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    Clinical Trial Results:
    A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of patients with advanced neuroendocrine neoplasms of gastroenteropancreatic or lung origin (the DUNE trial).

    Summary
    EudraCT number
    		 2016-002858-20
    Trial protocol
    		 ES  
    Global end of trial date
    06 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Dec 2023
    First version publication date
    14 Dec 2023
    Other versions
    Summary report(s)
    		 DUNE- Final CSR ICH synopsis 2022

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ESR-15-11561-61/DUNE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03095274
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Espanol de Tumores Neuroendocrinos
    Sponsor organisation address
    Balmes 24, Escalera A , Barcelona, Spain, 08006
    Public contact
    Federico Nepote, MFAR Clinical Research, 34 910616228, investigacion@mfar.net
    Scientific contact
    Federico Nepote, MFAR Clinical Research, 34 934344412, investigacion@mfar.net
    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
    14 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cohorts 1 to 3: Clinical benefit rate by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, which is defined as the percentage of patients achieving complete response, partial response, or stable disease at month 9 after durvalumab plus tremelimumab was started. Cohort 4: Overall survival rate, which is defined as the percentage of patients alive at month 9 after durvalumab plus tremelimumab was started.
    Protection of trial subjects
    This assignment will designate the user as the primary user for the listed clinical trial in regards to result related information. It will enable them to prepare and post result related information for this trials on behalf of the sponsor in accordance with Commission Guideline 2012/C 302/03 and its technical guidance on the format of the data fields of result-related information on clinical trials submitted in accordance with article 57(2) of Regulation (EC) No 726/2004 and article 41(2) of Regulation (EC) No 1901/2006.
    Background therapy
    		 Well-differentiated gastroenteropancreatic and lung neuroendocrine tumors are generally malignancies with a prolonged natural history. However, clinical behavior is heterogeneous and when tumor progression is observed, treatment options are limited. The most used therapy for neuroendocrine tumors management are somatostatin analogs, with clear evidence of antitumor activity demonstrated by two phase III clinical trials in gastroenteropancreatic neuroendocrine tumors. However, even the use in lung carcinoids is quite usual, no antitumoral activity has been demonstrated in prospective clinical trials. In recent years, targeted therapies as sunitinib and everolimus have been approved for pancreatic neuroendocrine tumors and recently everolimus have showed a significant reduction in the risk of progression or death in patients with non-functional neuroendocrine tumors of lung and gastrointestinal origin. After the failure of these therapies, no drugs have demonstrated efficacy. Only Interferon alpha-2b is an option for these patients who have worsening symptoms of carcinoid syndrome while on treatment with somatostatin analogs and have showed some evidence of antitumoral activity in neuroendocrine tumors. The efficacy of Interferon alpha 2-b is not fully understood, but one of its antitumoral mechanisms of action could be related via stimulation of T cells. Tremelimumab and Durvalumab combination could be more efficient drugs to improve immune system activation and could obtain a significantly higher clinical benefit in these patients. We have analyzed presence of tumor-infiltrating lymphocytes (TILS) in these tumor types.
    Evidence for comparator
    		 Tremelimumab and Durvalumab combination could be more efficient drugs to improve immune system activation and could obtain a significantly higher clinical benefit in these patients. We have analyzed presence of tumor-infiltrating lymphocytes (TILS) in these tumor types. We found a high number of TILS that could be activated through Tremelimumab and Durvalumab. In cases of advanced high-grade G3 neuroendocrine carcinomas (NEC), regardless of the site of the primary tumor, combination chemotherapy using cisplatin/etoposide is recommended in first-line setting (provided that the patient has adequate organ function and performance status). There is no establishedsecond-line therapy for poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic origin. Tremelimumab and Durvalumab would be the first immune combination agents showing efficacy in neuroendocrine neoplasms of different origins.
    Actual start date of recruitment
    02 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 123
    Worldwide total number of subjects
    123
    EEA total number of subjects
    123
    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)
    123
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is a prospective, multi-center, open label, stratified, exploratory phase II study evaluating the efficacy and safety of durvalumab plus tremelimumab in different cohorts of patients with neuroendocrine neoplasms.

