 )
    21.9 ( 21.64 )
        Cycle 5 Day 1, n= 48 / 4
    4.8 ( 30.34 )
    31.8 ( 56.39 )
        Cycle 6 Day 1, n= 43 / 2
    -3.6 ( 19.18 )
    151.6 ( 204.21 )
        Cycle 7 Day 1, n= 41 / 2
    7.6 ( 39.44 )
    -3.0 ( 17.75 )
        Cycle 8 Day 1, n= 25 / 1
    1.0 ( 22.19 )
    40.4 ( 999999 )
        Cycle 9 Day 1, n= 25 / 1
    2.6 ( 8.64 )
    -12.7 ( 999999 )
        Cycle 10 Day 1, n= 21 / 1
    10.3 ( 33.74 )
    -15.0 ( 999999 )
        Cycle 11 Day 1, n= 18 / 0
    2.3 ( 8.89 )
    999999 ( 999999 )
        Cycle 12 Day 1, n= 17 / 1
    -2.4 ( 23.04 )
    -12.3 ( 999999 )
        Cycle 13 Day 1, n= 14 / 1
    -3.9 ( 24.22 )
    -17.8 ( 999999 )
        Cycle 14 Day 1, n= 15 / 0
    -4.5 ( 22.71 )
    999999 ( 999999 )
        Cycle 15 Day 1, n= 11 / 0
    -3.4 ( 29.73 )
    999999 ( 999999 )
        Cycle 16 Day 1, n= 3 / 0
    26.5 ( 35.38 )
    999999 ( 999999 )
        Cycle 17 Day 1, n= 1 / 0
    15.1 ( 999999 )
    999999 ( 999999 )
        Cycle 18 Day 1, n= 1 / 0
    13.8 ( 999999 )
    999999 ( 999999 )
        End of treatment, n= 33 / 7
    47.7 ( 136.78 )
    44.3 ( 66.73 )
    No statistical analyses for this end point

    Secondary: PDR001 plasma concentration

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    End point title
    		 PDR001 plasma concentration
    End point description
    Blood samples will be taken to evaluate the pharmacokinetics by assessing plasma concentration of PDR001 at selected time points. Only those participants with evaluable data at the specified time points for this outcome measure were analyzed (represented by n=X / Y in the category titles). Note: 999999 indicates value is not evaluable.
    End point type
    Secondary
    End point timeframe
    Cycle(C)1 Day(D)1 pre-dose and 30min post-infusion,C2D1 Pre-dose,C3D1 Pre-dose and 30min post-infusion,D1 pre-dose from C4 to C13, assessed up to approx. 1.5 years. Cycle=28 days.
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    94
    18
    Units: nanogram/mililiter (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 pre-dose, n= 89 / 17
    0 ( 0 )
    0 ( 0 )
        Cycle 1 Day 1 30 min post-dose, n= 87 / 14
    106 ( 32.9 )
    100 ( 52.2 )
        Cycle 2 Day 1 Pre-dose, n= 85 / 14
    26.8 ( 9.76 )
    25.8 ( 9.30 )
        Cycle 3 Day 1 pre-dose, n= 72 / 9
    43.7 ( 18.9 )
    42.3 ( 19.6 )
        Cycle 3 Day 1 30 min post-dose, n= 73 / 9
    140 ( 46.7 )
    142 ( 44.3 )
        Cycle 4 Day 1 pre-dose, n= 64 / 4
    52.8 ( 25.1 )
    40.7 ( 17.2 )
        Cycle 5 Day 1 pre-dose, n= 49 / 4
    52.0 ( 32.3 )
    41.8 ( 8.88 )
        Cycle 6 Day 1 pre-dose, n= 42 / 1
    58.2 ( 31.6 )
    49.9 ( 999999 )
        Cycle 7 Day 1 pre-dose, n= 36 / 2
    64.3 ( 37.6 )
    66.9 ( 30.1 )
        Cycle 8 Day 1 pre-dose, n= 28 / 2
    59.6 ( 38.2 )
    64.7 ( 31.4 )
        Cycle 9 Day 1 pre-dose, n= 23 / 1
    65.1 ( 38.1 )
    93.7 ( 999999 )
        Cycle 10 Day 1 pre-dose, n= 25 / 0
    70.2 ( 40.2 )
    999999 ( 999999 )
        Cycle 11 Day 1 pre-dose, n= 19 / 1
    69.2 ( 39.1 )
    99.0 ( 999999 )
        Cycle 12 Day 1 pre-dose, n= 14 / 1
    71.7 ( 38.1 )
    111 ( 999999 )
        Cycle 13 Day 1 pre-dose, n= 13 / 0
    91.8 ( 46.0 )
    999999 ( 999999 )
    No statistical analyses for this end point

