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    Clinical Trial Results:
    A Randomised, Open-Label, Proof-of-Concept, Phase II Trial Comparing Gemcitabine with and without IMM-101 in Advanced Pancreatic Cancer

    Summary
    EudraCT number
    2010-022757-42
    Trial protocol
    GB   ES   IT   IE  
    Global end of trial date
    14 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Feb 2019
    First version publication date
    08 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IMM-101-002/IMM-101-002A
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01303172
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IMAGE 1: IMAGE 1
    Sponsors
    Sponsor organisation name
    Immodulon Therapeutics
    Sponsor organisation address
    6-9 The Square, Stockley Park, Uxbridge, United Kingdom, UB11 1FW
    Public contact
    Clinical Trials Co-ordinator, Immodulon Therapeutics Ltd, 00 44 0203317 6346, info@immodulon.com
    Scientific contact
    Clinical Trials Co-ordinator, Immodulon Therapeutics Ltd, 00 44 0203 317 6346, info@immodulon.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
    27 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare, in treatment-naive patients with advanced pancreatic cancer, the effects of gemcitabine (GEM) in combination with IMM-101 to GEM alone on: • Safety and tolerability, including Quality of Life (QoL). • Clinical signs and symptoms of disease. • Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). The objectives of the Sub-Study (for patients who completed the Main Study and who provided informed consent for long-term follow-up) were to: Describe the long-term safety profile of IMM-101 administered intradermally for extended use in patients completing the Main Study. Document the clinical course of the patients who previously completed the Main Study and agreed to enter the Sub-Study.
    Protection of trial subjects
    Protection of trial subjects: The trial was conducted in accordance with the study protocol, the guidelines of the World Medical Association Declaration of Helsinki as amended (Fortaleza, 2013), the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines (CPMP/ICH/135/95) , designated standard operating procedures (SOPs), and with local laws and regulations relevant to the use of new therapeutic agents. A Data Monitoring Committee (DMC) consisting of oncologists and clinicians with relevant expertise, that was established for the purposes of reviewing safety data on an ongoing basis throughout the Main and Sub studies. The DMC responsibility was to safeguard the interests of the studies' patients, with respect to safety and efficacy of IMM-101, study conduct, and compliance with the protocol.
    Background therapy
    In the Main Study (IMM-101-002), all patients received GEM administered intravenously at 1000 mg/m2 over 30 minutes once weekly for 3 consecutive weeks out of every 4 weeks up to a maximum of 12 cycles. Patients in the IMM-101 treated group began GEM at least 14 days after the first dose of IMM-101. Upon disease progression or toxicity to GEM, second-line chemotherapy of the investigator's choice was allowed. For the IMM-101 treated group this second-line chemotherapy was alongside continued treatment with IMM-101. Patients in the IMM-101 treated group could also continue on study and receive IMM-101 alone. All patients entering the Sub-Study (IMM-101-002A) received IMM-101 and were free to receive any other anti-cancer therapy (including GEM) as considered appropriate by the Investigator.
    Evidence for comparator
    Gemcitabine was the standard care for treatment of inoperable advanced pancreatic cancer at the time IMM-101-002 was initiated having been established as such since first approval in 1995. Significant improvement in disease-related symptoms and prolonged survival were demonstrated in a comparative study between GEM and 5-fluorouracil (5-FU) (1-year survival: 18% versus 2%, respectively, Burris, 1997 ). In that study, median survival was 5.65 months for GEM-treated patients and 4.41 months for 5-FU treated patients.
    Actual start date of recruitment
    15 Jul 2011
    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: 49
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Cyprus: 6
    Worldwide total number of subjects
    110
    EEA total number of subjects
    110
    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)
    37
    From 65 to 84 years
    72
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    110 patients were randomised into the study at 20 sites in 5 countries. Patients were randomised to receive either IMM-101 and GEM (75) or GEM (35). 12 patients who completed the Main Study were enrolled into the Sub-Study; 11 of these patients had previously been randomised to the IMM-101 treated group and 1 to the GEM group.

    Pre-assignment
    Screening details
    Patients aged ≥18 years were eligible for the study if they had histologically and/or cytologically confirmed inoperable ductal adenocarcinoma of the pancreas, including the mucinous variant. This included locally advanced and metastatic disease (stage III/IV). In total 142 patients were screened of whom 32 failed screening.

