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    Clinical Trial Results:
    STOMP: Small cell lung cancer Trial of Olaparib (AZD2281) as Maintenance Programme: a randomised, double blind, multicentre phase II trial.

    Summary
    EudraCT number
    		 2010-021165-76
    Trial protocol
    		 GB  
    Global end of trial date
    11 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2021
    First version publication date
    26 Dec 2021
    Other versions
    Summary report(s)
    		 Baseline Tables for (Non-) Target Lesions

    Trial information

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    Trial identification
    Sponsor protocol code
    LU2006 / STH15845
    Additional study identifiers
    ISRCTN number
    		 ISRCTN73164486
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor Protocol Number: STH15845
    Sponsors
    Sponsor organisation name
    Sheffield Teaching Hospitals NHS Foundation Trust
    Sponsor organisation address
    Trust Headquarters, 8 Beech Hill Road, Sheffield, United Kingdom, S10 2SB
    Public contact
    Dr Dipak Patel, Sheffield Teaching Hospitals NHS Foundation Trust, sth.ResearchAdministration@nhs.net
    Scientific contact
    Dr Dipak Patel, Sheffield Teaching Hospitals NHS Foundation Trust, sth.ResearchAdministration@nhs.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the activity and safety of the PARP inhibitor olaparib as maintenance treatment for patients with chemoresponsive SCLC.
    Protection of trial subjects
    This study was carried out in accordance with current guidelines for Good clinical Practice and the Declaration of Helsinki. The protocol gained ethical approval from the NRES Committee Yorkshire & The Humber - Leeds East. Before entering patients into the study, the Principal Investigator ensured that the protocol had approval from their local Research and Development (R&D) Office. Participants were provided with ethically approved comprehensive information about the trial and trial treatments, and given advice on who to contact with any questions or concerns at any time. A participant’s treatment response was determined by their treating physician who reviewed the patient every 4 weeks with: Physical examination, ECOG performance status, blood pressure, pulse and temperature measurements, haematological and biochemical tests, adverse event and concomitant medication reviews and alternate CT and X-ray scans. Prohibited concomitant therapies were listed in the olaparib Investigators Brochure and trial protocol. All concomitant therapies were required to be recorded. Any toxicity observed during the course of the trial was managed by dose interruption or permanent dose reduction if deemed appropriate by the treating physician and in accordance with the protocol. Participants of child bearing potential were required to agree to use two highly effective forms of contraception throughout their participation in the trial and for 3 months after last dose of trial drug. The independent monitoring committee (IDMC) met on a yearly basis during the trial recruitment phase. The IDMC could consider discontinuing the trial if the recruitment rate or data quality were found to be unacceptable or if any issues are identified which may compromise patient safety.
    Background therapy
    		 Completed 3 cycles of first line chemotherapy or chemo-radiotherapy with: (a) cisplatin in combination with etoposide or (b) carboplatin in combination with etoposide.
    Evidence for comparator
    		 Olaparib (AZD2281, KU-0059436, KuDOS/AstraZeneca) is a PARP inhibitor in development for the treatment of patients who have cancers associated with genetic BRCA mutations and in patients with deficiency in DNA repair, specifically homologous recombination repair deficiency. Clinical study data to date in patients with advanced cancer have shown olaparib to have significant anti-tumour activity as a single agent in ovarian and breast cancer patients with known homologous recombination deficiency: BRCA1-/- or BRCA2-/-. Due to the molecular targeting of olaparib to specific subsets of tumours and sparing of normal cells, this has raised the opportunity for relatively less toxic cancer monotherapy using such a PARP 1 inhibitor compared with conventional treatments, such as chemotherapy. Olaparib has been tested in a standard range of safety pharmacology studies e.g. dog cardiovascular and respiratory function tests, and the rat Irwin test. There were no noticeable effects on the cardiovascular or respiratory parameters in the anaesthetised dog or any behavioural, autonomic or motor effects in the rat at the doses studied. The toxicology studies indicate that the target organ of toxicity is the bone marrow. Further information can be found in the current version of the olaparib Investigator's Brochure. More than 950 patients have now received olaparib either as monotherapy (11 studies) or in combination with other chemotherapy agents. Data from these studies indicate that olaparib is generally well tolerated as monotherapy at doses up to 400 mg bd capsules in patients with solid tumours.
    Actual start date of recruitment
    21 Nov 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research, Efficacy
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 220
    Worldwide total number of subjects
    220
    EEA total number of subjects
    0
    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)
    115
    From 65 to 84 years
    103
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between 21 November 2013 and 11 December 2015 at multiple centres across the United Kingdom.