    Secondary: Change from baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) global health status/quality of life score

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    End point title
    		 Change from baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) global health status/quality of life score
    End point description
    The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. Global health status/QoL response options are 1 to 4. Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from Baseline indicates improvement. Only those participants with evaluable data at the specified time points for this outcome measure were analyzed (represented by n=X / Y in the category titles). Note: 999999 indicates value is not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 weeks from Cycle 13 Day 1 thereafter and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days.
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 3 Day 1, n= 67 / 9
    -1.00 ( 19.491 )
    -11.11 ( 27.003 )
        Cycle 5 Day 1, n= 48 / 4
    -1.91 ( 27.838 )
    -4.17 ( 17.347 )
        Cycle 7 Day 1, n= 34 / 2
    1.96 ( 29.945 )
    25.00 ( 35.355 )
        Cycle 9 Day 1, n= 25 / 1
    1.67 ( 31.823 )
    33.33 ( 999999 )
        Cycle 11 Day 1, n= 21 / 0
    -1.19 ( 28.048 )
    999999 ( 999999 )
        Cycle 13 Day 1, n= 17 / 1
    1.96 ( 27.088 )
    41.67 ( 999999 )
        Cycle 16 Day 1, n= 3 / 0
    -16.67 ( 16.667 )
    999999 ( 999999 )
        End of Treatment, n= 40 / 8
    -6.46 ( 23.607 )
    -22.92 ( 23.465 )
    No statistical analyses for this end point

    Secondary: Change from baseline in EQ-5D-5L index score

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    End point title
    		 Change from baseline in EQ-5D-5L index score
    End point description
    The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of these dimensions, the participant self-assigned a score: from 1 (no problems) to 5 (extreme problems). The 5 digit health states obtained for each dimension was converted into a single mean index value based on the EQ-5D crosswalk value set for the UK using the time trade-off method. This index ranges from -0.594 (worst health) to 1.0 (best health). Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from baseline indicates improvement. Only those participants with evaluable data at the specified time points for this outcome measure were analyzed (represented by n=X / Y in the category titles). Note: 999999 indicates value is not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 weeks from Cycle 13 Day 1 thereafter, and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days.
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    95
    21
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 3 Day 1, n= 66 / 8
    0.03 ( 0.169 )
    -0.09 ( 0.157 )
        Cycle 5 Day 1, n= 48 / 4
    -0.02 ( 0.247 )
    0.02 ( 0.111 )
        Cycle 7 Day 1, n= 33 / 2
    -0.04 ( 0.241 )
    0.16 ( 0.135 )
        Cycle 9 Day 1, n= 25 / 1
    0.02 ( 0.247 )
    0.02 ( 999999 )
        Cycle 11 Day 1, n= 21 / 0
    0.02 ( 0.262 )
    999999 ( 999999 )
        Cycle 13 Day 1, n= 16 / 1
    -0.03 ( 0.299 )
    0.03 ( 999999 )
        Cycle 16 Day 1, n= 3 / 0
    -0.17 ( 0.085 )
    999999 ( 999999 )
        End of treatment, n= 40 / 8
    -0.10 ( 0.209 )
    -0.30 ( 0.263 )
    No statistical analyses for this end point