    Period 1
    Period 1 title
    Complete study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not Applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ITT IMM-101 + GEM
    Arm description
    ITT IMM-101 + Gemcitabine
    Arm type
    Experimental

    Investigational medicinal product name
    Heat killed Mycobacterium obuense NCTC13365 (IMM-101)
    Investigational medicinal product code
    UPI EMA/569517 (IMM-101)
    Other name
    IMM-101
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    During the Main Study, patients received a single 0.1 mL intradermal (i.d.) injection of IMM-101 every 2 weeks for the first 3 doses, followed by a 4-week rest period, then IMM-101 every 2 weeks for the next 3 doses. Thereafter, patients received doses every 4 weeks to a maximum of 15 doses. IMM-101 was given via i.d. injection into the skin overlying the deltoid muscle, with the arm being alternated between each dose. Patients enrolling in the Sub-Study continued to receive IMM-101 every 4 weeks. GEM was administered intravenously at 1000 mg/m2 over 30 minutes once weekly for 3 consecutive weeks out of every 4 weeks to a maximum of 12 cycles. The first dose of GEM was given at least 14 days after the first dose of IMM-101. Patients enrolling in the Sub-Study from the Main study GEM group received IMM-101 every 2 weeks for the first 3 doses, then a rest of 4 weeks, then 1 dose every 2 weeks for the next 3 doses. Thereafter, the treatment regimen was 1 dose every 4 weeks.

    Arm title
    ITT GEM
    Arm description
    ITT Gemcitabine
    Arm type
    Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    GEM
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered intravenously at 1000 mg/m2 over 30 minutes once weekly for 3 consecutive weeks out of every 4 weeks to a maximum of 12 cycles. In the experimental arm (IMM-101 + GEM) the first dose of GEM was given at least 14 days after the first dose of IMM-101. GEM could be continued in the Sub-Study at the Investigator's discretion.

    Number of subjects in period 1
    ITT IMM-101 + GEM ITT GEM
    Started
    75
    35
    Completion of main study
    12
    1
    Completion of sub-study
    0
    0
    Completed
    0
    0
    Not completed
    75
    35
         Change in therapy
             2
             -
         Death
             22
             7
         Consent withdrawn and patient decision
             7
             2
         Fracture
             1
             -
         Completed main study then lost to follow up
             1
             -
         Adverse event, non-fatal
             5
             -
         Toxicity
             -
             2
         Disease progression/clinical deterioration
             37
             23
         Functional impairment(without disease progression)
             -
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Complete study
    Reporting group description
    All randomised patients

    Reporting group values
    Complete study Total
    Number of subjects
    110 110
    Age categorical
    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)
    37 37
        From 65-84 years
    72 72
        85 years and over
    1 1
    Age continuous
    Units: years
        median (full range (min-max))
    67 (45 to 88) -
    Gender categorical
    Units: Subjects
        Female
    51 51
        Male
    59 59

    End points

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    End points reporting groups
    Reporting group title
    ITT IMM-101 + GEM
    Reporting group description
    ITT IMM-101 + Gemcitabine

    Reporting group title
    ITT GEM
    Reporting group description
    ITT Gemcitabine

    Subject analysis set title
    ITT IMM-101 + GEM patients with metastatic disease
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All IMM-101 + Gemcitabine treated patients who had metastatic disease at study entry

    Subject analysis set title
    ITT GEM patients with metastatic disease
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All Gemcitabine treated patients who had metastatic disease at study entry

    Primary: Overall survival in the ITT IMM-101 + GEM arm compared with that in the ITT GEM arm until completion of the Main Study

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    End point title
    Overall survival in the ITT IMM-101 + GEM arm compared with that in the ITT GEM arm until completion of the Main Study
    End point description
    OS was defined as the time in months from randomisation in the Main Study to death due to any cause. Patients without death date were censored at the date the patient was last known to be alive.
    End point type
    Primary
    End point timeframe
    From randomisation to death due to any cause with a data cutoff date of 9 September 2014.
    End point values
    ITT IMM-101 + GEM ITT GEM ITT IMM-101 + GEM patients with metastatic disease ITT GEM patients with metastatic disease
    Number of subjects analysed
    75
    35
    64
    28
    Units: Months
        median (confidence interval 95%)
    6.7 (5.4 to 7.5)
    5.6 (3.2 to 7.2)
    7.0 (5.5 to 9.0)
    4.4 (2.8 to 6.5)
    Statistical analysis title
    Overall survival
    Statistical analysis description
    The difference in OS between treatment groups was assessed using Kaplan-Meier methods and a 2-sided logrank test. The HR was estimated using a Cox regression model
    Comparison groups
    ITT IMM-101 + GEM v ITT GEM
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.074
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.04
    Statistical analysis title
    Overall survival (metastatic disease patients)
    Statistical analysis description
    The difference in OS between treatment groups was assessed using Kaplan-Meier methods and a 2-sided logrank test for the ITT subgroup of patients with metastatic disease. The HR was estimated using a Cox regression model. Statistical values relate to the treatment effect of IMM-101 + GEM treated patients relative to that of GEM treated patients.
    Comparison groups
    ITT GEM patients with metastatic disease v ITT IMM-101 + GEM patients with metastatic disease
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.87

