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    Clinical Trial Results:
    An Open-label, Multicenter, Phase 2 Study of Oral IXAZOMIB (MLN9708) in Adult Patients With Relapsed and/or Refractory Follicular Lymphoma

    Summary
    EudraCT number
    		 2013-002302-32
    Trial protocol
    		 BE   GB   IT   ES  
    Global end of trial date
    23 Mar 2017

    Results information
    Results version number
    		 v1
    This version publication date
    05 Apr 2018
    First version publication date
    05 Apr 2018
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    C16017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01939899
    WHO universal trial number (UTN)
    		 U1111-1164-7551
    Sponsors
    Sponsor organisation name
    Millennium Pharmaceuticals, Inc.
    Sponsor organisation address
    61 Aldwych, London, United Kingdom, WC2B 4AE
    Public contact
    Medical Director, Clinical Science, Millennium Pharmaceuticals, Inc., 001 8778253327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Millennium Pharmaceuticals, Inc., 001 8778253327, trialdisclosures@takeda.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
    23 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the anti-tumor activity of oral Ixazomib as measured by overall response rate (ORR) in adult subjects with relapsed and/or refractory follicular lymphoma (FL).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    29
    EEA total number of subjects
    20
    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)
    11
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 11 investigative sites in the United States, Belgium, Canada, United Kingdom and Italy from 31 October 2013 to 23 March 2017.

    Pre-assignment
    Screening details
    		 Subjects with follicular lymphoma (FL) prior to treatment were enrolled in this 2 phase study: Lead in dose finding phase in which maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ixazomib was evaluated and Phase 2 proteasome subunit beta type-1 (PSMB1) was done to evaluate the safety, efficacy, tolerability of ixazomib.

    Period 1
    Period 1 title
    Baseline Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg
    Arm description
    		 Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in non-hodgkin lymphoma (NHL) subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Arm title
    		 Lead-in Dose Finding Phase: Ixazomib 5.3 mg
    Arm description
    		 Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Arm title
    		 Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Arm description
    		 Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Arm title
    		 Phase 2: PSMB1 Positive
    Arm description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in relapsed Or refractory follicular lymphoma (RRFL) subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Arm title
    		 Phase 2: PSMB1 Negative
    Arm description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Number of subjects in period 1
    		Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Started
    3
    7
    6
    12
    1
    Completed
    3
    7
    6
    12
    1
    Period 2
    Period 2 title
    Lead-in Dose Finding Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg
    Arm description
    		 Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in non-hodgkin lymphoma (NHL) subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Arm title
    		 Lead-in Dose Finding Phase: Ixazomib 5.3 mg
    Arm description
    		 Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Arm title
    		 Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Arm description
    		 Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Number of subjects in period 2 [1]
    		Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Started
    3
    7
    6
    Completed
    1
    0
    1
    Not completed
    2
    7
    5
         Adverse event, serious fatal
    -
    3
    1
         Other
    -
    -
    1
         Disease Progression
    2
    4
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The subjects in the preceding period were evaluated for baseline characteristics. The subjects then started the lead in dose finding period.
    Period 3
    Period 3 title
    Phase 2
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Phase 2: PSMB1 Positive
    Arm description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Arm title
    		 Phase 2: PSMB1 Negative
    Arm description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Number of subjects in period 3
    		Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Started
    12
    1
    Completed
    1
    0
    Not completed
    11
    1
         Consent withdrawn by subject
    2
    -
         Disease Progression
    9
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 4 mg
    Reporting group description
    		 Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in non-hodgkin lymphoma (NHL) subjects.

    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 5.3 mg
    Reporting group description
    		 Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Reporting group description
    		 Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Reporting group title
    Phase 2: PSMB1 Positive
    Reporting group description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in relapsed Or refractory follicular lymphoma (RRFL) subjects.