    Secondary: PDR001 Anti-drug antibodies (ADA) prevalence at baseline

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    End point title
    		 PDR001 Anti-drug antibodies (ADA) prevalence at baseline
    End point description
    ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    88
    17
    Units: Participants
        number (not applicable)
    1.1
    0
    No statistical analyses for this end point

    Secondary: PDR001 ADA incidence on-treatment

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    End point title
    		 PDR001 ADA incidence on-treatment
    End point description
    ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
    End point type
    Secondary
    End point timeframe
    Cycle(C)1 Day(D)1 pre-dose and 30min post-infusion,C2D1 Pre-dose,C3D1 Pre-dose and 30min post-infusion,D1 pre-dose from C4 to C13 and every 6 cycles until C25, and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days.
    End point values
    		 Well-differentiated NET Poorly-differentiated GEP-NEC
    Number of subjects analysed
    84
    17
    Units: Participants
        number (not applicable)
    11.9
    11.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approximately 3 years.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    PDR001 400mg Q4w@well-differentiated NET
    Reporting group description
    		 PDR001 400mg Q4w@well-differentiated NET

    Reporting group title
    All subjects
    Reporting group description
    		 All subjects

    Reporting group title
    PDR001 400mg Q4w@poorly-differentiated GEP-NEC
    Reporting group description
    		 PDR001 400mg Q4w@poorly-differentiated GEP-NEC