    Other pre-specified: Progression-free survival in the ITT IMM-101 + GEM arm compared with that in the ITT GEM arm until completion of the Main Study

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    End point title
    Progression-free survival in the ITT IMM-101 + GEM arm compared with that in the ITT GEM arm until completion of the Main Study
    End point description
    PFS was defined as the time in months from randomisation to objective tumour progression or death (whichever occurred first). Progression included biological progression, clinical progression, withdrawal due to progression, and death due to any cause. Patients with no event were censored at the last contact.
    End point type
    Other pre-specified
    End point timeframe
    From randomisation to progression or death (whichever occurred first) with a data cutoff of 9 September 2014
    End point values
    ITT IMM-101 + GEM ITT GEM ITT IMM-101 + GEM patients with metastatic disease ITT GEM patients with metastatic disease
    Number of subjects analysed
    75
    35
    64
    28
    Units: months
        median (confidence interval 95%)
    4.1 (3.3 to 4.8)
    2.4 (2.1 to 4.0)
    4.4 (3.3 to 5.1)
    2.3 (1.9 to 2.8)
    Statistical analysis title
    Progression free survival
    Statistical analysis description
    The difference in PFS between treatment groups was assessed using Kaplan-Meier methods and a 2-sided logrank test for the ITT population. The HR was estimated using a Cox regression model.
    Comparison groups
    ITT IMM-101 + GEM v ITT GEM
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.016
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    0.91
    Statistical analysis title
    Progression free survival - metastatic disease
    Statistical analysis description
    The difference in PFS between treatment groups was assessed using Kaplan-Meier methods and a 2-sided logrank test for the ITT subgroup of patients with metastatic disease. The HR was estimated using a Cox regression model. Statistical values relate to the treatment effect of IMM-101 + GEM treated patients relative to that of GEM treated patients.
    Comparison groups
    ITT GEM patients with metastatic disease v ITT IMM-101 + GEM patients with metastatic disease
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    0.75

    Other pre-specified: Overall Response rate

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    End point title
    Overall Response rate
    End point description
    ORR was defined as the percentage of patients with a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria. A responder was defined as a patient experiencing either a CR or PR by these criteria.
    End point type
    Other pre-specified
    End point timeframe
    From randomisation to death with a data cut-off date of 9 September 2014
    End point values
    ITT IMM-101 + GEM ITT GEM ITT IMM-101 + GEM patients with metastatic disease ITT GEM patients with metastatic disease
    Number of subjects analysed
    75
    35
    64
    28
    Units: Patients
        Complete response
    0
    0
    0
    0
        Partial response
    8
    1
    7
    1
    Statistical analysis title
    Overall Response Rate
    Statistical analysis description
    The difference between the percentage of patients with a response (complete response (CR) or partial response (PR) by RECIST 1.1) in the IMM-101 + GEM group to that in the GEM group was assessed.
    Comparison groups
    ITT IMM-101 + GEM v ITT GEM
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.164
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    Overall Response Rate
    Statistical analysis description
    The difference between the percentage of patients with a response (complete response (CR) or partial response (PR) by RECIST 1.1) in the IMM-101 + GEM group to that in the GEM group was assessed.
    Comparison groups
    ITT IMM-101 + GEM patients with metastatic disease v ITT GEM patients with metastatic disease
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.249
    Method
    Chi-squared
    Confidence interval

    Other pre-specified: Overall survival in the ITT IMM-101 + GEM arm compared to that in the ITT GEM arm including Sub-Study survival