    Pre-assignment
    Screening details
    		 Cohort 1: Well-moderately differentiated lung neuroendocrine tumors (classically known as typical and atypical carcinoids) after progression to somatostatin analogs and one prior targeted therapy or chemotherapy. Cohort 2: G1/G2 (WHO grade 1 and 2) gastrointestinal neuroendocrine tumors after progression to somatostatin analogs and one prior targ

    Period 1
    Period 1 title
    Treatment and follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Expeimental: Durvalumab+Tremelimumab
    Arm description
    		 Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w starting on Week 16 for up to 8 months (9 doses). Dosing outside the window should be discussed with the Study Physician. Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 hour for each infusion. A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab. If no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736I
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w starting on Week 16 for up to 8 months (9 doses). Dosing outside the window should be discussed with the Study Physician. Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 hour for each infusion. A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab. If no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab and tremelimumab infusion).

    Number of subjects in period 1
    		Expeimental: Durvalumab+Tremelimumab
    Started
    123
    Completed
    123
    Period 2
    Period 2 title
    Baseline
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 PATIENTS WITH ADVANCED NEUROENDOCRINE NEOPLASMS OF GASTROENTER
    Arm description
    		 Screening will occur between Day -28 and Day -1. The purpose of the screening period is to establish protocol eligibility. Informed consent will be obtained up to 4 weeks prior to Cycle 1 Day 1 and after the study has been fully explained to each subject and prior to the conduct of any screening procedures or assessments. The purpose of the baseline visit is to establish disease characteristics prior to allocation and treatment and to confirm protocol eligibility as specified in the inclusion/exclusion criteria. Results of baseline assessments must be obtained prior to the first dose of study drug (Cycle 1/Day 1). Baseline assessments may be performed on Day -1 or on Cycle 1/Day 1 prior to dosing. Clinical laboratory tests including pregnancy test (where applicable) can be performed within 72 hours of the first dose of study drug. Subjects who complete the baseline visit and continue to meet the criteria for inclusion/exclusion will begin the treatment phase of this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Not treatment period
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w starting on Week 16 for up to 8 months (9 doses). Dosing outside the window should be discussed with the Study Physician. Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 hour for each infusion. A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab. If no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab and tremelimumab infusion).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 include all study states
    Number of subjects in period 2
    		PATIENTS WITH ADVANCED NEUROENDOCRINE NEOPLASMS OF GASTROENTER
    Started
    123
    Completed
    123

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PATIENTS WITH ADVANCED NEUROENDOCRINE NEOPLASMS OF GASTROENTER
    Reporting group description
    		 Screening will occur between Day -28 and Day -1. The purpose of the screening period is to establish protocol eligibility. Informed consent will be obtained up to 4 weeks prior to Cycle 1 Day 1 and after the study has been fully explained to each subject and prior to the conduct of any screening procedures or assessments. The purpose of the baseline visit is to establish disease characteristics prior to allocation and treatment and to confirm protocol eligibility as specified in the inclusion/exclusion criteria. Results of baseline assessments must be obtained prior to the first dose of study drug (Cycle 1/Day 1). Baseline assessments may be performed on Day -1 or on Cycle 1/Day 1 prior to dosing. Clinical laboratory tests including pregnancy test (where applicable) can be performed within 72 hours of the first dose of study drug. Subjects who complete the baseline visit and continue to meet the criteria for inclusion/exclusion will begin the treatment phase of this study.

    Reporting group values
    		 PATIENTS WITH ADVANCED NEUROENDOCRINE NEOPLASMS OF GASTROENTER Total
    Number of subjects
    		 123 123
    Age categorical
    Age, Continuous Mean (Standard Deviation) Unit of measure: years Age (years at informed consent signed)
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 123 123
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        Age (years at informed consent signed)
    		 0 0
    Age continuous
    Age, Continuous Mean (Standard Deviation) Unit of measure: years Age (years at informed consent signed)
    Units: years
        geometric mean (standard deviation)
    		 61.54 ( 11.56 ) -
    Gender categorical
    Sex: Female, Male
    Units: Subjects
        Female
    		 51 51
        Male
    		 72 72
    Race/Ethnicity, Customized
    Measure Type: Count of Participants Unit of measure: participants
    Units: Subjects
        Caucasic
    		 122 122
        African
    		 1 1
    Race/Ethnicity, Customized
    MeasureType: Count of Participants Unit of measure: participants
    Units: Subjects
        Caucasic
    		 122 122
        African
    		 1 1
    Subject analysis sets

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Well-moderately differentiated lung neuroendocrine tumors (classically known as typical and atypical carcinoids) after progression to somatostatin analogs and one prior targeted therapy or chemotherapy.

