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    Clinical Trial Results:
    A multicentre Phase IIb trial to evaluate the efficacy and tolerability of ModraDoc006/r in subjects with metastatic Castration Resistant Prostate Cancer (mCRPC), suitable for treatment with a taxane.

    Summary
    EudraCT number
    		 2019-000582-21
    Trial protocol
    		 DE   CZ   HU  
    Global end of trial date
    29 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Oct 2022
    First version publication date
    20 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M18MDP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04028388
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Modra Pharmaceuticals
    Sponsor organisation address
    Barbara Strozzilaan 201, Amsterdam, Netherlands, 1083 HN
    Public contact
    Project director, Modra Pharmaceuticals, +31 20205 0188, info@modrapharmaceuticals.com
    Scientific contact
    Project director, Modra Pharmaceuticals, +31 20205 0188, info@modrapharmaceuticals.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
    30 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of ModraDoc006/r, as measured by radiographic Progression-Free Survival (rPFS), compared to standard treatment with i.v. docetaxel in patients with mCRPC.
    Protection of trial subjects
    To minimize the risk to patients and maximize safety, the following factors were incorporated into the trial design: • Detailed safety and laboratory assessments were be performed. • Patients were provided with diet and hydration instructions and a home prescription for loperamide, with instructions on how to use this medication in case diarrhea occurred at home • All clinical observations were evaluated by the Investigator on an ongoing basis. • The trial was planned to minimize the time interval which would influence routine procedure to the patient • As anti-emetic therapy, all patients were given bi-daily a 5HT3 antagonist (1 mg of granisetron 1 hour -, or 8 mg of ondansetron 2 hours -) prior to oral ModraDoc006/r administration during the first two weeks. In subsequent cycles, 5HT3 antagonist premedication may have been given if indicated. All patients were provided with a home prescription for anti-emetics (metoclopramide 10 mg maximum 4 times daily) and instructions on its use in case nausea/vomiting occurred at home. If metoclopramide (or domperidone) proved insufficient, a 5HT3 antagonist may have been taken on study treatment days, and these could continue for up to 3 days after the intake of study treatment. If these medications proved insufficient, dexamethasone and lorazepam were allowed to be added as anti-emetic treatment. Dexamethasone was to be taken at a low dose of 1 mg, because if used concomitantly with ritonavir could have led to increased exposure to dexamethasone. If vomiting occurred after intake, the patient was instructed not to take any new study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 May 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Russian Federation: 46
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    103
    EEA total number of subjects
    30
    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)
    21
    From 65 to 84 years
    82
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 135 [1]
    Number of subjects completed
    		 103

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 did not meet inclusion criteria: 32
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics have only been provided for the evaluable patients (Full Analysis Set). Reasons for exclusion from the FAS analysis were: • 2 patients not treated • 9 patients excluded due to both evaluations missing (post-baseline RECIST and postbaseline bone scan)
    Period 1
    Period 1 title
    Screening and Randomisation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: IV docetaxel
    Arm description
    		 Treatment with docetaxel 75 mg/m2 administered intravenous every 3 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Patients received docetaxel 75 mg/m2 infused intravenous over 1 hour on Day 1 every 21 days (every 3 weeks) plus prednisone 5 mg orally, twice daily. Premedication with dexamethasone was required.

    Arm title
    		 Cohort 2: ModraDoc006/r
    Arm description
    		 Treatment with ModraDoc006/r administered orally, bi-daily once weekly (BIDW)
    Arm type
    		 Experimental

    Investigational medicinal product name
    ModraDoc006
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients initially received ModraDoc006 30 mg in combination with ritonavir 200 mg in the morning and ModraDoc006 20 mg in combination with 100 mg ritonavir in the afternoon (7 to 12 hours after the morning dose), on Days 1, 8, and 15 of a 21-day cycle, plus prednisone 5 mg orally, twice daily. After 39 randomized patients (21 in ModraDoc006/r arm), the morning dose was amended to 20 mg in combination with ritonavir 200 mg.

    Investigational medicinal product name
    ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients initially received ModraDoc006 30 mg in combination with ritonavir 200 mg in the morning and ModraDoc006 20 mg in combination with 100 mg ritonavir in the afternoon (7 to 12 hours after the morning dose), on Days 1, 8, and 15 of a 21-day cycle, plus prednisone 5 mg orally, twice daily. After 39 randomized patients (21 in ModraDoc006/r arm), the morning dose was amended to 20 mg in combination with ritonavir 200 mg.