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    End point title
    Overall survival in the ITT IMM-101 + GEM arm compared to that in the ITT GEM arm including Sub-Study survival
    End point description
    OS was defined as the time in months from randomisation in the Main study to death due to any cause including extended follow-up from the Sub-Study and post study survival status. Patients without a death date were censored at the date the patient was last known to be alive
    End point type
    Other pre-specified
    End point timeframe
    From randomisation to death with a data cutoff date of 5 February 2016
    End point values
    ITT IMM-101 + GEM ITT GEM ITT IMM-101 + GEM patients with metastatic disease ITT GEM patients with metastatic disease
    Number of subjects analysed
    75
    35
    64
    28
    Units: Months
        median (confidence interval 95%)
    6.7 (5.4 to 7.5)
    5.6 (3.2 to 7.2)
    7.0 (5.5 to 9.0)
    4.4 (2.8 to 6.5)
    Statistical analysis title
    Overall survival
    Statistical analysis description
    The difference in OS between treatment groups was assessed using Kaplan-Meier methods and a 2-sided logrank test. The HR was estimated using a Cox regression model
    Comparison groups
    ITT IMM-101 + GEM v ITT GEM
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0706
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.04
    Statistical analysis title
    Overall survival (metastatic disease patients)
    Comparison groups
    ITT IMM-101 + GEM patients with metastatic disease v ITT GEM patients with metastatic disease
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0093
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.86

    Other pre-specified: Progression free survival in the ITT IMM-101 + GEM arm compared to that in the ITT GEM arm until completion of the Sub-Study

    Close Top of page
    End point title
    Progression free survival in the ITT IMM-101 + GEM arm compared to that in the ITT GEM arm until completion of the Sub-Study
    End point description
    PFS was defined as the time in months from randomisation to objective tumour progression or death (whichever occurred first). Progression included biological progression, clinical progression, withdrawal due to progression, and death due to any cause. Patients with no event were censored at the last contact.
    End point type
    Other pre-specified
    End point timeframe
    From randomisation to progression or death (whichever occurred first) with a data cutoff of 14 Jan 2016
    End point values
    ITT IMM-101 + GEM ITT GEM ITT IMM-101 + GEM patients with metastatic disease ITT GEM patients with metastatic disease
    Number of subjects analysed
    75
    35
    64
    28
    Units: months
        median (confidence interval 95%)
    4.1 (3.3 to 4.8)
    2.4 (2.1 to 4.0)
    4.4 (3.3 to 5.1)
    2.3 (1.9 to 2.8)
    Statistical analysis title
    Progression free survival
    Statistical analysis description
    The difference in PFS between treatment groups was assessed using Kaplan-Meier methods and a 2-sided logrank test for the ITT population. The HR was estimated using a Cox regression model. Statistical values relate to the treatment effect of IMM-101 + GEM treated patients relative to that of GEM treated patients.
    Comparison groups
    ITT GEM v ITT IMM-101 + GEM
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0158
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    0.91
    Statistical analysis title
    Progression free survival - metastatic disease
    Statistical analysis description
    The difference in PFS between treatment groups was assessed using Kaplan-Meier methods and a 2-sided logrank test for the ITT population. The HR was estimated using a Cox regression model.
    Comparison groups
    ITT IMM-101 + GEM patients with metastatic disease v ITT GEM patients with metastatic disease
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0012
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    0.75

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Complete study duration
    Adverse event reporting additional description
    AE data were collected from informed consent until patient completion, withdrawal or death and followed until 30 days after end of study/withdrawal visit. AEs leading to hospitalisation/death due to disease progression were reported as AEs, not SAEs, if this was expected as a normal course of the disease and was not more rapid than was expected.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    IMM-101 + GEM Main study only
    Reporting group description
    Treatment-emergent AEs reported for IMM-101 + GEM treated patients during the 12-cycle Main study. Treatment-emergent AEs were those commencing or worsening after first exposure to IMM-101. Only treatment-emergent fatalities are reported. One additional fatality occurred in this group prior to exposure to any study drug. Treatment-related events refer to those with a reported causality to either IMM-101, GEM, or both.

    Reporting group title
    GEM Main study only
    Reporting group description
    Treatment-emergent AEs reported for GEM treated patients during the 12-cycle Main study. Treatment-emergent AEs were those commencing or worsening after first exposure to GEM. Only treatment-emergent fatalities are reported. Treatment-related events refer to those with a reported causality to GEM.

    Reporting group title
    IMM-101 + GEM Main and Sub studies combined
    Reporting group description
    Treatment-emergent AEs reported for IMM-101 treated patients combined with additional AE data for the 11 patients who entered the long term follow up Sub-Study. Treatment-emergent AEs were those commencing or worsening after first exposure to IMM-101 in the Main study. Only treatment-emergent fatalities are reported. One additional fatality occurred in this group prior to exposure to any study drug. Treatment-related events refer to those with reported causality to IMM-101, GEM or both in the Main study and to IMM-101 in the Sub-Study.