    Reporting group title
    Phase 2: PSMB1 Negative
    Reporting group description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Reporting group values
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative Total
    Number of subjects
    		 3 7 6 12 1 29
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 0 4 3 4 0 11
        From 65-84 years
    		 3 3 3 8 1 18
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Here, 99999 in the standard deviation signifies not estimable since only 1 subject was analyzed.
    Units: years
        arithmetic mean (standard deviation)
    		 72.0 ± 6.56 57.9 ± 11.13 64.3 ± 7.71 64.7 ± 11.73 79.0 ± 99999 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 1 1 1 4 1 8
        Male
    		 2 6 5 8 0 21
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0
        White
    		 3 7 6 12 0 28
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 1 1
    Region of Enrollment
    Units: Subjects
        Belgium|
    		 1 2 3 3 0 9
        Canada|
    		 0 1 2 0 0 3
        United Kingdom|
    		 0 3 1 2 0 6
        Italy|
    		 0 0 0 5 0 5
        United States|
    		 2 1 0 2 1 6
    Smoking classification
    Units: Subjects
        Never smoked
    		 2 4 5 7 1 19
        Current smoker
    		 0 2 0 0 0 2
        Ex-smoker
    		 1 1 1 5 0 8
    Height
    Here, 99999 in the standard deviation signifies not estimable since only 1 subject was analyzed.
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    		 170.0 ± 7.04 175.0 ± 11.50 169.2 ± 9.11 168.8 ± 6.70 157.5 ± 99999 -
    Weight
    Here, 99999 in the standard deviation signifies not estimable since only 1 subject was analyzed.
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    		 76.1 ± 11.27 85.8 ± 20.72 85.3 ± 10.95 78.7 ± 13.54 82.4 ± 99999 -

    End points

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    End points reporting groups
    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 4 mg
    Reporting group description
    		 Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in non-hodgkin lymphoma (NHL) subjects.

    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 5.3 mg
    Reporting group description
    		 Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Reporting group description
    		 Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Reporting group title
    Phase 2: PSMB1 Positive
    Reporting group description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in relapsed Or refractory follicular lymphoma (RRFL) subjects.

    Reporting group title
    Phase 2: PSMB1 Negative
    Reporting group description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.
    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 4 mg
    Reporting group description
    		 Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in non-hodgkin lymphoma (NHL) subjects.

    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 5.3 mg
    Reporting group description
    		 Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Reporting group description
    		 Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.
    Reporting group title
    Phase 2: PSMB1 Positive
    Reporting group description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Reporting group title
    Phase 2: PSMB1 Negative
    Reporting group description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Subject analysis set title
    All Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Subject analysis set title
    Lead-in Dose Finding Phase: Ixazomib 5.3 mg (RP2D)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Subject analysis set title
    Phase 2: PSMB1 Positive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Subject analysis set title
    Phase 2: PSMB1 Negative
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Primary: Number of Subjects with Overall Response Rate (ORR)

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    End point title
    		 Number of Subjects with Overall Response Rate (ORR) [1]
    End point description
    ORR is defined as the percentage of subjects with complete response (CR) or partial response (PR) as assessed by the investigator using the international Working Group criteria for subjects CR: disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. The response-evaluable population included all subjecs who received at least 1 dose of ixazomib, had measurable disease at baseline, and had at least 1 post baseline disease assessment.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 15 Cycle 29 (approximately up to Day 802) or until PD or the start of alternate therapies
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analysed for this endpoint.
    End point values
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Number of subjects analysed
    3
    5
    5
    12
    1
    Units: subjects
        CR|
    0
    0
    0
    0
    0
        PR|
    0
    0
    0
    1
    0
        Stable Disease (SD)|
    1
    2
    2
    4
    0
        PD|
    2
    3
    3
    7
    1
    No statistical analyses for this end point

    Secondary: Lead-in Dose Finding Phase: Recommended Phase 2 Dose (RP2D)

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    End point title
    		 Lead-in Dose Finding Phase: Recommended Phase 2 Dose (RP2D)
    End point description
    The dose limiting toxicity (DLT)- evaluable population included all subjects who received all Cycle 1 doses of ixazomib and had completed Cycle 1 safety procedures, or experience a DLT in Cycle 1 in the lead-in dose finding phase of the study.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 1 Day 28
    End point values
    		 All Subjects
    Number of subjects analysed
    16
    Units: mg
        number (not applicable)
    5.3
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS is defined as the time from the date of the first dose of study treatment to the date of first documented PD or death. Subjects without documentation of PD will be censored at the date of last response assessment that is SD or better. Subjects without response assessment will be censored at the date of the first dose. The modified intent-to-treat (mITT) population included all subjects who received at least 1 dose of ixazomib in the phase 2 portion of the study or who received at least 1 dose of ixazomib and are treated at the RP2D in the lead-in dose finding phase of the study. Here, 99999 in the confidence interval signifies not estimable since only 1 subject was analyzed.
    End point type
    Secondary
    End point timeframe
    Time from the date of first dose of study treatment to the date of first documented PD or death (approximately up to Day 802)
    End point values
    		 Lead-in Dose Finding Phase: Ixazomib 5.3 mg (RP2D) Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Number of subjects analysed
    7
    12
    1
    Units: months
        median (confidence interval 95%)
    1.9 (1.68 to 3.71)
    2.4 (1.87 to 11.50)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 2: Rate of Disease Control