    Number of subjects in period 1
    		Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Started
    51
    52
    Randomised and Treated
    49
    52
    Completed
    46
    46
    Not completed
    5
    6
         Evaluations missing
    3
    6
         Not treated
    2
    -
    Period 2
    Period 2 title
    Full Analysis Set
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: IV docetaxel
    Arm description
    		 Treatment with docetaxel 75 mg/m2 administered intravenous every 3 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Patients received docetaxel 75 mg/m2 infused intravenous over 1 hour on Day 1 every 21 days (every 3 weeks plus prednisone 5 mg orally, twice daily. Premedication with dexamethasone was required.

    Arm title
    		 Cohort 2: ModraDoc006/r
    Arm description
    		 Treatment with ModraDoc006/r administered orally bi-daily once weekly (BIDW)
    Arm type
    		 Experimental

    Investigational medicinal product name
    ModraDoc006
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients initially received ModraDoc006 30 mg in combination with ritonavir 200 mg in the morning and ModraDoc006 20 mg in combination with 100 mg ritonavir in the afternoon (7 to 12 hours after the morning dose), on Days 1, 8, and 15 of a 21-day cycle, plus prednisone 5 mg orally, twice daily.After 39 randomized patients (21 in ModraDoc006/r arm), the morning dose was amended to 20 mg in combination with ritonavir 200 mg.

    Investigational medicinal product name
    ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients initially received ModraDoc006 30 mg in combination with ritonavir 200 mg in the morning and ModraDoc006 20 mg in combination with 100 mg ritonavir in the afternoon (7 to 12 hours after the morning dose), on Days 1, 8, and 15 of a 21-day cycle, plus prednisone 5 mg orally, twice daily. After 39 randomized patients (21 in ModraDoc006/r arm), the morning dose was amended to 20 mg in combination with ritonavir 200 mg.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics have only been provided for the evaluable patients (Full Analysis Set). Reasons for exclusion from the FAS analysis were: • 2 patients not treated • 9 patients excluded due to both evaluations missing (post-baseline RECIST and postbaseline bone scan)
    Number of subjects in period 2 [3]
    		Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Started
    46
    46
    Completed
    16
    27
    Not completed
    30
    19
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    7
    -
         Adverse event, non-fatal
    12
    12
         No longer clinically benefitting
    -
    4
         No longer clinically benefiting
    1
    -
         Database did not allow for further specification
    8
    3
         Lost to follow-up
    1
    -
    Notes
    [3] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics have only been provided for the evaluable patients (Full Analysis Set). Reasons for exclusion from the FAS analysis were: • 2 patients not treated • 9 patients excluded due to both evaluations missing (post-baseline RECIST and postbaseline bone scan)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: IV docetaxel
    Reporting group description
    		 Treatment with docetaxel 75 mg/m2 administered intravenous every 3 weeks

    Reporting group title
    Cohort 2: ModraDoc006/r
    Reporting group description
    		 Treatment with ModraDoc006/r administered orally bi-daily once weekly (BIDW)

    Reporting group values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r Total
    Number of subjects
    		 46 46 92
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 11 11 22
        From 65-84 years
    		 35 35 70
    Age continuous
    Units: years
        median (standard deviation)
    		 67.8 ± 6.6 67.0 ± 6.9 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 46 46 92
    Race
    Units: Subjects
        African American
    		 2 2 4
        White
    		 44 44 88
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 0 2
        Not Hispanic or Latino
    		 44 45 89
        Unknown
    		 0 1 1
    ECOG Performance Status
    Eastern Cooperative Oncology Group Performance Status
    Units: Subjects
        Performance status 0
    		 17 29 46
        Performance status 1
    		 28 15 43
        Performance status 2
    		 1 2 3
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 173.0 ± 5.6 176.4 ± 6.3 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 87.24 ± 17.23 90.60 ± 11.77 -
    Body Mass Index
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 29.04 ± 5.27 29.08 ± 3.64 -
    BSA
    Body surface area
    Units: metre squared
        arithmetic mean (standard deviation)
    		 2.04 ± 0.21 2.10 ± 0.15 -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: IV docetaxel
    Reporting group description
    		 Treatment with docetaxel 75 mg/m2 administered intravenous every 3 weeks

    Reporting group title
    Cohort 2: ModraDoc006/r
    Reporting group description
    		 Treatment with ModraDoc006/r administered orally, bi-daily once weekly (BIDW)
    Reporting group title
    Cohort 1: IV docetaxel
    Reporting group description
    		 Treatment with docetaxel 75 mg/m2 administered intravenous every 3 weeks