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Well-moderately differentiated G1/G2 (WHO grade 1 and 2) gastrointestinal neuroendocrine tumors after progression to somatostatin analogs and one targeted therapy (prior targeted therapy could be everolimus or a multikinase inhibitor). Prior therapies with interferon alpha-2b or radionucleotide therapy are allowed.

    Subject analysis set title
    Cohort 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Well-moderately differentiated neuroendocrine tumors G1/G2 (WHO grade 1 and 2) from pancreatic origin after progression to standard therapies (chemotherapy, somatostatin analogs and target therapy); patients must be treated with at least two prior systemic treatment lines and a maximum of four previous treatment lines.

    Subject analysis set title
    Cohort 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin or unknown primary site (excluding lung primary tumors), patients will be treated in second line only, after

    Subject analysis sets values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects
    27
    31
    32
    33
    Age categorical
    Age, Continuous Mean (Standard Deviation) Unit of measure: years Age (years at informed consent signed)
    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)
    27
    31
    32
    33
        From 65-84 years
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
        Age (years at informed consent signed)
    0
    63
    0
    0
    Age continuous
    Age, Continuous Mean (Standard Deviation) Unit of measure: years Age (years at informed consent signed)
    Units: years
        geometric mean (standard deviation)
    62.32 ( 11.40 )
    62.77 ( 10.7 )
    65.06 ( 11.29 )
    56.33 ( 11.97 )
    Gender categorical
    Sex: Female, Male
    Units: Subjects
        Female
    9
    13
    18
    11
        Male
    18
    18
    14
    22
    Race/Ethnicity, Customized
    Measure Type: Count of Participants Unit of measure: participants
    Units: Subjects
        Caucasic
    26
    31
    32
    32
        African
    1
    0
    0
    0
    Race/Ethnicity, Customized
    MeasureType: Count of Participants Unit of measure: participants
    Units: Subjects
        Caucasic
    26
    31
    32
    33
        African
    1
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Expeimental: Durvalumab+Tremelimumab
    Reporting group description
    		 Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w starting on Week 16 for up to 8 months (9 doses). Dosing outside the window should be discussed with the Study Physician. Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 hour for each infusion. A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab. If no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion
    Reporting group title
    PATIENTS WITH ADVANCED NEUROENDOCRINE NEOPLASMS OF GASTROENTER
    Reporting group description
    		 Screening will occur between Day -28 and Day -1. The purpose of the screening period is to establish protocol eligibility. Informed consent will be obtained up to 4 weeks prior to Cycle 1 Day 1 and after the study has been fully explained to each subject and prior to the conduct of any screening procedures or assessments. The purpose of the baseline visit is to establish disease characteristics prior to allocation and treatment and to confirm protocol eligibility as specified in the inclusion/exclusion criteria. Results of baseline assessments must be obtained prior to the first dose of study drug (Cycle 1/Day 1). Baseline assessments may be performed on Day -1 or on Cycle 1/Day 1 prior to dosing. Clinical laboratory tests including pregnancy test (where applicable) can be performed within 72 hours of the first dose of study drug. Subjects who complete the baseline visit and continue to meet the criteria for inclusion/exclusion will begin the treatment phase of this study.

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Well-moderately differentiated lung neuroendocrine tumors (classically known as typical and atypical carcinoids) after progression to somatostatin analogs and one prior targeted therapy or chemotherapy.

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Well-moderately differentiated G1/G2 (WHO grade 1 and 2) gastrointestinal neuroendocrine tumors after progression to somatostatin analogs and one targeted therapy (prior targeted therapy could be everolimus or a multikinase inhibitor). Prior therapies with interferon alpha-2b or radionucleotide therapy are allowed.

    Subject analysis set title
    Cohort 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Well-moderately differentiated neuroendocrine tumors G1/G2 (WHO grade 1 and 2) from pancreatic origin after progression to standard therapies (chemotherapy, somatostatin analogs and target therapy); patients must be treated with at least two prior systemic treatment lines and a maximum of four previous treatment lines.