    Pre-assignment
    Screening details
    		 ≥18 years, SCLC +ve (M0 or M1a/B, any T/N stage), complete/ partial response to ≥3 cycles of (chemo +/-)radiotherapy, ECOG 0-2. Without uncontrolled brain mets, interstitial lung disease, previous malignancies, history of malabsorption or major GI tract resection, treatment with PARP or CYP3A4 inhibitors, breast feeding women, poor medical risk.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Active and placebo tablets were matching in terms of size, colour and packaging to ensure blinding of the trial medication. Treatment allocation was by telephone to the central randomisation service. Treatment pack number was allocated to patients sequentially using a block randomisation scheme loaded onto the Cenduit Interactive Web Recognition System (IWRS) database and accessed by CRCTU on behalf of randomising sites.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 placebo 300mg BD and placebo 200mg TDS
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matched placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo 300mg po bd or 200mg po tds, taken continuously until death, disease progression, unacceptable toxicities or withdrawal of patient consent up to a maximum of 2 years.

    Arm title
    		 Olaparib BD
    Arm description
    		 olaparib 300mg BD
    Arm type
    		 Experimental

    Investigational medicinal product name
    olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Olaparib 300mg po bd taken continuously until death, disease progression, unacceptable toxicities or withdrawal of patient consent up to a maximum of 2 years.

    Arm title
    		 Olaparib TDS
    Arm description
    		 olaparib 200mg TDS
    Arm type
    		 Experimental

    Investigational medicinal product name
    olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200mg tds taken continuously until death, disease progression, unacceptable toxicities or withdrawal of patient consent up to a maximum of 2 years.

    Number of subjects in period 1
    		Placebo Olaparib BD Olaparib TDS
    Started
    74
    73
    73
    Completed
    74
    73
    73
    Period 2
    Period 2 title
    Overall Trial - Intention to Treat
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Active and placebo tablets were matching in terms of size, colour and packaging to ensure blinding of the trial medication. Treatment allocation was by telephone to the central randomisation service. Treatment pack number was allocated to patients sequentially using a block randomisation scheme loaded onto the Cenduit Interactive Web Recognition System (IWRS) database and accessed by CRCTU on behalf of randomising sites.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo - ITT
    Arm description
    		 placebo 300mg BD and placebo 200mg TDS
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matched placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo 300mg po bd or 200mg po tds, taken continuously until death, disease progression, unacceptable toxicities or withdrawal of patient consent up to a maximum of 2 years.

    Arm title
    		 Olaparib BD - ITT
    Arm description
    		 olaparib 300mg BD
    Arm type
    		 Experimental

    Investigational medicinal product name
    olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300mg po bd taken continuously until death, disease progression, unacceptable toxicities or withdrawal of patient consent up to a maximum of 2 years.

    Arm title
    		 Olaparib TDS - ITT
    Arm description
    		 olaparib 200mg TDS
    Arm type
    		 Experimental

    Investigational medicinal product name
    olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200mg tds taken continuously until death, disease progression, unacceptable toxicities or withdrawal of patient consent up to a maximum of 2 years.

    Number of subjects in period 2
    		Placebo - ITT Olaparib BD - ITT Olaparib TDS - ITT
    Started
    74
    73
    73
    Completed
    74
    73
    73

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 placebo 300mg BD and placebo 200mg TDS

    Reporting group title
    Olaparib BD
    Reporting group description
    		 olaparib 300mg BD

    Reporting group title
    Olaparib TDS
    Reporting group description
    		 olaparib 200mg TDS