    Reporting group title
    Cohort 2: ModraDoc006/r
    Reporting group description
    		 Treatment with ModraDoc006/r administered orally bi-daily once weekly (BIDW)

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received at least 1 dose of intravenous docetaxel (Cohort 1) or 1 full cycle of ModraDoc006/r (Cohort 2) and had at least 1 post-baseline tumor assessment. To be included in the Full Analysis Set, there was no requirement to have prostate-specific antigen measurement. The FAS was used for the evaluation of primary and secondary criteria (otherwise stated) and the Health-Related Quality of Life evaluation

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients receiving at least 1 dose of trial medication in either study arm. The Safety Population was used for the evaluation of safety. Safety data were analyzed according to the treatment actually received.

    Primary: Radiographic Progression-Free Survival according to Prostate Cancer Clinical Trials Working Group 3 criteria

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    End point title
    		 Radiographic Progression-Free Survival according to Prostate Cancer Clinical Trials Working Group 3 criteria
    End point description
    Note: Upper CI for ModraDoc006/r group not evaluable (referred to as number '99.9' in table)
    End point type
    Primary
    End point timeframe
    Time from the date of randomization to the date of the first radiologic progression (per Prostate Cancer Clinical Trials Working Group 3 criteria) or death from any cause, whichever occurred first.
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    13
    13
    Units: month
        median (confidence interval 95%)
    11.1 (7.9 to 13.1)
    9.5 (6.8 to 99.9)
    Statistical analysis title
    		 Hazard Ratio: IV docetaxel vs Modra006/r
    Comparison groups
    Cohort 2: ModraDoc006/r v Cohort 1: IV docetaxel
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1465
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 2.65

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Proportion of responders in Subjects evaluable for radiological response
    End point type
    Secondary
    End point timeframe
    During study period, including follow-up visit
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    31
    34
    Units: percent
        number (confidence interval 95%)
    38.7 (21.8 to 57.8)
    44.1 (27.2 to 62.1)
    No statistical analyses for this end point

    Secondary: Disease control rate

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    End point title
    		 Disease control rate
    End point description
    Disease control rate, defined as CR plus PR plus SD, is presented by treatment group for patients that were evaluable for radiological response for the overall study. Clopper-Pearson estimates.
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    31
    34
    Units: percent
        number (confidence interval 95%)
    96.8 (83.3 to 99.9)
    88.2 (72.5 to 96.7)
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    The DOR, calculated in the subpopulation of patients experiencing a CR or PR, is presented by treatment group for patients that were evaluable for radiological response for the overall study. The numbers '99' and '99.9' in table refer to 'not evaluable'.
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    31 [1]
    34 [2]
    Units: percent
        number (confidence interval 95%)
    99 (1.5 to 99.9)
    4.9 (1.6 to 99.9)
    Notes
    [1] - Duration of response and upper CI not evaluable
    [2] - Upper CI not evaluable
    Statistical analysis title
    		 Docetaxel i.v. vs ModraDoc006/r
    Statistical analysis description
    DOR is calculated in the subpopulation of subjects experiencing a response (CR or PR). Hazard Ratio < 1 means that tested drug (ModraDoc006/r) has better outcome.
    Comparison groups
    Cohort 1: IV docetaxel v Cohort 2: ModraDoc006/r
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4576
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 7.93

    Secondary: Time to Progression

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    End point title
    		 Time to Progression
    End point description
    Time to Progression is defined as the time from the date of randomization to the date of the first radiologic progression per PCWG3 criteria. The numbers '99' and '99.9' in table refer to 'not evaluable'.
    End point type
    Secondary
    End point timeframe
    Time from the date of randomization to the date of the first radiologic progression
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    46 [3]
    46 [4]
    Units: month
        median (confidence interval 95%)
    11.1 (8.4 to 99.9)
    99 (6.8 to 99.9)
    Notes
    [3] - Upper CI not evaluable
    [4] - Median time to progression and upper CI not evaluable
    Statistical analysis title
    		 Docetaxel i.v. vs ModraDoc006/r
    Statistical analysis description
    Difference between the cohorts is tested with Log-rank test and estimated using Univariate Cox model. Wilcoxon test is used if proportional hazards assumption is not fulfilled. Hazard Ratio < 1 means that tested drug (ModraDoc006/r) has better outcome
    Comparison groups
    Cohort 1: IV docetaxel v Cohort 2: ModraDoc006/r
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0776
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 3.48