    Reporting group title
    GEM Main and Sub studies combined
    Reporting group description
    Treatment-emergent AEs reported for GEM treated patients in the main study combined with AE data for the one patient who entered the long-term follow-up Sub-Study. Treatment-emergent AEs were those commencing or worsening after first exposure to GEM in the Main study, but before first exposure to IMM-101 in the Sub-Study. Note any AEs starting or worsening after first exposure to IMM-101 in this GEM patient are treatment emergent to IMM-101. Only treatment-emergent fatalities are reported. Treatment-related events refer to those with a reported causality to GEM in the Main study only. There were no SAEs which were related to IMM-101 after commencing IMM-101 treatment in this reporting group.

    Serious adverse events
    IMM-101 + GEM Main study only GEM Main study only IMM-101 + GEM Main and Sub studies combined GEM Main and Sub studies combined
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 74 (48.65%)
    10 / 35 (28.57%)
    38 / 74 (51.35%)
    10 / 35 (28.57%)
         number of deaths (all causes)
    20
    7
    22
    7
         number of deaths resulting from adverse events
    14
    5
    15
    5
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 35 (0.00%)
    2 / 74 (2.70%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    2 / 74 (2.70%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (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
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 35 (2.86%)
    1 / 74 (1.35%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IVth nerve paralysis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 35 (2.86%)
    0 / 74 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Disease progression
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 35 (5.71%)
    3 / 74 (4.05%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
    0 / 2
    Pyrexia
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 35 (2.86%)
    4 / 74 (5.41%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 35 (2.86%)
    0 / 74 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 35 (0.00%)
    4 / 74 (5.41%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 35 (0.00%)
    3 / 74 (4.05%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 35 (0.00%)
    3 / 74 (4.05%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 35 (2.86%)
    1 / 74 (1.35%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 35 (2.86%)
    0 / 74 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Small intestine perforation
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 35 (2.86%)
    0 / 74 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pancreatic duct stenosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (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
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 35 (0.00%)
    2 / 74 (2.70%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 35 (2.86%)
    0 / 74 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 35 (2.86%)
    0 / 74 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Biliary sepsis
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 35 (0.00%)
    4 / 74 (5.41%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 35 (0.00%)
    3 / 74 (4.05%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 35 (0.00%)
    3 / 74 (4.05%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 35 (2.86%)
    1 / 74 (1.35%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 35 (0.00%)
    2 / 74 (2.70%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 35 (0.00%)
    2 / 74 (2.70%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 35 (2.86%)
    0 / 74 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Urinary tract infection fungal
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 35 (0.00%)
    1 / 74 (1.35%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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: 5%
    Non-serious adverse events
    IMM-101 + GEM Main study only GEM Main study only IMM-101 + GEM Main and Sub studies combined GEM Main and Sub studies combined
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 74 (97.30%)
    35 / 35 (100.00%)
    72 / 74 (97.30%)
    35 / 35 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 35 (8.57%)
    4 / 74 (5.41%)
    3 / 35 (8.57%)
         occurrences all number
    7
    6
    7
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    32 / 74 (43.24%)
    12 / 35 (34.29%)
    34 / 74 (45.95%)
    12 / 35 (34.29%)
         occurrences all number
    69
    46
    77
    46
    Fatigue
         subjects affected / exposed
    19 / 74 (25.68%)
    10 / 35 (28.57%)
    19 / 74 (25.68%)
    10 / 35 (28.57%)
         occurrences all number
    46