    Reporting group values
    		 Placebo Olaparib BD Olaparib TDS Total
    Number of subjects
    		 74 73 73 220
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 42 35 38 115
        From 65-84 years
    		 31 37 35 103
        85 years and over
    		 1 1 0 2
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 64 (58 to 68) 66 (58 to 70) 63 (55 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 40 37 42 119
        Male
    		 34 36 31 101
    T-stage at diagnosis
    Units: Subjects
        TX
    		 4 4 1 9
        T0
    		 0 1 2 3
        T1
    		 3 5 5 13
        T1a
    		 3 1 3 7
        T1b
    		 2 0 3 5
        T2
    		 4 2 3 9
        T2a
    		 4 3 4 11
        T2b
    		 0 5 1 6
        T3
    		 18 20 13 51
        T4
    		 36 32 38 106
    N-stage at diagnosis
    Units: Subjects
        NX
    		 2 0 0 2
        N0
    		 4 5 3 12
        N1
    		 9 6 4 19
        N2
    		 24 28 29 81
        N3
    		 35 34 37 106
    M-stage at diagnosis
    Units: Subjects
        M0
    		 21 22 23 66
        M1a
    		 6 6 5 17
        M1b
    		 47 45 45 137
    Number of previous chemotherapy cycles
    Units: Subjects
        3 cycles
    		 1 0 2 3
        4 cycles
    		 31 27 23 81
        5 cycles
    		 5 3 4 12
        6 cycles
    		 37 43 44 124
    Prior chemotherapy type
    Units: Subjects
        Etoposide-Carboplatin
    		 52 56 54 162
        Etoposide-Cisplatin
    		 18 16 13 47
        Etoposide-Cisplatin-Carboplatin
    		 4 1 6 11
    Prior radiotherapy type
    Units: Subjects
        Thoracic & cranial
    		 40 33 36 109
        Thoracic only
    		 2 5 5 12
        Cranial only
    		 25 25 24 74
        None
    		 7 10 8 25
    Response to prior treatment at study baseline
    Units: Subjects
        Complete response
    		 5 4 7 16
        Partial response
    		 69 64 66 199
        Progression
    		 0 5 0 5
    Physical examination and assessment performed
    Units: Subjects
        No
    		 0 1 1 2
        Yes
    		 74 72 72 218
    ECOG Performance Status
    Units: Subjects
        Category 0
    		 18 17 25 60
        Category 1
    		 48 51 44 143
        Category 2
    		 8 5 3 16
        Not Known
    		 0 0 1 1
    Number of target lesions
    Units: Subjects
        1 Target lesion
    		 25 31 18 74
        2 Target lesion
    		 11 14 18 43
        3 Target lesion
    		 6 5 6 17
        4 Target lesion
    		 1 1 0 2
        5 Target lesion
    		 1 0 1 2
        No target lesions
    		 30 22 30 82
    Number of non-target lesions per patient
    Units: Subjects
        1 non-target lesion
    		 23 28 19 70
        2 non-target lesions
    		 22 13 17 52
        3 non-target lesions
    		 4 9 12 25
        4 non-target lesions
    		 3 2 3 8
        5 non-target lesions
    		 0 0 2 2
        6 non-target lesions
    		 0 1 0 1
        7 non-target lesions
    		 0 1 1 2
        0 non-target lesions
    		 22 19 19 60
    Liver metastases present at baseline
    Units: Subjects
        No
    		 55 54 53 162
        Yes
    		 19 19 20 58
    Time from diagnosis to randomisation
    Units: Weeks
        median (full range (min-max))
    		 22 (15 to 34) 25 (16 to 38) 24 (15 to 32) -
    Time between last chemotherapy dose and trial entry
    Units: Weeks
        median (full range (min-max))
    		 6.6 (2.3 to 16.7) 7.3 (3.7 to 15.6) 7.6 (3.6 to 14.6) -
    Chemotherapy duration
    Units: Weeks between first and last dose given
        median (full range (min-max))
    		 14.6 (9.0 to 20.7) 15.0 (7.1 to 20.0) 15.0 (6.0 to 21.0) -
    Time between most recent radiotherapy dose and trial entry
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    		 1.7 (1.0 to 2.6) 2.1 (1.6 to 2.7) 2.1 (1.6 to 2.9) -
    Blood pressure (systolic)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 127 ( 19 ) 124 ( 17 ) 132 ( 19 ) -
    Blood pressure (diastolic)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 76 ( 13 ) 75 ( 11 ) 78 ( 10 ) -
    Pulse
    Units: bpm
        arithmetic mean (standard deviation)
    		 84 ( 13 ) 84 ( 13 ) 83 ( 14 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 167 ( 9 ) 167 ( 10 ) 167 ( 10 ) -
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 74 ( 15 ) 75 ( 18 ) 74 ( 20 ) -
    Haemoglobin
    Units: g/L
        arithmetic mean (standard deviation)
    		 120.4 ( 10.8 ) 119.9 ( 12.3 ) 120.7 ( 14.4 ) -
    Absolute neutrophil count
    Units: x109/L
        arithmetic mean (standard deviation)
    		 4.7 ( 2.4 ) 4.3 ( 1.8 ) 4.6 ( 2.3 ) -
    White blood cells
    Units: x109/L
        arithmetic mean (standard deviation)
    		 6.7 ( 2.7 ) 6.1 ( 2.0 ) 6.5 ( 2.4 ) -
    Platelets
    Units: x109/L
        median (inter-quartile range (Q1-Q3))
    		 236.5 (190.0 to 300.0) 229.0 (181.0 to 276.0) 218.0 (175.0 to 280.0) -
    Bilirubin
    Units: umol/L)
        arithmetic mean (standard deviation)
    		 7 ( 3 ) 7 ( 4 ) 7 ( 3 ) -
    Aspartate aminotransferase (AST)
    Units: units/L
        arithmetic mean (standard deviation)
    		 21 ( 6 ) 20 ( 8 ) 19 ( 6 ) -
    Alanine transaminase (ALT)
    Units: units/L
        arithmetic mean (standard deviation)
    		 18 ( 8 ) 22 ( 10 ) 23 ( 19 ) -
    Alkaline Phosphatase
    Units: units/L
        arithmetic mean (standard deviation)
    		 94 ( 46 ) 93 ( 54 ) 87 ( 38 ) -
    Total Serum Protein
    Units: g/L
        arithmetic mean (standard deviation)
    		 69 ( 4 ) 68 ( 4 ) 68 ( 5 ) -
    Urea
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 5.3 ( 2.0 ) 5.4 ( 1.9 ) 5.1 ( 1.9 ) -
    Potassium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.1 ( 0.3 ) 4.2 ( 0.3 ) 4.3 ( 0.4 ) -
    Creatinine
    Units: umol/L
        arithmetic mean (standard deviation)
    		 75 ( 18 ) 72 ( 15 ) 72 ( 18 ) -
    Sodium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 139 ( 3 ) 138 ( 4 ) 138 ( 4 ) -
    Calcium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.38 ( 0.11 ) 2.37 ( 0.12 ) 2.38 ( 0.11 ) -
    Lesion diameter
    Units: mm
        arithmetic mean (standard deviation)
    		 29 ( 17 ) 25 ( 14 ) 23 ( 10 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 placebo 300mg BD and placebo 200mg TDS