    Secondary: Prostate-Specific Antigen Response Rate

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    End point title
    		 Prostate-Specific Antigen Response Rate
    End point description
    A prostate-specific antigen response is defined as prostate-specific antigen decline of ≥50% from baseline with confirmatory read ≥3 weeks later, based on the Prostate Cancer Clinical Trials Working Group 3 criteria recommendations
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    46
    46
    Units: number of responders
    26
    23
    No statistical analyses for this end point

    Secondary: Prostate-Specific Antigen Progression-Free Survival

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    End point title
    		 Prostate-Specific Antigen Progression-Free Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Time from the date of randomization to the date of the first prostate-specific antigen progression or death from any cause, whichever occurred first.
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    46
    46
    Units: months
        median (confidence interval 95%)
    7.7 (4.9 to 11.3)
    4.9 (3.5 to 7.6)
    Statistical analysis title
    		 Docetaxel i.v. vs ModraDoc006/r
    Statistical analysis description
    Difference between the cohorts is tested with Log-rank test and estimated using Univariate Cox model. Wilcoxon test is used if proportional hazards assumption is not fulfilled. Hazard Ratio < 1 means that tested drug (ModraDoc006/r) has better outcome
    Comparison groups
    Cohort 1: IV docetaxel v Cohort 2: ModraDoc006/r
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2539
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.49

    Secondary: Time to prostate-specific antigen progression

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    End point title
    		 Time to prostate-specific antigen progression
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    46
    46
    Units: month
        median (confidence interval 95%)
    7.7 (4.9 to 11.3)
    4.9 (3.5 to 7.6)
    Statistical analysis title
    		 Docetaxel i.v. vs ModraDoc006/r
    Statistical analysis description
    Difference between the cohorts is tested with Log-rank test and estimated using Univariate Cox model. Wilcoxon test is used if proportional hazards assumption is not fulfilled. Hazard Ratio < 1 means that tested drug (ModraDoc006/r) has better outcome.
    Comparison groups
    Cohort 1: IV docetaxel v Cohort 2: ModraDoc006/r
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3062
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 2.42

    Secondary: Time to First Skeletal-Related Event

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    End point title
    		 Time to First Skeletal-Related Event
    End point description
    Due to small number of SREs the median time to SRE was not evaluable in this patient population.
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    46
    46
    Units: number
        Event
    2
    0
        Censored
    44
    46
    No statistical analyses for this end point

    Secondary: Overall Health-Related Quality of Life response

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    End point title
    		 Overall Health-Related Quality of Life response
    End point description
    An overall Health-Related Quality of Life improvement was defined by a 10-point or greater increase in the Functional Assessment of Cancer Therapy-global total score assessment at a post-baseline assessment compared with baseline, at least once during the study.
    End point type
    Secondary
    End point timeframe
    From baseline to end of Cycle 10
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    46
    46
    Units: subjects with overall improvement
    15
    15
    No statistical analyses for this end point

    Secondary: Summary of Improvement by Individual Health- Related Quality of Life Domains

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    End point title
    		 Summary of Improvement by Individual Health- Related Quality of Life Domains
    End point description
    Improvement in individual Health-Related Quality of Life domains was defined by a ≥3-point increase in the score at a post-baseline assessment compared with baseline, at least once during study. Improvement was derived using all assessments collected per protocol schedule. Therefore, any assessment collected after the "End of Cycle 10" assessment was not included, even if it was "End of Treatment". FACT = Functional Assessment of Cancer Therapy FACT-G = Functional Assessment of Cancer Therapy-global PCS = prostate cancer subscale
    End point type
    Secondary
    End point timeframe
    Baseline to end of Cycle 10
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    46
    46
    Units: number of subjects with improvement
        ≥3 for FACT-G physical well-being
    9
    13
        ≥3 for FACT-G social or family well-being
    16
    16
        ≥3 for FACT-G emotional well-being
    23
    18
        ≥3 for FACT-G functional well-being
    18
    21
        ≥3 for PCS
    21
    23
        ≥3 for FACT-taxane specific items
    19
    23
    No statistical analyses for this end point