    Subject analysis set title
    Cohort 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin or unknown primary site (excluding lung primary tumors), patients will be treated in second line only, after

    Primary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR) [1]
    End point description
    Clinical Benefit Rate (CBR) by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, which is defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) at month 9 after durvalumab plus tremelimumab was started.
    End point type
    Primary
    End point timeframe
    9 months
    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: Clinical Benefit Rate (CBT) according to the Evaluation Criteria of response in solid tumors (RECIST 1.1), which was defined as the percentage of patients who achieved a complete response (CR), partial response (PR) or stable disease (SE) at month 9 after starting durvalumab plus tremelimumab.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    25
    29
    29
    29
    Units: patients
        CR
    0
    0
    1
    1
        PR
    1
    0
    0
    1
        SD
    6
    11
    2
    0
        PD
    18
    16
    6
    27
        Follow-up less than 9m (without previous PD/ Death
    0
    2
    20
    0
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Response Rate by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    19
    21
    23
    11
    Units: months
        median (confidence interval 95%)
    00 (00 to 00)
    29.49 (21.86 to 37.11)
    24.83 (15.33 to 34.32)
    7.04 (4.08 to 10.01)
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Overall Response Rate by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    27
    31
    32
    33
    Units: patients
        CR or PR
    3
    0
    2
    3
        No response
    24
    31
    30
    30
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of Response by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Cohort 1 Cohort 3 Cohort 4
    Number of subjects analysed
    3
    2
    3
    Units: months
        median (confidence interval 95%)
    2.98 (2.68 to 15.50)
    16.31 (10.64 to 21.98)
    10.08 (3.90 to 24.26)
    No statistical analyses for this end point

    Secondary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    Progression Free Survival by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    24
    27
    29
    33
    Units: months
        median (confidence interval 95%)
    5.55 (4.94 to 6.17)
    5.79 (3.12 to 8.45)
    5.52 (2.38 to 8.66)
    2.41 (2.08 to 2.75)
    No statistical analyses for this end point

    Secondary: Response Status 12 months

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    End point title
    		 Response Status 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    27
    31
    32
    33
    Units: Overall Number of Participants Analyzed
        CR or PR
    1
    0
    1
    2
        No response
    26
    31
    31
    31
    No statistical analyses for this end point

    Secondary: Response Status 9 months

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    End point title
    		 Response Status 9 months
    End point description
    by irRECIST criteria, at 6, 9 and 12 months after start of study treatment.
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    27
    31
    32
    33
    Units: patient
        CR or PR
    1
    0
    2
    2
        No response
    26
    31
    30
    31
    No statistical analyses for this end point

    Secondary: Response Status 6 months

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    End point title
    		 Response Status 6 months
    End point description
    Response Status 6 monthsby irRECIST criteria, at 6, 9 and 12 months after start of study treatment.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    27
    31
    32
    33
    Units: patients number
        CR or PR
    1
    0
    2
    2
        No response
    26
    31
    30
    31
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    5 years
    Adverse event reporting additional description
    CTCAE Common Terminology Criteria for Adverse Events;
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE, v4.03
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Well-moderately differentiated lung neuroendocrine tumors (classically known as typical and atypical carcinoids) after progression to somatostatin analogs and one prior targeted therapy or chemotherapy.

    Reporting group title
    cohort 2
    Reporting group description
    		 Well-moderately differentiated G1/G2 (WHO grade 1 and 2) gastrointestinal neuroendocrine tumors after progression to somatostatin analogs and one targeted therapy (prior targeted therapy could be everolimus or a multikinase inhibitor). Prior therapies with interferon alpha-2b or radionucleotide therapy are allowed.

    Reporting group title
    cohort 3
    Reporting group description
    		 Well-moderately differentiated neuroendocrine tumors G1/G2 (WHO grade 1 and 2) from pancreatic origin after progression to standard therapies (chemotherapy, somatostatin analogs and target therapy); patients must be treated with at least two prior systemic treatment lines and a maximum of four previous treatment lines.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Cohort 4 : Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin or unknown primary site (excluding lung primary tumors), p atients will be treated in second line only, after