    Reporting group title
    Olaparib BD
    Reporting group description
    		 olaparib 300mg BD

    Reporting group title
    Olaparib TDS
    Reporting group description
    		 olaparib 200mg TDS
    Reporting group title
    Placebo - ITT
    Reporting group description
    		 placebo 300mg BD and placebo 200mg TDS

    Reporting group title
    Olaparib BD - ITT
    Reporting group description
    		 olaparib 300mg BD

    Reporting group title
    Olaparib TDS - ITT
    Reporting group description
    		 olaparib 200mg TDS

    Subject analysis set title
    Intention to Treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Primary analysis

    Subject analysis set title
    Per Protocol Analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Secondary analysis

    Subject analysis set title
    Sensitivity analysis
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Olaparib BD vs placebo only

    Primary: Progression free survival time

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    End point title
    		 Progression free survival time
    End point description
    End point type
    Primary
    End point timeframe
    Months
    End point values
    		 Placebo - ITT Olaparib BD - ITT Olaparib TDS - ITT
    Number of subjects analysed
    74
    73
    73
    Units: Months
        median (confidence interval 90%)
    2.50 (1.81 to 3.68)
    3.65 (3.12 to 4.60)
    3.58 (2.79 to 4.67)
    Statistical analysis title
    		 PFS Olaparib BD vs Placebo
    Statistical analysis description
    Olaparib BD vs Placebo
    Comparison groups
    Placebo - ITT v Olaparib BD - ITT
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1801
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 PFS Olaparib TDS vs Placebo
    Comparison groups
    Placebo - ITT v Olaparib TDS - ITT
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1641
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 PFS Olaparib BD vs Placebo
    Comparison groups
    Olaparib BD - ITT v Placebo - ITT
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.125
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.02
    Statistical analysis title
    		 PFS Olaparib TDS vs Placebo
    Comparison groups
    Placebo - ITT v Olaparib TDS - ITT
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.402
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.15

    Secondary: Progression-free survival at 4 months from randomisation

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    End point title
    		 Progression-free survival at 4 months from randomisation
    End point description
    End point type
    Secondary
    End point timeframe
    4 months
    End point values
    		 Placebo Olaparib BD Olaparib TDS
    Number of subjects analysed
    74
    73
    73
    Units: Percentage
        number (confidence interval 90%)
    36 (27 to 45)
    45 (35 to 54)
    45 (35 to 54)
    No statistical analyses for this end point

