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    Clinical Trial Results:
    A Phase I/II, Open-Label, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Oral Rucaparib in Patients with gBRCA Mutation Ovarian Cancer or Other Solid Tumor

    Summary
    EudraCT number
    		 2011-004250-26
    Trial protocol
    		 GB   ES   DE  
    Global end of trial date
    30 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2020
    First version publication date
    14 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CO-338-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01482715
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clovis Oncology UK Ltd
    Sponsor organisation address
    Granta Centre, Granta Park, Great Abington, Cambridge, United Kingdom, CB21 6GP
    Public contact
    Dr Lindsey Rolfe, Clovis Oncology UK Ltd, +44 01223645500, lrolfe@clovisoncology.com
    Scientific contact
    Dr Lindsey Rolfe, Clovis Oncology UK Ltd, +44 01223645500, lrolfe@clovisoncology.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
    29 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To evaluate the safety profile of escalating doses of continuous daily oral rucaparib in patients with advanced solid tumors, and to determine the maximum tolerated dose and recommended Phase II Dose (Part 1 only) 2. To characterize the pharmacokinetic profile of oral rucaparib when administered as a continuous daily dose (Part 1 and Part 3 only) 3. To evaluate overall response rate in patients with platinum-sensitive, relapsed, high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer associated with a BRCA mutation[henceforth abbreviated to platinum- sensitive OC population]
    Protection of trial subjects
    The following safety assessments were performed: Monitoring of adverse events (AEs), physical examination, clinical laboratory evaluations (hematology, serum chemistry, and urinalysis), vital signs, and 12-lead ECG.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Nov 2011
    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
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 55
    Country: Number of subjects enrolled
    United States: 58
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Canada: 6
    Worldwide total number of subjects
    136
    EEA total number of subjects
    57
    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)
    103
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 15 investigative sites in the United States (6 sites), United Kingdom (5 sites), Spain (1 site), Israel (2 sites), and Canada (1 site).

    Pre-assignment
    Screening details
    		 Patients enrolled into Part 1, Part 2A, Part 2B, or Part 3 of the study, not into multiple parts.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 (Phase 1)
    Arm description
    		 Rucaparib 40 to 500 mg QD and 240 to 840 mg BID, for continuous 21-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rucaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rucaparib 40 to 500 mg QD and 240 to 840 mg BID, for continuous 21-day cycles.

    Arm title
    		 Part 2A (Phase 2)
    Arm description
    		 Rucaparib 600 mg BID for 21-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rucaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rucaparib 600 mg BID for 21-day cycles.

    Arm title
    		 Part 2B (Phase 2)
    Arm description
    		 Rucaparib 600 mg BID for 21-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rucaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rucaparib 600 mg BID for 21-day cycles.

    Arm title
    		 Part 3 (Phase 2)
    Arm description
    		 Rucaparib 600 mg BID for 21-day cycles. Patients also received a single administration of 600 mg rucaparib on both Day -7 and Day 1 for assessing the effect of food on PK.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rucaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rucaparib 600 mg BID for continuous 21-day cycles.

    Number of subjects in period 1
    		Part 1 (Phase 1) Part 2A (Phase 2) Part 2B (Phase 2) Part 3 (Phase 2)
    Started
    56
    42
    12
    26
    Completed
    56
    42
    12
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 (Phase 1)
    Reporting group description
    		 Rucaparib 40 to 500 mg QD and 240 to 840 mg BID, for continuous 21-day cycles.

    Reporting group title
    Part 2A (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles.

    Reporting group title
    Part 2B (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles.

    Reporting group title
    Part 3 (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles. Patients also received a single administration of 600 mg rucaparib on both Day -7 and Day 1 for assessing the effect of food on PK.