    Serious adverse events
    		 Cohort 1 cohort 2 cohort 3 Cohort 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 27 (62.96%)
    9 / 31 (29.03%)
    16 / 32 (50.00%)
    16 / 33 (48.48%)
         number of deaths (all causes)
    13
    19
    23
    23
         number of deaths resulting from adverse events
    Vascular disorders
    Cellulitis G3
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flushing
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension - G2
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leg edemas
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thromboembolic event - G3
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Abdominal pain - G2
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death NOS - G5
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pain - G2
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    clinical deterioration
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased G1
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased - G2
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased - G1
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    3 / 32 (9.38%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creatinine increased - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GGT increased G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Serum amylase increased - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight loss - G1
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction - G1
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury to superior vena cava - G3
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation G3
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction G4
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis G5
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Seizure - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anemia G3
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia G4
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye disorders_diplopia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    3 / 33 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites - G3
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites - G5
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis - G2
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhea - G2
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhea - G3
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 31 (9.68%)
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Diarrhea - G4
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    3 / 32 (9.38%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhea - G5
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction - G5
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal hemorrhage - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visceral arterial ischemia - G5
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting - G2
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting - G3
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Edema limbs - G2
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis G4
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure G5
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Hepatobiliary disorders - Other, specify - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cholangitis G2
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hepatitis G4
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    trasnaminitis G2
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin hypopigmentation
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury - G1
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury - G5
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Acute renal injury G5
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Rectal hemorrhage - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure G3
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency G3
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism - G2
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism - G3
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myositis G2
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Encephalitis infection - G5
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Sepsis-G2
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory infection - G5
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Urinary tract infection - G2
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hepatitis G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory infection G2
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory infection G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis G3
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycemia-G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycemia - G4
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatremia - G3
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Cohort 1 cohort 2 cohort 3 Cohort 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 27 (100.00%)
    31 / 31 (100.00%)
    32 / 32 (100.00%)
    33 / 33 (100.00%)
    Vascular disorders
    Flushing Grade
         subjects affected / exposed
    1 / 27 (3.70%)
    8 / 31 (25.81%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    8
    0
    0
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 31 (6.45%)
    3 / 32 (9.38%)
    4 / 33 (12.12%)
         occurrences all number
    2
    2
    3
    4
    Fatigue
         subjects affected / exposed
    13 / 27 (48.15%)
    16 / 31 (51.61%)
    20 / 32 (62.50%)
    18 / 33 (54.55%)
         occurrences all number
    13
    16
    20
    18
    Flu like symptoms
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 31 (12.90%)
    1 / 32 (3.13%)
    1 / 33 (3.03%)
         occurrences all number
    2
    4
    1
    1
    General disorders and administration site conditions
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 31 (9.68%)
    1 / 32 (3.13%)
    1 / 33 (3.03%)
         occurrences all number
    2
    3
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 31 (6.45%)
    2 / 32 (6.25%)
    2 / 33 (6.06%)
         occurrences all number
    3
    2
    2
    2
    Dyspnea
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 31 (9.68%)
    1 / 32 (3.13%)
    1 / 33 (3.03%)
         occurrences all number
    4
    3
    1
    1
    Respiratory, thoracic and mediastinal disorders - Other, specify Grade
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 31 (6.45%)
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    2