    Secondary: Overall survival time

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    End point title
    		 Overall survival time
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo - ITT Olaparib BD - ITT Olaparib TDS - ITT
    Number of subjects analysed
    74
    73
    73
    Units: Months
        number (confidence interval 90%)
    9.69 (7.13 to 12.19)
    11.01 (7.85 to 12.94)
    9.63 (6.80 to 11.76)
    Statistical analysis title
    		 Overall Survival - Olaparib BD vs Placebo
    Comparison groups
    Placebo - ITT v Olaparib BD - ITT
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7094
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Overall Survival - Olaparib TDS vs Placebo
    Comparison groups
    Placebo - ITT v Olaparib TDS - ITT
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9904
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Overall Survival - Olaparib BD vs Placebo (HR)
    Comparison groups
    Placebo - ITT v Olaparib BD - ITT
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.376
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.15
    Statistical analysis title
    		 Overall Survival - Olaparib TDS vs Placebo (HR)
    Comparison groups
    Placebo - ITT v Olaparib TDS - ITT
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.39

    Secondary: Overall survival at 6 months

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    End point title
    		 Overall survival at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Placebo - ITT Olaparib BD - ITT Olaparib TDS - ITT
    Number of subjects analysed
    74
    73
    73
    Units: percent
        number (confidence interval 90%)
    66 (56 to 75)
    69 (60 to 77)
    66 (56 to 75)
    No statistical analyses for this end point

    Secondary: Changes in performance status

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    End point title
    		 Changes in performance status
    End point description
    ECOG Performance status at cycle 6. Note: ECOG . category refers to patients where ECOG data is not available due to either patient death, trial withdrawal or that the data are missing.
    End point type
    Secondary
    End point timeframe
    12 treatment cycles
    End point values
    		 Placebo - ITT Olaparib BD - ITT Olaparib TDS - ITT
    Number of subjects analysed
    74
    73
    73
    Units: Performance status
        ECOG 0
    2
    6
    3
        ECOG 1
    15
    13
    9
        ECOG 2
    1
    0
    0
        ECOG 3
    0
    1
    0
        ECOG .
    56
    53
    60
    Attachments
    		 Table of ECOG scores cycle 7 to 12
    Table of ECOG scores cycle 1 to 6
    Plots of ECOG performance data
    No statistical analyses for this end point

    Secondary: Quality of life (EQ-5D)

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    End point title
    		 Quality of life (EQ-5D)
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Placebo - ITT Olaparib BD - ITT Olaparib TDS - ITT
    Number of subjects analysed
    74
    73
    73
    Units: Quality of Life Adjusted Life months
    number (confidence interval 90%)
        Utility QALM
    3.16 (2.80 to 3.52)
    2.98 (2.65 to 3.31)
    3.21 (2.87 to 3.56)
        Thermometer QALM
    292.25 (259.21 to 325.30)
    301.60 (273.38 to 329.82)
    294.13 (264.37 to 323.89)
    Attachments
    		 Untitled (Filename: Table of EQ5D Thermometer Questionnaire Results BL_Cycle1-6.pdf)
    Untitled (Filename: Table of EQ5D Utility Questionnaire Results BL_Cycle1-6.pdf)
    Untitled (Filename: Plots of QOL data.pdf)
    Untitled (Filename: Plots of QOL data 2.pdf)
    No statistical analyses for this end point

    Secondary: Adverse events (experienced by >5% of population)