    Reporting group values
    		 Part 1 (Phase 1) Part 2A (Phase 2) Part 2B (Phase 2) Part 3 (Phase 2) Total
    Number of subjects
    		 56 42 12 26 136
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 51.0 (21.0 to 71.0) 56.5 (42.0 to 84.0) 57.5 (46.0 to 72.0) 59.5 (39.0 to 79.0) -
    Gender categorical
    Units: Subjects
        Female
    		 51 42 12 21 126
        Male
    		 5 0 0 5 10
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 3 3 0 1 7
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 4 3 0 2 9
        White
    		 49 35 11 22 117
        More than one race
    		 0 1 0 1 2
        Unknown or Not Reported
    		 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Part 1 (Phase 1)
    Reporting group description
    		 Rucaparib 40 to 500 mg QD and 240 to 840 mg BID, for continuous 21-day cycles.

    Reporting group title
    Part 2A (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles.

    Reporting group title
    Part 2B (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles.

    Reporting group title
    Part 3 (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles. Patients also received a single administration of 600 mg rucaparib on both Day -7 and Day 1 for assessing the effect of food on PK.

    Subject analysis set title
    Rucaparib 40-500 mg QD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 40 to 500 mg QD for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 40 mg QD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 40 mg QD for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 80 mg QD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 80 mg QD for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 160 mg QD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 160 mg QD for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 300 mg QD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 300 mg QD for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 500 mg QD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 500 mg QD for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 240 mg BID
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 240 mg BID for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 360 mg BID
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 360 mg BID for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 480 mg BID
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 480 mg BID for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 600 mg BID
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 600 mg BID for continuous 21-day cycles.

    Subject analysis set title
    Rucaparib 840 mg BID
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Rucaparib 840 mg BID for continuous 21-day cycles.

    Primary: Overall Response Rate Per RECIST Version 1.1 (Part 2)

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    End point title
    		 Overall Response Rate Per RECIST Version 1.1 (Part 2) [1] [2]
    End point description
    The confirmed response rate by RECIST v1.1 is defined as the proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR) on subsequent tumor assessment at least 28 days after first response documentation. Analysis Population Description: Efficacy-Evaluable Population - all Part 2 patients who met eligibility criteria, received at least 1 dose of rucaparib, had measurable tumor lesions at baseline, and had at least 1 post-baseline disease assessment. 2 patients in Part 2A discontinued treatment due to an AE and did not have a post-baseline disease assessment.
    End point type
    Primary
    End point timeframe
    Time from first dose to date of progression, up to approximately 8 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol no statistical test was performed between arms for the ORR end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point reports ORR for Part 2 patients only.
    End point values
    		 Part 2A (Phase 2) Part 2B (Phase 2)
    Number of subjects analysed
    40
    12
    Units: Percentage of patients
        number (confidence interval 95%)
    62.5 (45.8 to 77.3)
    58.3 (27.7 to 84.8)
    No statistical analyses for this end point

    Primary: Dose Limiting Toxicity (DLT) Incidence

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    End point title
    		 Dose Limiting Toxicity (DLT) Incidence [3]
    End point description
    The number of Part 1 (Phase 1) patients who experienced dose limiting toxicities after one cycle (21 days) of study drug. Analysis Population Description: DLT-evaluable population - all patients enrolled into Part 1 of the study who received at least 17 complete days of rucaparib and completed Cycle 1 of treatment, or who experienced a DLT in Cycle 1. Note: A MTD was not established based on observation of DLTs in Cycle 1 of treatment. The 600 mg BID dose was considered to be the maximum dose with an acceptable toxicity profile that could be continuously administered to patients and was selected as the recommended Phase 2 dose (RP2D).
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 to Cycle 1 Day 21
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses was not performed for DLT end point.
    End point values
    		 Rucaparib 40-500 mg QD Rucaparib 240 mg BID Rucaparib 360 mg BID Rucaparib 480 mg BID Rucaparib 600 mg BID Rucaparib 840 mg BID
    Number of subjects analysed
    26
    3
    8
    9
    7
    3
    Units: Number of participants
    0
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: PK Profile of Rucaparib - Cmax (Part 1)