    Secondary: Overall Health-Related Utility

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    End point title
    		 Overall Health-Related Utility
    End point description
    Mean change from baseline to end of treatment in the European Quality of Life-Five Dimension-Five Level Scale is presented. For the European Quality of Life-Five Dimension-Five Level Scale, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were scored on a 5-point scale: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Lower scores and decreases from baseline indicate improved quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment. Analysis Visit "End of Treatment" excludes assessments collected after the "End of Cycle 10" assessment.
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    46
    46
    Units: number of subjects
    arithmetic mean (standard deviation)
        Mobility
    0.4 ± 1.1
    0.4 ± 1.0
        Self-care
    0.3 ± 1.1
    0.0 ± 0.7
        Usual activities
    0.5 ± 1.3
    0.1 ± 0.9
        Pain/discomfort
    0.4 ± 1.3
    0.1 ± 0.7
        Anxiety/depression
    0.0 ± 0.8
    0.0 ± 0.8
        Visual Analog Scale
    -9.4 ± 22.2
    -5.9 ± 20.5
    No statistical analyses for this end point

    Secondary: World Health Organization Performance Status (Eastern Cooperative Oncology Group)

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    End point title
    		 World Health Organization Performance Status (Eastern Cooperative Oncology Group)
    End point description
    Eastern Cooperative Oncology Group (ECOG) scores at the time of last on treatment visit are presented. 0 = Normal activity 1 = Symptoms, but nearly ambulatory 2 = Symptomatic, but in bed <50% of the day 3 = Needs to be in bed >50% of the day, but not bedridden 4 = Unable to get out of bed 5 = Dead
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment visit
    End point values
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Number of subjects analysed
    49 [5]
    52 [6]
    Units: number of subjects
        ECOG Score 0
    10
    17
        ECOG Score 1
    16
    13
        ECOG Score 2
    4
    3
        ECOG Score 3
    0
    1
        ECOG Score 4
    0
    0
        ECOG Score 5
    2
    1
    Notes
    [5] - Safety Population
    [6] - Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events were monitored and collected from the time the patient gave informed consent and throughout the study until 30 days after the last ModraDoc006/r or intravenous docetaxel administration.
    Adverse event reporting additional description
    Safety analysis population assessed for all adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Cohort 1: IV docetaxel
    Reporting group description
    		 Patients received docetaxel 75 mg/m2 infused intravenous over 1 hour on Day 1 every 21 days (every 3 weeks plus prednisone 5 mg orally, twice daily. Premedication with dexamethasone was required.

    Reporting group title
    Cohort 2: ModraDoc006/r
    Reporting group description
    		 Patients initially received ModraDoc006 30 mg in combination with ritonavir 200 mg in the morning and ModraDoc006 20 mg in combination with 100 mg ritonavir in the afternoon (7 to 12 hours after the morning dose), on Days 1, 8, and 15 of a 21-day cycle (bi-daily once weekly dosing), plus prednisone 5 mg orally, twice daily. After 39 patients were enrolled, the morning dose was amended to ModraDoc006 20 mg in combination with ritonavir 200 mg.