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    End point title
    		 Adverse events (experienced by >5% of population)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo - ITT Olaparib BD - ITT Olaparib TDS - ITT Per Protocol Analysis
    Number of subjects analysed
    74
    73
    73
    217
    Units: Number
        Anemia
    15
    37
    41
    93
        Sinus tachycardia
    4
    0
    1
    5
        Abdominal pain
    6
    6
    8
    20
        Bloating
    2
    4
    1
    7
        Constipation
    19
    16
    14
    49
        Diarrhea
    18
    13
    12
    43
        Dry mouth
    3
    1
    7
    11
        Dyspepsia
    13
    11
    6
    30
        Dysphagia
    5
    5
    3
    13
        Mucositis oral
    10
    7
    2
    19
        Nausea
    44
    47
    51
    142
        Stomach pain
    2
    3
    5
    10
        Vomiting
    21
    25
    33
    79
        Fatigue
    55
    64
    58
    177
        Non-cardiac chest pain
    9
    10
    3
    22
        Pain
    6
    3
    5
    14
        Lung infection
    12
    14
    12
    38
        Mucosal infection
    6
    7
    4
    17
        Upper respiratory infection
    5
    7
    7
    19
        Urinary tract infection
    3
    3
    6
    12
        Lymphocyte count decreased
    0
    8
    9
    17
        Neutrophil count decreased
    0
    5
    2
    7
        Platelet count decreased
    2
    4
    5
    11
        Anorexia
    30
    34
    28
    92
        Hyperglycemia
    4
    2
    6
    12
        Hypoalbuminemia
    4
    4
    7
    15
        Hypocalcemia
    2
    9
    3
    14
        Hypokalemia
    4
    4
    4
    12
        Hypomagnesemia
    5
    2
    1
    8
        Hyponatremia
    12
    7
    10
    29
        Arthralgia
    17
    6
    9
    32
        Back pain
    18
    13
    14
    45
        Bone pain
    7
    2
    0
    9
        Joint effusion
    2
    5
    4
    11
        Myalgia
    4
    2
    3
    9
        Pain in extremity
    2
    13
    5
    20
        Dizziness
    14
    16
    15
    45
        Dysgeusia
    12
    12
    12
    36
        Headache
    18
    19
    17
    54
        Paresthesia
    5
    2
    7
    14
        Peripheral sensory neuropathy
    2
    4
    4
    10
        Anxiety
    8
    2
    4
    14
        Confusion
    3
    1
    5
    9
        Depression
    7
    7
    6
    20
        Insomnia
    10
    8
    5
    23
        Cough
    26
    22
    25
    73
        Dyspnea
    21
    26
    28
    75
        Productive cough
    1
    4
    4
    9
        Wheezing
    5
    2
    2
    9
        Alopecia
    11
    13
    16
    40
        Dry skin
    5
    6
    4
    15
        Pruritus
    7
    4
    4
    15
        Rash maculo-papular
    8
    5
    5
    18
        Hypertension
    8
    5
    4
    17
        Hypotension
    1
    1
    4
    6
        Thromboembolic event
    3
    3
    6
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the date of consent until 28 days after the administration of the last dose of trial medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 placebo 300mg BD and placebo 200mg TDS. Per protocol population.

    Reporting group title
    Olaparib BD
    Reporting group description
    		 olaparib 300mg BD. Per protocol population.

    Reporting group title
    Olaparib TDS
    Reporting group description
    		 olaparib 200mg TDS. Per protocol population.