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    End point title
    		 Phase 2: Rate of Disease Control
    End point description
    Rate of disease control is defined as percentage of subjects who achieved a SD or better for greater than or equal to (>=) 6 months. The response-evaluable population included all subjects who received at least 1 dose of ixazomib, had measurable disease at baseline, and had at least 1 post baseline disease assessment. Here, 99999 signifies not estimable since only 1 subject was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline or until occurrence of disease progression, unacceptable toxicities, or discontinuation of study due to any other reasons (approximately up to Day 805)
    End point values
    		 Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Number of subjects analysed
    12
    1
    Units: percentage of subjects
        number (confidence interval 95%)
    16.7 (2.09 to 48.41)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    TTR is defined as the time from the date of the first dose of study treatment to the date of the first documentation of a PR or better response in a subject who responded. The response-evaluable population included all subjects who received at least 1 dose of ixazomib, had measurable disease at baseline, and had at least 1 post baseline disease assessment. Here, 99999 in the data signifies not estimable since low number of subjects with CR and PR.
    End point type
    Secondary
    End point timeframe
    Time from the date of first dose of study treatment to the date of first documented PD or death (approximately up to Day 802)
    End point values
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Number of subjects analysed
    3
    5
    5
    12
    1
    Units: months
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    The DOR is defined as the time from the date of first documentation of a response to the date of first documented PD. Responders without documentation of PD will be censored at the date of last response assessment. DOR will be categorized as CR+PR and CR. The response-evaluable population included all subjects who received at least 1 dose of ixazomib, had measurable disease at baseline, and had at least 1 post baseline disease assessment. Here, 99999 in the data signifies not estimable since low number of subjects with CR and PR.
    End point type
    Secondary
    End point timeframe
    Time from the date of first documentation of a response to the date of first documented PD (approximately up to Day 802)
    End point values
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Number of subjects analysed
    3
    7
    6
    12
    1
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Subjects with Response Rates in PSMB1 Positive and PSMB1 Negative

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    End point title
    		 Phase 2: Number of Subjects with Response Rates in PSMB1 Positive and PSMB1 Negative
    End point description
    The biomarker population included all subjects positive or negative for the PSMB1 biomarker and where the assay has passed quality control. Data will be derived from a baseline blood sample.
    End point type
    Secondary
    End point timeframe
    Baseline up to occurrence of disease progression, unacceptable toxicities, or discontinuation of study due to any other reasons (approximately up to Day 802)
    End point values
    		 Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Number of subjects analysed
    12
    1
    Units: subjects
    12
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    The safety population included all enrolled subjects who had received at least 1 dose of ixazomib.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (approximately up to Day 832)
    End point values
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Number of subjects analysed
    3
    7
    6
    12
    1
    Units: subjects
        TEAE|
    3
    7
    6
    11
    1
        SAE|
    1
    3
    4
    4
    1
    No statistical analyses for this end point

    Secondary: Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib

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    End point title
    		 Lead-in Dose Finding Phase: Cmax: Maximum Observed Plasma Concentration for Ixazomib
    End point description
    The plasma pharmacokinetic (PK) analysis population included all subjects enrolled in the lead-in dose finding phase that had sufficient dosing data and ixazomib concentration-time data. The PK analysis population where data at specified time points was available.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose
    End point values
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Number of subjects analysed
    3
    7
    6
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1|
    141.3333 ± 52.27173
    103.4717 ± 57.53181
    121.1167 ± 69.07212
        Cycle 1 Day 15|
    124.2667 ± 71.01840
    144.0667 ± 105.15884
    152.0667 ± 102.71131
    No statistical analyses for this end point