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    End point title
    		 PK Profile of Rucaparib - Cmax (Part 1) [4]
    End point description
    Cmax = maximum concentration following administration of rucaparib. Analysis Population Description: PK-evaluable population - all patients enrolled into Part 1 of the study who received at least one dose of rucaparib and had adequate PK assessments drawn for determination of the PK profile. For some arms, the number analyzed at Day 1 and Day 15 differs from the overall number based on number of evaluable samples collected at each time point.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses are not performed for PK end points.
    End point values
    		 Rucaparib 40 mg QD Rucaparib 80 mg QD Rucaparib 160 mg QD Rucaparib 300 mg QD Rucaparib 500 mg QD Rucaparib 240 mg BID Rucaparib 360 mg BID Rucaparib 480 mg BID Rucaparib 600 mg BID Rucaparib 840 mg BID
    Number of subjects analysed
    3
    3
    4 [5]
    3
    3
    3
    8 [6]
    9 [7]
    7
    3 [8]
    Units: ng/mL
    median (full range (min-max))
        Day 1 Cmax
    120 (98.9 to 168)
    119 (65.7 to 158)
    255 (107 to 426)
    700 (368 to 818)
    699 (629 to 1520)
    132 (123 to 401)
    603 (244 to 1170)
    1090 (312 to 2440)
    972 (271 to 1790)
    954 (705 to 2470)
        Day 15 Cmax
    159 (80.7 to 174)
    180 (108 to 237)
    267 (217 to 380)
    439 (340 to 1300)
    1250 (1170 to 1750)
    783 (619 to 1510)
    1220 (728 to 2320)
    2480 (922 to 6870)
    2330 (477 to 3670)
    3030 (3000 to 3060)
    Notes
    [5] - Day 1 = 4 patients analyzed, Day 15 = 3 patients analyzed
    [6] - Day 1 = 8 patients analyzed, Day 15 = 6 patients analyzed
    [7] - Day 1 = 9 patients analyzed, Day 15 = 8 patients analyzed
    [8] - Day 1 = 3 patients analyzed, Day 15 = 2 patients analyzed
    No statistical analyses for this end point

    Primary: PK Profile of Rucaparib - Tmax (Part 1)

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    End point title
    		 PK Profile of Rucaparib - Tmax (Part 1) [9]
    End point description
    Tmax = time to maximum concentration following administration of rucaparib. Analysis Population Description: PK-evaluable population - all patients enrolled into Part 1 of the study who received at least one dose of rucaparib and had adequate PK assessments drawn for determination of the PK profile. For some arms, the number analyzed at Day 1 and Day 15 differs from the overall number based on number of evaluable samples collected at each time point.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses are not performed for PK end points.
    End point values
    		 Rucaparib 40 mg QD Rucaparib 80 mg QD Rucaparib 160 mg QD Rucaparib 300 mg QD Rucaparib 500 mg QD Rucaparib 240 mg BID Rucaparib 360 mg BID Rucaparib 480 mg BID Rucaparib 600 mg BID Rucaparib 840 mg BID
    Number of subjects analysed
    3
    3
    4 [10]
    3
    3
    3
    8 [11]
    9 [12]
    7
    3 [13]
    Units: Hours
    median (full range (min-max))
        Day 1 Tmax
    2.5 (1 to 4)
    1.5 (1 to 2.5)
    4 (4 to 6.05)
    2.5 (1 to 4.08)
    4 (4 to 4)
    6 (4.05 to 6)
    3.23 (1.5 to 6)
    2.5 (1.5 to 4)
    4 (2.42 to 10)
    4 (2.5 to 8)
        Day 15 Tmax
    4 (1 to 4.05)
    2.5 (2.5 to 2.57)
    3.75 (2.5 to 4)
    2.53 (2.5 to 8)
    4 (4 to 4.17)
    1.5 (1 to 4)
    3.3 (0 to 6.33)
    1.51 (0 to 6)
    4 (2.53 to 10)
    4.04 (4 to 4.07)
    Notes
    [10] - Day 1 = 4 patients analyzed, Day 15 = 3 patients analyzed
    [11] - Day 1 = 8 patients analyzed, Day 15 = 6 patients analyzed
    [12] - Day 1 = 9 patients analyzed, Day 15 = 8 patients analyzed
    [13] - Day 1 = 3 patients analyzed, Day 15 = 2 patients analyzed
    No statistical analyses for this end point