    24
    50
    24
    Pyrexia
         subjects affected / exposed
    18 / 74 (24.32%)
    2 / 35 (5.71%)
    18 / 74 (24.32%)
    2 / 35 (5.71%)
         occurrences all number
    28
    2
    30
    2
    Oedema peripheral
         subjects affected / exposed
    12 / 74 (16.22%)
    7 / 35 (20.00%)
    12 / 74 (16.22%)
    7 / 35 (20.00%)
         occurrences all number
    19
    9
    22
    9
    Mucosal inflammation
         subjects affected / exposed
    6 / 74 (8.11%)
    1 / 35 (2.86%)
    6 / 74 (8.11%)
    1 / 35 (2.86%)
         occurrences all number
    8
    1
    8
    1
    Chills
         subjects affected / exposed
    6 / 74 (8.11%)
    0 / 35 (0.00%)
    6 / 74 (8.11%)
    0 / 35 (0.00%)
         occurrences all number
    7
    0
    7
    0
    Injection site pain
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 35 (0.00%)
    4 / 74 (5.41%)
    0 / 35 (0.00%)
         occurrences all number
    6
    0
    6
    0
    Pain
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 35 (5.71%)
    5 / 74 (6.76%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    6
    2
    Injection site reaction
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 35 (0.00%)
    5 / 74 (6.76%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    8
    0
    Oedema
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 35 (0.00%)
    4 / 74 (5.41%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    6
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 74 (10.81%)
    2 / 35 (5.71%)
    9 / 74 (12.16%)
    2 / 35 (5.71%)
         occurrences all number
    8
    4
    9
    4
    Insomnia
         subjects affected / exposed
    7 / 74 (9.46%)
    3 / 35 (8.57%)
    9 / 74 (12.16%)
    3 / 35 (8.57%)
         occurrences all number
    7
    4
    9
    4
    Depression
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 35 (5.71%)
    5 / 74 (6.76%)
    2 / 35 (5.71%)
         occurrences all number
    5
    2
    6
    2
    Investigations
    Platelet count decreased
         subjects affected / exposed
    7 / 74 (9.46%)
    7 / 35 (20.00%)
    7 / 74 (9.46%)
    7 / 35 (20.00%)
         occurrences all number
    24
    14
    24
    14
    Weight decreased
         subjects affected / exposed
    12 / 74 (16.22%)
    1 / 35 (2.86%)
    14 / 74 (18.92%)
    1 / 35 (2.86%)
         occurrences all number
    12
    1
    17
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 74 (8.11%)
    2 / 35 (5.71%)
    6 / 74 (8.11%)
    2 / 35 (5.71%)
         occurrences all number
    15
    2
    15
    2
    Neutrophil count decreased
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 35 (5.71%)
    5 / 74 (6.76%)
    2 / 35 (5.71%)
         occurrences all number
    8
    3
    8
    3
    White blood cell count decreased
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 35 (11.43%)
    2 / 74 (2.70%)
    4 / 35 (11.43%)
         occurrences all number
    7
    7
    7
    7
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 35 (2.86%)
    4 / 74 (5.41%)
    1 / 35 (2.86%)
         occurrences all number
    11
    2
    11
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 35 (2.86%)
    4 / 74 (5.41%)
    1 / 35 (2.86%)
         occurrences all number
    11
    1
    11
    1
    Haemoglobin decreased
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 35 (5.71%)
    3 / 74 (4.05%)
    2 / 35 (5.71%)
         occurrences all number
    8
    3
    10
    3
    Blood bilirubin increased
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 35 (2.86%)
    5 / 74 (6.76%)
    1 / 35 (2.86%)
         occurrences all number
    5
    1
    12
    1
    Vitamin D decreased
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 35 (0.00%)
    5 / 74 (6.76%)
    0 / 35 (0.00%)
         occurrences all number
    6
    0
    6
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 35 (5.71%)
    1 / 74 (1.35%)
    2 / 35 (5.71%)
         occurrences all number
    3
    4
    3
    4
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 35 (0.00%)
    4 / 74 (5.41%)
    0 / 35 (0.00%)
         occurrences all number
    4
    0
    4
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 74 (31.08%)
    9 / 35 (25.71%)
    23 / 74 (31.08%)
    9 / 35 (25.71%)
         occurrences all number
    37
    14
    40
    14
    Neutropenia
         subjects affected / exposed
    16 / 74 (21.62%)
    10 / 35 (28.57%)
    16 / 74 (21.62%)
    10 / 35 (28.57%)
         occurrences all number
    37
    24
    48
    24
    Thrombocytopenia
         subjects affected / exposed
    10 / 74 (13.51%)
    7 / 35 (20.00%)
    11 / 74 (14.86%)
    7 / 35 (20.00%)
         occurrences all number
    20
    13
    21
    13
    Leukopenia
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 35 (8.57%)