    Serious adverse events
    		 Placebo Olaparib BD Olaparib TDS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 73 (31.51%)
    21 / 71 (29.58%)
    29 / 73 (39.73%)
         number of deaths (all causes)
    60
    61
    66
         number of deaths resulting from adverse events
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Unspecified
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    New primary tumour
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 71 (1.41%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 71 (2.82%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deteriorating condition
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 71 (1.41%)
    3 / 73 (4.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute exacerbation of COPD
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Splenic rupture
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular systolic dysfunction
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemia cerebrovascular
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial hemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 73 (0.00%)
    5 / 71 (7.04%)
    5 / 73 (6.85%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Double vision
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 71 (1.41%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Diarrhoea
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalized muscle weakness
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle weakness lower limb
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle weakness right-sided
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 71 (1.41%)
    5 / 73 (6.85%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Upper respiratory infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis infective
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 71 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 71 (1.41%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Olaparib BD Olaparib TDS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 73 (98.63%)
    70 / 71 (98.59%)
    72 / 73 (98.63%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 73 (10.96%)
    5 / 71 (7.04%)
    4 / 73 (5.48%)
         occurrences all number
    59
    9
    31
    Hypotension
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 71 (1.41%)
    4 / 73 (5.48%)
         occurrences all number
    1
    3
    4
    Thromboembolic event
         subjects affected / exposed
    3 / 73 (4.11%)
    3 / 71 (4.23%)
    6 / 73 (8.22%)
         occurrences all number
    16
    14
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    55 / 73 (75.34%)
    64 / 71 (90.14%)
    58 / 73 (79.45%)
         occurrences all number
    307
    254
    198
    Non-cardiac chest pain
         subjects affected / exposed
    9 / 73 (12.33%)
    10 / 71 (14.08%)
    3 / 73 (4.11%)
         occurrences all number
    34
    19
    4
    Pain
         subjects affected / exposed
    6 / 73 (8.22%)
    3 / 71 (4.23%)
    5 / 73 (6.85%)
         occurrences all number
    7
    4
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 73 (35.62%)
    22 / 71 (30.99%)
    25 / 73 (34.25%)
         occurrences all number
    103
    81
    67
    Dyspnoea
         subjects affected / exposed
    21 / 73 (28.77%)
    26 / 71 (36.62%)
    28 / 73 (38.36%)
         occurrences all number
    87
    102
    70
    Pneumonia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 71 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    0
    5
    Productive cough
         subjects affected / exposed
    1 / 73 (1.37%)
    4 / 71 (5.63%)
    4 / 73 (5.48%)
         occurrences all number
    2
    5
    6
    Wheezing
         subjects affected / exposed
    5 / 73 (6.85%)
    2 / 71 (2.82%)
    2 / 73 (2.74%)
         occurrences all number
    17
    4
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 73 (10.96%)
    2 / 71 (2.82%)
    4 / 73 (5.48%)
         occurrences all number
    15
    8
    7
    Confusion
         subjects affected / exposed
    3 / 73 (4.11%)
    1 / 71 (1.41%)
    5 / 73 (6.85%)
         occurrences all number
    5
    1
    5
    Depression
         subjects affected / exposed
    7 / 73 (9.59%)
    7 / 71 (9.86%)
    6 / 73 (8.22%)
         occurrences all number
    29
    19
    15
    Insomnia
         subjects affected / exposed
    10 / 73 (13.70%)
    8 / 71 (11.27%)
    5 / 73 (6.85%)
         occurrences all number
    18
    20
    9
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    8 / 71 (11.27%)
    9 / 73 (12.33%)
         occurrences all number
    0
    20
    19
    Neutrophil count decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    5 / 71 (7.04%)
    2 / 73 (2.74%)
         occurrences all number
    0
    10
    4
    Platelet count decreased
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 71 (5.63%)
    5 / 73 (6.85%)
         occurrences all number
    2
    7
    7
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 71 (0.00%)
    1 / 73 (1.37%)
         occurrences all number
    12
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 73 (19.18%)
    16 / 71 (22.54%)
    15 / 73 (20.55%)
         occurrences all number
    46
    37
    21
    Dysgeusia
         subjects affected / exposed
    12 / 73 (16.44%)
    12 / 71 (16.90%)
    12 / 73 (16.44%)
         occurrences all number
    34
    34
    29
    Headache
         subjects affected / exposed
    18 / 73 (24.66%)
    19 / 71 (26.76%)
    17 / 73 (23.29%)
         occurrences all number
    40
    35
    45
    Paresthesia
         subjects affected / exposed
    5 / 73 (6.85%)
    2 / 71 (2.82%)
    7 / 73 (9.59%)
         occurrences all number
    18
    6
    26
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 71 (5.63%)
    4 / 73 (5.48%)
         occurrences all number
    10
    12
    9
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    15 / 73 (20.55%)
    37 / 71 (52.11%)
    41 / 73 (56.16%)
         occurrences all number
    49
    242
    221
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 73 (8.22%)
    6 / 71 (8.45%)
    8 / 73 (10.96%)
         occurrences all number
    13
    7
    29
    Bloating
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 71 (5.63%)
    1 / 73 (1.37%)