    Serious adverse events
    		 PDR001 400mg Q4w@well-differentiated NET All subjects PDR001 400mg Q4w@poorly-differentiated GEP-NEC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 95 (30.53%)
    35 / 116 (30.17%)
    6 / 21 (28.57%)
         number of deaths (all causes)
    1
    2
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour necrosis
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 95 (3.16%)
    3 / 116 (2.59%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Insulin autoimmune syndrome
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 95 (2.11%)
    2 / 116 (1.72%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pneumonitis
         subjects affected / exposed
    2 / 95 (2.11%)
    2 / 116 (1.72%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Torsade de pointes
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 95 (6.32%)
    7 / 116 (6.03%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 95 (2.11%)
    2 / 116 (1.72%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 116 (1.72%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 95 (2.11%)
    2 / 116 (1.72%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Candida infection
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 116 (0.86%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 116 (1.72%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 116 (0.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         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
    		 PDR001 400mg Q4w@well-differentiated NET All subjects PDR001 400mg Q4w@poorly-differentiated GEP-NEC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 95 (90.53%)
    104 / 116 (89.66%)
    18 / 21 (85.71%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 95 (12.63%)
    12 / 116 (10.34%)
    0 / 21 (0.00%)
         occurrences all number
    16
    16
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    12 / 95 (12.63%)
    14 / 116 (12.07%)
    2 / 21 (9.52%)
         occurrences all number
    14
    16
    2
    Fatigue
         subjects affected / exposed
    36 / 95 (37.89%)
    39 / 116 (33.62%)
    3 / 21 (14.29%)
         occurrences all number
    44
    47
    3
    Oedema peripheral
         subjects affected / exposed
    14 / 95 (14.74%)
    17 / 116 (14.66%)
    3 / 21 (14.29%)
         occurrences all number
    15
    18
    3
    Pain
         subjects affected / exposed
    2 / 95 (2.11%)
    4 / 116 (3.45%)
    2 / 21 (9.52%)
         occurrences all number
    2
    4
    2
    Pyrexia
         subjects affected / exposed
    24 / 95 (25.26%)
    26 / 116 (22.41%)
    2 / 21 (9.52%)
         occurrences all number
    32
    34
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 95 (14.74%)
    16 / 116 (13.79%)
    2 / 21 (9.52%)
         occurrences all number
    17
    19
    2
    Dyspnoea
         subjects affected / exposed
    9 / 95 (9.47%)
    15 / 116 (12.93%)
    6 / 21 (28.57%)
         occurrences all number
    10
    16
    6
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 95 (7.37%)
    7 / 116 (6.03%)
    0 / 21 (0.00%)
         occurrences all number
    7
    7
    0
    Insomnia
         subjects affected / exposed
    3 / 95 (3.16%)
    5 / 116 (4.31%)
    2 / 21 (9.52%)
         occurrences all number
    3
    5
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 95 (3.16%)
    6 / 116 (5.17%)
    3 / 21 (14.29%)
         occurrences all number
    3
    6
    3
    Amylase increased
         subjects affected / exposed
    5 / 95 (5.26%)
    6 / 116 (5.17%)
    1 / 21 (4.76%)
         occurrences all number
    5
    6
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 95 (1.05%)
    5 / 116 (4.31%)
    4 / 21 (19.05%)
         occurrences all number
    1
    5
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 95 (3.16%)
    6 / 116 (5.17%)
    3 / 21 (14.29%)
         occurrences all number
    3
    6
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 95 (6.32%)
    9 / 116 (7.76%)
    3 / 21 (14.29%)
         occurrences all number
    6
    9
    3
    Lipase increased
         subjects affected / exposed
    6 / 95 (6.32%)
    7 / 116 (6.03%)
    1 / 21 (4.76%)
         occurrences all number
    7
    8
    1
    Weight decreased
         subjects affected / exposed
    9 / 95 (9.47%)
    10 / 116 (8.62%)
    1 / 21 (4.76%)
         occurrences all number
    10
    11
    1
    Weight increased
         subjects affected / exposed
    4 / 95 (4.21%)
    6 / 116 (5.17%)
    2 / 21 (9.52%)
         occurrences all number
    5
    7
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 95 (8.42%)
    9 / 116 (7.76%)
    1 / 21 (4.76%)
         occurrences all number
    8
    9
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 95 (18.95%)
    21 / 116 (18.10%)
    3 / 21 (14.29%)
         occurrences all number
    21
    24
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    5 / 95 (5.26%)
    7 / 116 (6.03%)
    2 / 21 (9.52%)
         occurrences all number
    7
    9
    2
    Abdominal pain
         subjects affected / exposed
    17 / 95 (17.89%)
    18 / 116 (15.52%)
    1 / 21 (4.76%)
         occurrences all number
    21
    22
    1
    Abdominal pain upper
         subjects affected / exposed
    7 / 95 (7.37%)
    7 / 116 (6.03%)
    0 / 21 (0.00%)
         occurrences all number
    9
    9
    0
    Constipation
         subjects affected / exposed