    4 / 74 (5.41%)
    3 / 35 (8.57%)
         occurrences all number
    15
    9
    24
    9
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 74 (8.11%)
    3 / 35 (8.57%)
    7 / 74 (9.46%)
    3 / 35 (8.57%)
         occurrences all number
    8
    4
    10
    4
    Cough
         subjects affected / exposed
    6 / 74 (8.11%)
    1 / 35 (2.86%)
    7 / 74 (9.46%)
    1 / 35 (2.86%)
         occurrences all number
    10
    1
    11
    1
    Epistaxis
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 35 (5.71%)
    1 / 74 (1.35%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    1
    2
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    13 / 74 (17.57%)
    2 / 35 (5.71%)
    13 / 74 (17.57%)
    2 / 35 (5.71%)
         occurrences all number
    17
    2
    17
    2
    Lethargy
         subjects affected / exposed
    8 / 74 (10.81%)
    1 / 35 (2.86%)
    9 / 74 (12.16%)
    1 / 35 (2.86%)
         occurrences all number
    11
    2
    15
    2
    Dizziness
         subjects affected / exposed
    7 / 74 (9.46%)
    1 / 35 (2.86%)
    8 / 74 (10.81%)
    1 / 35 (2.86%)
         occurrences all number
    8
    1
    9
    1
    Headache
         subjects affected / exposed
    8 / 74 (10.81%)
    0 / 35 (0.00%)
    8 / 74 (10.81%)
    0 / 35 (0.00%)
         occurrences all number
    9
    0
    9
    0
    Paraesthesia
         subjects affected / exposed
    3 / 74 (4.05%)
    1 / 35 (2.86%)
    4 / 74 (5.41%)
    1 / 35 (2.86%)
         occurrences all number
    3
    1
    4
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    32 / 74 (43.24%)
    14 / 35 (40.00%)
    33 / 74 (44.59%)
    14 / 35 (40.00%)
         occurrences all number
    55
    27
    65
    27
    Abdominal pain
         subjects affected / exposed
    32 / 74 (43.24%)
    11 / 35 (31.43%)
    35 / 74 (47.30%)
    11 / 35 (31.43%)
         occurrences all number
    46
    22
    56
    22
    Nausea
         subjects affected / exposed
    32 / 74 (43.24%)
    13 / 35 (37.14%)
    33 / 74 (44.59%)
    13 / 35 (37.14%)
         occurrences all number
    55
    26
    59
    26
    Constipation
         subjects affected / exposed
    29 / 74 (39.19%)
    11 / 35 (31.43%)
    31 / 74 (41.89%)
    11 / 35 (31.43%)
         occurrences all number
    36
    21
    42
    21
    Vomiting
         subjects affected / exposed
    21 / 74 (28.38%)
    14 / 35 (40.00%)
    22 / 74 (29.73%)
    14 / 35 (40.00%)
         occurrences all number
    32
    19
    34
    19
    Stomatitis
         subjects affected / exposed
    8 / 74 (10.81%)
    4 / 35 (11.43%)
    8 / 74 (10.81%)
    4 / 35 (11.43%)
         occurrences all number
    10
    8
    11
    8
    Ascites
         subjects affected / exposed
    5 / 74 (6.76%)
    3 / 35 (8.57%)
    7 / 74 (9.46%)
    3 / 35 (8.57%)
         occurrences all number
    10
    3
    13
    3
    Abdominal distension
         subjects affected / exposed
    6 / 74 (8.11%)
    3 / 35 (8.57%)
    6 / 74 (8.11%)
    3 / 35 (8.57%)
         occurrences all number
    6
    3
    7
    3
    Abdominal pain upper
         subjects affected / exposed
    8 / 74 (10.81%)
    0 / 35 (0.00%)
    9 / 74 (12.16%)
    0 / 35 (0.00%)
         occurrences all number
    12
    0
    15
    0
    Dyspepsia
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 35 (5.71%)
    7 / 74 (9.46%)
    2 / 35 (5.71%)
         occurrences all number
    6
    2
    9
    2
    Abdominal discomfort
         subjects affected / exposed
    6 / 74 (8.11%)
    0 / 35 (0.00%)
    6 / 74 (8.11%)
    0 / 35 (0.00%)
         occurrences all number
    8
    0
    8
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 74 (8.11%)
    0 / 35 (0.00%)
    6 / 74 (8.11%)
    0 / 35 (0.00%)
         occurrences all number
    7
    0
    8
    0
    Malabsorption
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 35 (0.00%)
    4 / 74 (5.41%)
    0 / 35 (0.00%)
         occurrences all number
    4
    0
    6
    0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 35 (0.00%)
    4 / 74 (5.41%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 35 (5.71%)
    1 / 74 (1.35%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    1
    2
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    8 / 74 (10.81%)
    1 / 35 (2.86%)
    9 / 74 (12.16%)
    1 / 35 (2.86%)
         occurrences all number
    9
    1
    10
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    6 / 74 (8.11%)
    2 / 35 (5.71%)
    6 / 74 (8.11%)
    2 / 35 (5.71%)
         occurrences all number
    10
    2
    10
    2
    Pruritus
         subjects affected / exposed
    6 / 74 (8.11%)
    2 / 35 (5.71%)
    7 / 74 (9.46%)
    2 / 35 (5.71%)
         occurrences all number
    7
    3
    8
    3
    Dry skin
         subjects affected / exposed