    Primary: PK Profile of Rucaparib - AUC Last (Part 1)

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    End point title
    		 PK Profile of Rucaparib - AUC Last (Part 1) [14]
    End point description
    AUC last = Area under the plasma concentration-time curve from time 0 to the last recorded observation. Analysis Population Description: PK-evaluable population - all patients enrolled into Part 1 of the study who received at least one dose of rucaparib and had adequate PK assessments drawn for determination of the PK profile. For some arms, the number analyzed at Day 1 and Day 15 differs from the overall number based on number of evaluable samples collected at each time point.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses are not performed for PK end points.
    End point values
    		 Rucaparib 40 mg QD Rucaparib 80 mg QD Rucaparib 160 mg QD Rucaparib 300 mg QD Rucaparib 500 mg QD Rucaparib 240 mg BID Rucaparib 360 mg BID Rucaparib 480 mg BID Rucaparib 600 mg BID Rucaparib 840 mg BID
    Number of subjects analysed
    3 [15]
    3
    4 [16]
    3
    3
    3
    8 [17]
    9 [18]
    7
    3 [19]
    Units: hr*ng/mL
    median (full range (min-max))
        Day 1 AUC last
    915 (850 to 981)
    916 (555 to 930)
    2730 (1520 to 5230)
    5820 (3540 to 7860)
    7670 (6640 to 18700)
    875 (835 to 2430)
    4160 (1060 to 6670)
    6190 (1270 to 17200)
    6700 (1650 to 10900)
    5930 (5140 to 16700)
        Day 15 AUC last
    2270 (889 to 2280)
    1870 (1340 to 2000)
    3510 (3130 to 5670)
    6090 (4020 to 18700)
    16500 (13900 to 29200)
    6340 (5100 to 12600)
    9110 (5950 to 17200)
    19400 (7480 to 55100)
    19700 (3090 to 32600)
    24900 (24100 to 25700)
    Notes
    [15] - Day 1 = 2 patients analyzed, Day 15 = 3 patients analyzed
    [16] - Day 1 = 4 patients analyzed, Day 15 = 3 patients analyzed
    [17] - Day 1 =8 patients analyzed, Day 15 = 6 patients analyzed
    [18] - Day 1 = 9 patients analyzed, Day 15 = 8 patients analyzed
    [19] - Day 1 = 3 patients analyzed, Day 15 = 2 patients analyzed
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) According to RECIST v1.1, as Assessed by the Investigator (Part 2)

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    End point title
    		 Progression-free Survival (PFS) According to RECIST v1.1, as Assessed by the Investigator (Part 2) [20]
    End point description
    PFS is calculated as 1+ the number of days from the first dose of study drug to disease progression by RECIST, as determined by the investigator or death due to any cause, whichever occurs first. Analysis Population Description: Safety population - Consists of all Part 2 patients who received at least one dose of rucaparib.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 to End of Treatment, up to approximately 51 months
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point reports PFS for Part 2 patients only.
    End point values
    		 Part 2A (Phase 2) Part 2B (Phase 2)
    Number of subjects analysed
    42
    12
    Units: Days
        median (confidence interval 95%)
    260 (203 to 373)
    280 (40 to 551)
    No statistical analyses for this end point

    Secondary: Duration of Response Per RECIST Version 1.1 (Part 2)