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 31 (16.13%)
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    1
    5
    2
    0
    Investigations
    GGT increased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    3 / 32 (9.38%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    3
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 31 (9.68%)
    3 / 32 (9.38%)
    0 / 33 (0.00%)
         occurrences all number
    3
    3
    3
    0
    Somnolence
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 31 (6.45%)
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 31 (12.90%)
    3 / 32 (9.38%)
    3 / 33 (9.09%)
         occurrences all number
    1
    4
    3
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 27 (7.41%)
    11 / 31 (35.48%)
    5 / 32 (15.63%)
    5 / 33 (15.15%)
         occurrences all number
    2
    11
    5
    5
    Ascites
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    3 / 33 (9.09%)
         occurrences all number
    0
    1
    1
    3
    Constipation Grade
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 31 (9.68%)
    9 / 32 (28.13%)
    5 / 33 (15.15%)
         occurrences all number
    4
    3
    9
    5
    Diarrhea
         subjects affected / exposed
    14 / 27 (51.85%)
    15 / 31 (48.39%)
    12 / 32 (37.50%)
    7 / 33 (21.21%)
         occurrences all number
    14
    15
    12
    7
    Gastrointestinal disorders - Other, specify Grade
         subjects affected / exposed
    4 / 27 (14.81%)
    7 / 31 (22.58%)
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    4
    7
    2
    1
    Gastrointestinal pain
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 31 (9.68%)
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences all number
    2
    3
    1
    2
    Mucositis oral
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 31 (9.68%)
    6 / 32 (18.75%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    6
    3
    Nausea
         subjects affected / exposed
    2 / 27 (7.41%)
    7 / 31 (22.58%)
    3 / 32 (9.38%)
    7 / 33 (21.21%)
         occurrences all number
    2
    7
    3
    7
    Pain
         subjects affected / exposed
    3 / 27 (11.11%)
    5 / 31 (16.13%)
    4 / 32 (12.50%)
    1 / 33 (3.03%)
         occurrences all number
    3
    5
    4
    1
    Vomiting psychogenic
         subjects affected / exposed
    2 / 27 (7.41%)
    7 / 31 (22.58%)
    3 / 32 (9.38%)
    7 / 33 (21.21%)
         occurrences all number
    2
    7
    3
    7
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 31 (12.90%)
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    0
    4
    2
    1
    Pruritus Grade
         subjects affected / exposed
    5 / 27 (18.52%)
    11 / 31 (35.48%)
    11 / 32 (34.38%)
    6 / 33 (18.18%)
         occurrences all number
    5
    11
    11
    6
    Rash acneiform
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 31 (16.13%)
    4 / 32 (12.50%)
    1 / 33 (3.03%)
         occurrences all number
    0
    5
    4
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 31 (3.23%)
    2 / 32 (6.25%)
    4 / 33 (12.12%)
         occurrences all number
    1
    1
    2
    4
    Skin and subcutaneous tissue disorders - Other, specify Grade
         subjects affected / exposed
    4 / 27 (14.81%)
    4 / 31 (12.90%)
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    4
    4
    2
    1
    Renal and urinary disorders
    Renal and urinary disorders - Other, specify Grade
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    0
    2
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 31 (3.23%)
    2 / 32 (6.25%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    2
    2
    Hypothyroidism
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 31 (9.68%)
    6 / 32 (18.75%)
    4 / 33 (12.12%)
         occurrences all number
    0
    3
    6
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 31 (12.90%)
    7 / 32 (21.88%)
    1 / 33 (3.03%)
         occurrences all number
    2
    4
    7
    1
    Back pain
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 31 (3.23%)
    2 / 32 (6.25%)
    2 / 33 (6.06%)
         occurrences all number
    1
    1
    2
    2
    Bone pain
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 31 (6.45%)
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    2
    2
    1
    Generalized muscle weakness
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 31 (9.68%)
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    3
    3
    0
    2
    Musculoskeletal and connective tissue disorder
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 31 (9.68%)
    1 / 32 (3.13%)
    1 / 33 (3.03%)
         occurrences all number
    3
    3
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 31 (12.90%)
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences all number
    1
    4
    1
    0
    Pain in extremity
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    2 / 33 (6.06%)
         occurrences all number
    2
    0
    2
    2
    Infections and infestations
    Upper respiratory infection Grade
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 31 (9.68%)
    4 / 32 (12.50%)
    0 / 33 (0.00%)
         occurrences all number
    4
    3
    4
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 31 (9.68%)
    6 / 32 (18.75%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    6
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 31 (12.90%)
    5 / 32 (15.63%)
    3 / 33 (9.09%)
         occurrences all number
    2
    4
    5
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    6 / 27 (22.22%)
    9 / 31 (29.03%)
    0 / 32 (0.00%)
    7 / 33 (21.21%)
         occurrences all number
    6
    9
    0
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2020
    ● Cambios de seguridad debido a la actualización de los manuales del investigador de la versión 14 de Durvalumab a la versión 15 y de la versión 9 de Tremelimumab a la versión 10. Estos cambios se deben recoger en el protocolo del ensayo así como en la Hoja de Información al Paciente. ● Cambio de presentacion del Tremelimumab, hecho que repercute en su etiquetado.
    04 Aug 2021
    Cambios de seguridad debido a la actualización de los manuales del investigador de la versión 15 de Durvalumab a la versión 16 y 16.1. Estos cambios se deben recoger en el protocolo del ensayo así como en la Hoja de Información al Paciente.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37221181
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