    19 / 95 (20.00%)
    22 / 116 (18.97%)
    3 / 21 (14.29%)
         occurrences all number
    24
    27
    3
    Diarrhoea
         subjects affected / exposed
    26 / 95 (27.37%)
    30 / 116 (25.86%)
    4 / 21 (19.05%)
         occurrences all number
    35
    40
    5
    Dry mouth
         subjects affected / exposed
    5 / 95 (5.26%)
    5 / 116 (4.31%)
    0 / 21 (0.00%)
         occurrences all number
    6
    6
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 95 (2.11%)
    4 / 116 (3.45%)
    2 / 21 (9.52%)
         occurrences all number
    2
    4
    2
    Nausea
         subjects affected / exposed
    20 / 95 (21.05%)
    25 / 116 (21.55%)
    5 / 21 (23.81%)
         occurrences all number
    20
    25
    5
    Vomiting
         subjects affected / exposed
    11 / 95 (11.58%)
    14 / 116 (12.07%)
    3 / 21 (14.29%)
         occurrences all number
    15
    19
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 95 (8.42%)
    9 / 116 (7.76%)
    1 / 21 (4.76%)
         occurrences all number
    10
    11
    1
    Rash
         subjects affected / exposed
    10 / 95 (10.53%)
    12 / 116 (10.34%)
    2 / 21 (9.52%)
         occurrences all number
    12
    14
    2
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    6 / 95 (6.32%)
    7 / 116 (6.03%)
    1 / 21 (4.76%)
         occurrences all number
    9
    10
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    7 / 95 (7.37%)
    7 / 116 (6.03%)
    0 / 21 (0.00%)
         occurrences all number
    7
    7
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 95 (8.42%)
    8 / 116 (6.90%)
    0 / 21 (0.00%)
         occurrences all number
    11
    11
    0
    Back pain
         subjects affected / exposed
    12 / 95 (12.63%)
    14 / 116 (12.07%)
    2 / 21 (9.52%)
         occurrences all number
    15
    17
    2
    Muscular weakness
         subjects affected / exposed
    6 / 95 (6.32%)
    6 / 116 (5.17%)
    0 / 21 (0.00%)
         occurrences all number
    8
    8
    0
    Pain in extremity
         subjects affected / exposed
    7 / 95 (7.37%)
    7 / 116 (6.03%)
    0 / 21 (0.00%)
         occurrences all number
    7
    7
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 116 (1.72%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 95 (15.79%)
    18 / 116 (15.52%)
    3 / 21 (14.29%)
         occurrences all number
    21
    24
    3
    Hyperglycaemia
         subjects affected / exposed
    7 / 95 (7.37%)
    8 / 116 (6.90%)
    1 / 21 (4.76%)
         occurrences all number
    12
    13
    1
    Hypoalbuminaemia
         subjects affected / exposed
    8 / 95 (8.42%)
    8 / 116 (6.90%)
    0 / 21 (0.00%)
         occurrences all number
    8
    8
    0
    Hypoglycaemia
         subjects affected / exposed
    5 / 95 (5.26%)
    5 / 116 (4.31%)
    0 / 21 (0.00%)
         occurrences all number
    5
    5
    0
    Hyponatraemia
         subjects affected / exposed
    5 / 95 (5.26%)
    5 / 116 (4.31%)
    0 / 21 (0.00%)
         occurrences all number
    5
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Apr 2017
    The main purpose of this amendment was to add a group of approximately 20 patients with advanced or metastatic, poorly-differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). This cohort was added because of the following reasons: 1) biological rationale supporting the potential efficacy of immunotherapy; 2) no approved treatment and no consensus on the standard of care upon progression on 1st line chemotherapy. Moreover, the possibility of stopping the study early for futility at the time of the protocol defined interim analysis and the maximum treatment duration of 24 months was removed. Several inclusion/ exclusion criteria were modified.
    12 Jan 2018
    This amendment included the following modifications: 1) Inclusion of Part 2 (Expansion part) aiming to further characterize the efficacy and safety of PDR001 single agent in any of the well-differentiated NET cohorts if antitumor activity was observed in Part 1; 2) Possibility to implement the PDR001 liquid formulation for patients treated in Study Part 2 (expansion part); 3) Addition of an inclusion criterion regarding life expectancy of at least 3 months for patients treated in Study Part 2 in order to decrease the occurrence of deaths during the screening period and before the first tumor assessment scheduled 8 weeks after the first treatment dose.
    24 May 2018
    The major rationale for this amendment was to remove the possibility to expand the study to Part 2 when at least 20% overall response rate (ORR) per RECIST 1.1 by central radiology review was observed in any of the cohorts of the well-differentiated NET group. While the results of the additional efficacy analysis demonstrated an ORR of 20% in the thoracic cohort of the well-differentiated NET group and met the criterion for starting Part 2, no overwhelming supportive evidence of strong efficacy was observed on other endpoints. Moreover, all other cohorts showed ORR below 10%. Based on this, there was a change in the clinical development strategy for PDR001, which was no longer developed as a single agent immunotherapy in NET, and the study was not expanded into Part 2. Importantly, this change was not due to safety concerns.

    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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