         occurrences all number
    5
    7
    1
    Constipation
         subjects affected / exposed
    19 / 73 (26.03%)
    16 / 71 (22.54%)
    14 / 73 (19.18%)
         occurrences all number
    92
    28
    31
    Diarrhoea
         subjects affected / exposed
    18 / 73 (24.66%)
    13 / 71 (18.31%)
    12 / 73 (16.44%)
         occurrences all number
    59
    24
    21
    Dry mouth
         subjects affected / exposed
    3 / 73 (4.11%)
    1 / 71 (1.41%)
    7 / 73 (9.59%)
         occurrences all number
    9
    1
    25
    Dyspepsia
         subjects affected / exposed
    13 / 73 (17.81%)
    11 / 71 (15.49%)
    6 / 73 (8.22%)
         occurrences all number
    49
    20
    20
    Dysphagia
         subjects affected / exposed
    5 / 73 (6.85%)
    5 / 71 (7.04%)
    3 / 73 (4.11%)
         occurrences all number
    5
    10
    5
    Mucositis oral
         subjects affected / exposed
    10 / 73 (13.70%)
    7 / 71 (9.86%)
    2 / 73 (2.74%)
         occurrences all number
    27
    20
    7
    Nausea
         subjects affected / exposed
    44 / 73 (60.27%)
    47 / 71 (66.20%)
    51 / 73 (69.86%)
         occurrences all number
    119
    134
    133
    Stomach pain
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 71 (4.23%)
    5 / 73 (6.85%)
         occurrences all number
    2
    4
    9
    Vomiting
         subjects affected / exposed
    21 / 73 (28.77%)
    25 / 71 (35.21%)
    33 / 73 (45.21%)
         occurrences all number
    41
    40
    56
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    11 / 73 (15.07%)
    13 / 71 (18.31%)
    16 / 73 (21.92%)
         occurrences all number
    60
    33
    46
    Dry skin
         subjects affected / exposed
    5 / 73 (6.85%)
    6 / 71 (8.45%)
    4 / 73 (5.48%)
         occurrences all number
    37
    22
    9
    Erythema
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 71 (0.00%)
    2 / 73 (2.74%)
         occurrences all number
    6
    0
    2
    Pruritus
         subjects affected / exposed
    7 / 73 (9.59%)
    4 / 71 (5.63%)
    4 / 73 (5.48%)
         occurrences all number
    22
    10
    9
    Rash maculo-papular
         subjects affected / exposed
    8 / 73 (10.96%)
    5 / 71 (7.04%)
    5 / 73 (6.85%)
         occurrences all number
    23
    22
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 73 (23.29%)
    6 / 71 (8.45%)
    9 / 73 (12.33%)
         occurrences all number
    68
    8
    63
    Back pain
         subjects affected / exposed
    18 / 73 (24.66%)
    13 / 71 (18.31%)
    14 / 73 (19.18%)
         occurrences all number
    45
    34
    31
    Bone pain
         subjects affected / exposed
    7 / 73 (9.59%)
    2 / 71 (2.82%)
    0 / 73 (0.00%)
         occurrences all number
    21
    7
    0
    Cramp
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 71 (2.82%)
    3 / 73 (4.11%)
         occurrences all number
    5
    12
    15
    Joint effusion
         subjects affected / exposed
    2 / 73 (2.74%)
    5 / 71 (7.04%)
    4 / 73 (5.48%)
         occurrences all number
    3
    7
    8
    Myalgia
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 71 (2.82%)
    3 / 73 (4.11%)
         occurrences all number
    25
    7
    4
    Pain in extremity
         subjects affected / exposed
    2 / 73 (2.74%)
    13 / 71 (18.31%)
    5 / 73 (6.85%)
         occurrences all number
    5
    25
    10
    Infections and infestations
    Lung infection
         subjects affected / exposed
    12 / 73 (16.44%)
    14 / 71 (19.72%)
    12 / 73 (16.44%)
         occurrences all number
    28
    37
    21
    Mucosal infection
         subjects affected / exposed
    6 / 73 (8.22%)
    7 / 71 (9.86%)
    4 / 73 (5.48%)
         occurrences all number
    8
    14
    5
    Upper respiratory infection
         subjects affected / exposed
    5 / 73 (6.85%)
    7 / 71 (9.86%)
    7 / 73 (9.59%)
         occurrences all number
    8
    17
    15
    Urinary tract infection
         subjects affected / exposed
    3 / 73 (4.11%)
    3 / 71 (4.23%)
    6 / 73 (8.22%)
         occurrences all number
    4
    5
    8
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    30 / 73 (41.10%)
    34 / 71 (47.89%)
    28 / 73 (38.36%)
         occurrences all number
    71
    88
    62
    Decreased protein
         subjects affected / exposed
    0 / 73 (0.00%)
    4 / 71 (5.63%)
    1 / 73 (1.37%)
         occurrences all number
    0
    13
    1
    Hyperglycaemia
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 71 (2.82%)
    6 / 73 (8.22%)
         occurrences all number
    11
    3
    9
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 73 (5.48%)
    4 / 71 (5.63%)
    7 / 73 (9.59%)
         occurrences all number
    4
    5
    13
    Hypocalcaemia
         subjects affected / exposed
    2 / 73 (2.74%)
    9 / 71 (12.68%)
    3 / 73 (4.11%)
         occurrences all number
    4
    13
    4
    Hypokalaemia
         subjects affected / exposed
    4 / 73 (5.48%)
    4 / 71 (5.63%)
    4 / 73 (5.48%)
         occurrences all number
    14
    6
    6
    Hypomagnesaemia
         subjects affected / exposed
    5 / 73 (6.85%)
    2 / 71 (2.82%)
    1 / 73 (1.37%)
         occurrences all number
    13
    3
    1
    Hyponatraemia
         subjects affected / exposed
    12 / 73 (16.44%)
    7 / 71 (9.86%)
    10 / 73 (13.70%)
         occurrences all number
    21
    23
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 May 2013
    (1) The study design was amended to be a placebo controlled 3 arm study (2) Change of trial IMP from capsules to tablets (3) Increase in recruitment target (4) Change to the primary outcome measure
    06 Feb 2014
    (1) Change to eligibility criteria (2) Clarification of types of tumour sample
    11 Aug 2014
    (1) Change to definition of end of study (2) Clarification of indemnity arrangements (3) Clarification of treatment schedule assessments (4) Clarification of data reporting requirements (5) Change to SAE reporting period
    18 Feb 2015
    (1) Addition of AML as an SAE reporting requirement
    21 Jun 2019
    (1) Change to definition of end of study (2) Clarification to translational study details

    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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