    5 / 74 (6.76%)
    3 / 35 (8.57%)
    5 / 74 (6.76%)
    3 / 35 (8.57%)
         occurrences all number
    6
    3
    6
    3
    Alopecia
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 35 (5.71%)
    5 / 74 (6.76%)
    2 / 35 (5.71%)
         occurrences all number
    5
    3
    6
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 74 (22.97%)
    5 / 35 (14.29%)
    17 / 74 (22.97%)
    5 / 35 (14.29%)
         occurrences all number
    22
    6
    24
    6
    Arthralgia
         subjects affected / exposed
    6 / 74 (8.11%)
    2 / 35 (5.71%)
    7 / 74 (9.46%)
    2 / 35 (5.71%)
         occurrences all number
    7
    3
    9
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    30 / 74 (40.54%)
    11 / 35 (31.43%)
    33 / 74 (44.59%)
    11 / 35 (31.43%)
         occurrences all number
    40
    24
    45
    24
    Vitamin D deficiency
         subjects affected / exposed
    6 / 74 (8.11%)
    1 / 35 (2.86%)
    7 / 74 (9.46%)
    1 / 35 (2.86%)
         occurrences all number
    6
    1
    7
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 74 (2.70%)
    3 / 35 (8.57%)
    2 / 74 (2.70%)
    3 / 35 (8.57%)
         occurrences all number
    2
    5
    3
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 74 (9.46%)
    3 / 35 (8.57%)
    7 / 74 (9.46%)
    3 / 35 (8.57%)
         occurrences all number
    8
    4
    10
    4
    Nasopharyngitis
         subjects affected / exposed
    3 / 74 (4.05%)
    1 / 35 (2.86%)
    5 / 74 (6.76%)
    1 / 35 (2.86%)
         occurrences all number
    4
    3
    8
    3
    Respiratory tract infection
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 35 (0.00%)
    4 / 74 (5.41%)
    0 / 35 (0.00%)
         occurrences all number
    5
    0
    6
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2011
    1. To remove the assessment of circulating tumour cells as an exploratory endpoint and to provide further detail on the immune response analysis. 2. To add an additional 2 hours of vital signs monitoring (under medical supervision) following the first dose of IMM-101. 3. To clarify the maximum total blood volume collected from patients who are both in and out of the sub-set of patients recruited from the site(s) participating in the exploratory immune response analysis
    17 Apr 2012
    1. Changes to the manufacturer of IMM-101. 2. Addition of more sites and countries. 3. Clarification of inclusion criteria number 6 regarding acceptable baseline WBC. 4. Clarification of the treatment of local skin reactions and any subsequent dose reduction of IMM-101. 5. Clarification of the information to be recorded in the case report form following the Investigator’s inspection for local reactions. 6. Clarification of the timing of some procedures: • Confirmation that some screening procedures can occur on the same day as randomisation. • Confirmation that samples (haematology, chemistry, urinalysis) can be taken the day before a scheduled dosing day. • Clarification that blood samples for exploratory analysis must be taken prior to administration of IMM-101. 7. Confirmation that influenza vaccination history will be recorded at screening. 8. Clarification of sample size calculation. 9. Clarification that patients who change treatment regimen during the study will still be followed up for survival until what would have been the end of the 12 cycles. 10. Update of personnel details and removal of some personnel details to comply with ICH E6 Section 6.1.
    18 May 2012
    1. Inclusion of a the Sub-Study protocol for a long-term treatment phase to commence once patients have completed the 12 cycle treatment phase in the Main study.
    07 Jan 2014
    1. Changes to allow the Sponsor to follow up all withdrawn and completed patients for survival beyond the time corresponding to the end of 12 cycles, where appropriate including periodic follow-up of patients choosing not to enter the Sub-Study or who withdraw from the Main study early. 2. Inclusion of a larger volume vial presentation of investigational medicinal product (Note: injection volume and dose remain unchanged and the larger vial size is already approved by all Competent Authorities). 3. Assessments of CA19.9, CEA CRP and albumin were introduced part-way through the study however, the limited data collected did not allow for meaningful conclusions to be drawn.

    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.
    This proof of concept study was not formally sized to test a specific pre-defined efficacy hypothesis, however, it has provided important insights into the potential for efficacy improvements with the use of IMM-101 in advanced pancreatic cancer.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27599039
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