    Secondary: Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib

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    End point title
    		 Lead-in Dose Finding Phase: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
    End point description
    The plasma PK analysis population included all subjects enrolled in the lead-in dose finding phase that had sufficient dosing data and ixazomib concentration-time data. The PK analysis population where data at specified time points was available.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose
    End point values
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Number of subjects analysed
    3
    7
    6
    Units: hour
    median (full range (min-max))
        Cycle 1 Day 1|
    1.0000 (0.500 to 1.500)
    1.0000 (0.500 to 1.500)
    1.0500 (1.000 to 3.750)
        Cycle 1 Day 15|
    1.0000 (0.500 to 2.000)
    0.7500 (0.467 to 1.520)
    1.0000 (0.500 to 1.500)
    No statistical analyses for this end point

    Secondary: Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve from Time 0 to 168 Hours Postdose for Ixazomib

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    End point title
    		 Lead-in Dose Finding Phase: AUC(0-168): Area Under the Plasma Concentration-time Curve from Time 0 to 168 Hours Postdose for Ixazomib
    End point description
    The PK analysis set where Cycle 1 Day 1 and 15 assessment were available. The PK analysis population included all subjects enrolled in the lead-in dose finding phase that had sufficient dosing data and ixazomib concentration-time data. The PK analysis population where data at specified time points was available.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Days 1 and 15 pre-dose and at multiple time points (up to 168 hours) post-dose
    End point values
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Number of subjects analysed
    3
    7
    6
    Units: hour*nanogram per milliliter (h*ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1|
    1265.0000 ± 332.34019
    1030.1429 ± 367.90326
    1680.3333 ± 656.01240
        Cycle 1 Day 15|
    2440.0000 ± 272.21315
    2007.0000 ± 986.30117
    3120.0000 ± 2503.83706
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug (up to Cycle 29)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the subject or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 4 mg
    Reporting group description
    		 Ixazomib 4 milligram (mg), solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or progressive disease (PD) or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 5.3 mg
    Reporting group description
    		 Ixazomib 5.3 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Reporting group title
    Lead-in Dose Finding Phase: Ixazomib 7.0 mg
    Reporting group description
    		 Ixazomib 7 mg, solution, orally, once on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during lead-in dose finding in NHL subjects.

    Reporting group title
    Phase 2: PSMB1 Positive
    Reporting group description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Reporting group title
    Phase 2: PSMB1 Negative
    Reporting group description
    		 Ixazomib RP2D mg, solution, orally, once weekly on Day 1, 8, and 15 followed by 13 days of rest in a 28-days treatment cycle for a maximum of 29 cycles, or PD or the start of alternate therapies during phase 2 finding in RRFL subjects.

    Serious adverse events
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    4 / 6 (66.67%)
    4 / 12 (33.33%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    2
    1
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lead-in Dose Finding Phase: Ixazomib 4 mg Lead-in Dose Finding Phase: Ixazomib 5.3 mg Lead-in Dose Finding Phase: Ixazomib 7.0 mg Phase 2: PSMB1 Positive Phase 2: PSMB1 Negative
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    11 / 12 (91.67%)
    1 / 1 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    3 / 6 (50.00%)
    2 / 12 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    1
    5
    3
    3
    0
    Asthenia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    4 / 12 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    6
    0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    4 / 12 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    11
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    3
    5
    0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    1
    4
    0
    Epistaxis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    1
    0
    1
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    3
    0
    Dizziness
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    3 / 12 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    4
    4
    0
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    3 / 6 (50.00%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    6 / 6 (100.00%)
    5 / 12 (41.67%)
    1 / 1 (100.00%)
         occurrences all number
    1
    4
    10
    17
    1
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    3 / 6 (50.00%)
    5 / 12 (41.67%)
    1 / 1 (100.00%)
         occurrences all number
    5
    4
    7
    11
    1
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 7 (14.29%)
    4 / 6 (66.67%)
    5 / 12 (41.67%)
    1 / 1 (100.00%)
         occurrences all number
    3
    1
    10
    16
    1
    Abdominal pain
         subjects affected / exposed
    3 / 3 (100.00%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    3 / 12 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    2
    3
    0
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    1 / 12 (8.33%)
    1 / 1 (100.00%)
         occurrences all number
    1
    1
    2
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Haemorrhoids
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Arthralgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    2 / 12 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    3
    2
    3
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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

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