    Serious adverse events
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 49 (32.65%)
    13 / 52 (25.00%)
         number of deaths (all causes)
    4
    3
         number of deaths resulting from adverse events
    4
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dental caries
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
    Additional description: Covid-19
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: IV docetaxel Cohort 2: ModraDoc006/r
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 49 (65.31%)
    37 / 52 (71.15%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 49 (4.08%)
    10 / 52 (19.23%)
         occurrences all number
    6
    13
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 49 (4.08%)
    9 / 52 (17.31%)
         occurrences all number
    8
    12
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 49 (4.08%)
    7 / 52 (13.46%)
         occurrences all number
    2
    13
    Weight decreased
         subjects affected / exposed
    3 / 49 (6.12%)
    5 / 52 (9.62%)
         occurrences all number
    4
    5
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Blood bilirubin increased
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    6 / 49 (12.24%)
    2 / 52 (3.85%)
         occurrences all number
    9
    2
    Headache
         subjects affected / exposed
    1 / 49 (2.04%)
    5 / 52 (9.62%)
         occurrences all number
    1
    6
    Dysgeusia
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 52 (7.69%)
         occurrences all number
    1
    4
    Hypoaesthesia
         subjects affected / exposed
    4 / 49 (8.16%)
    0 / 52 (0.00%)
         occurrences all number
    5
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 52 (5.77%)
         occurrences all number
    1
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 49 (26.53%)
    11 / 52 (21.15%)
         occurrences all number
    25
    12
    Neutropenia
         subjects affected / exposed
    11 / 49 (22.45%)
    3 / 52 (5.77%)
         occurrences all number
    26
    3
    Thrombocytopenia
         subjects affected / exposed
    1 / 49 (2.04%)
    7 / 52 (13.46%)
         occurrences all number
    1
    14
    Leukopenia
         subjects affected / exposed
    6 / 49 (12.24%)
    0 / 52 (0.00%)
         occurrences all number
    12
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 49 (26.53%)
    11 / 52 (21.15%)
         occurrences all number
    15
    13
    Oedema peripheral
         subjects affected / exposed
    6 / 49 (12.24%)
    8 / 52 (15.38%)
         occurrences all number
    7
    13
    Asthenia
         subjects affected / exposed
    4 / 49 (8.16%)
    7 / 52 (13.46%)
         occurrences all number
    4
    9
    Peripheral swelling
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Extravasation
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 52 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 49 (24.49%)
    25 / 52 (48.08%)
         occurrences all number
    27
    51
    Nausea
         subjects affected / exposed
    9 / 49 (18.37%)
    17 / 52 (32.69%)
         occurrences all number
    10
    29
    Vomiting
         subjects affected / exposed
    1 / 49 (2.04%)
    13 / 52 (25.00%)
         occurrences all number
    1
    21
    Constipation
         subjects affected / exposed
    3 / 49 (6.12%)
    5 / 52 (9.62%)
         occurrences all number
    3
    5
    Stomatitis
         subjects affected / exposed
    4 / 49 (8.16%)
    3 / 52 (5.77%)
         occurrences all number
    13
    5
    Abdominal pain
         subjects affected / exposed
    0 / 49 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    0
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 49 (14.29%)
    2 / 52 (3.85%)
         occurrences all number
    7
    2
    Cough
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Epistaxis
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    21 / 49 (42.86%)
    13 / 52 (25.00%)
         occurrences all number
    22
    14
    Nail disorder
         subjects affected / exposed
    4 / 49 (8.16%)
    4 / 52 (7.69%)
         occurrences all number
    5
    6
    Dry skin
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 52 (1.92%)
         occurrences all number
    5
    1
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 49 (10.20%)
    4 / 52 (7.69%)
         occurrences all number
    5
    6
    Arthralgia
         subjects affected / exposed
    0 / 49 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    0
    6
    Muscular weakness
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Muscle spasms
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 52 (5.77%)
         occurrences all number
    1
    5
    Musculoskeletal pain
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 52 (1.92%)
         occurrences all number
    12
    1
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 52 (1.92%)
         occurrences all number
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 49 (6.12%)
    7 / 52 (13.46%)
         occurrences all number
    6
    9
    Dehydration
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Hypocalcaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 52 (5.77%)
         occurrences all number
    1
    4
    Hyponatraemia
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2019
    Changes included clarifications on exclusion criteria, dose modifications, and administrative aspects
    31 Mar 2020
    Initially the trial aimed to recruit a subset of patients with mCRPC eligible for treatment with docetaxel to test the feasibility of the ORR endpoint within a reasonable timeframe. As the proportion of mCRPC patients with measurable disease according to RECIST was low (order of 20-30%), the trial was set up with a relatively high number of clinical sites, to overcome the potential issue of slow recruitment. Nonetheless, it was a challenge to recruit the target patient population in a timely manner. Due to above feasibility concerns for this study, as well as a future phase III study, the study protocol was changed to allow the inclusion of a broader mCRPC patient population reflecting the reality that only few patients with prostate cancer have RECIST measurable disease. Consequently, the primary endpoint changed from ORR to rPFS. Adaption of the starting dose for Cohort 2 ModraDoc006 30-20mg to 20-20mg, both doses combined with ritonavir 200-100mg BIDW, to improve the profile of ModraDoc006/r as an effective, convenient and tolerable oral treatment. Harmonization of assessments for both arms, as the initial schedule of assessments induced potential AE reporting bias, due to additional weekly assessment time points during Cycle 1 and 2 for the ModraDoc006/r Cohort 2 only. In the limited number of patients treated initially, there was more extensive reporting of mostly mild Grade 1/2 AEs, in comparison with standard docetaxel i.v. Cohort 1. These reported AEs are common side effects for i.v. docetaxel as well. To correct for potential AE reporting bias, the assessment time points of ModraDoc006/r Cohort 2 were adapted and implemented for i.v. docetaxel Cohort 1 alike. Based on the expected lower number of AEs at the adjusted dose level, as well as the low overall level of severe toxicities demonstrated in the phase Ib study, it was considered safe to change to weekly safety assessments during Cycle 1 only. Widening of screening windows.

    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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