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    End point title
    		 Duration of Response Per RECIST Version 1.1 (Part 2) [21]
    End point description
    Duration of response (DOR) for any confirmed RECIST CR or PR measured from the date of the first occurrence of a response until the first occurrence of PD per RECIST. For patients who continued treatment post-progression, the first date of progression was used for the analysis. Any patients with an ongoing response were censored at the date of the last post-baseline scan. Analysis Population Description: Safety population - all Part 2 patients with confirmed response per investigator.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 to End of Treatment, up to approximately 48 months
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point reports DOR for Part 2 patients only.
    End point values
    		 Part 2A (Phase 2) Part 2B (Phase 2)
    Number of subjects analysed
    25
    7
    Units: Days
        median (confidence interval 95%)
    270 (170 to 393)
    318 (106 to 497)
    No statistical analyses for this end point

    Secondary: Overall Survival (Part 2B)

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    End point title
    		 Overall Survival (Part 2B) [22]
    End point description
    Overall survival (OS) is defined as the number of days from the date of first dose of study drug to the date of death, due to any cause. Patients without a documented event of death will be censored on the date of their last visit. Analysis Population Description: Safety population - Consists of all Part 2B patients who received at least one dose of rucaparib. Note: The upper confidence of the median is not reached due to not enough death events. 9999 is entered as a placeholder.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 to date of death, assessed up to 38 months
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point reports OS for Part 2B patients only.
    End point values
    		 Part 2B (Phase 2)
    Number of subjects analysed
    12
    Units: Days
        median (confidence interval 95%)
    764 (166 to 9999)
    No statistical analyses for this end point

    Secondary: Food Effect on PK of Rucaparib - Tmax (Part 1 and Part 3)

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    End point title
    		 Food Effect on PK of Rucaparib - Tmax (Part 1 and Part 3)
    End point description
    Tmax = time to maximum concentration following administration of rucaparib. The effect of food on rucaparib PK parameters was assessed over a 24hour period in blood samples from a subset of patients. Patients were given a single dose of 40 mg or 300 mg rucaparib (Part 1), or 600 mg rucaparib (Part 3) with and without a high-fat meal on Day -7 or Cycle 1 Day 1. On each day, patients underwent blood sampling for PK at the specified time points. Analysis Population Description: A subset of patients treated with either 40 mg, 300 mg, or 600 mg rucaparib.
    End point type
    Secondary
    End point timeframe
    Day -7 to Cycle 1 Day 1, or approximately 7 days
    End point values
    		 Rucaparib 40 mg QD Rucaparib 300 mg QD Rucaparib 600 mg BID
    Number of subjects analysed
    3
    6
    26
    Units: Hours
    median (full range (min-max))
        Tmax Fasted
    4 (2.5 to 4.05)
    4.09 (2.5 to 24.22)
    4.02 (0.53 to 24.83)
        Tmax Fed
    2.55 (1 to 4.08)
    5.95 (2.53 to 10)
    7.83 (1.5 to 24.45)
    No statistical analyses for this end point

    Secondary: Food Effect on PK of Rucaparib - Cmax (Part 1 and Part 3)

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    End point title
    		 Food Effect on PK of Rucaparib - Cmax (Part 1 and Part 3)
    End point description
    Cmax = maximum concentration following administration of rucaparib. The effect of food on rucaparib PK parameters was assessed over a 24-hour period in blood samples from a subset of patients. Patients were given a single dose of 40 mg or 300 mg rucaparib (Part 1), or 600 mg rucaparib (Part 3) with and without a high-fat meal on Day -7 or Cycle 1 Day 1. On each day, patients underwent blood sampling for PK at the specified time points. Analysis Population Description: A subset of patients treated with either 40 mg, 300 mg, or 600 mg rucaparib.
    End point type
    Secondary
    End point timeframe
    Day -7 to Cycle 1 Day 1, or approximately 7 days
    End point values
    		 Rucaparib 40 mg QD Rucaparib 300 mg QD Rucaparib 600 mg BID
    Number of subjects analysed
    3
    6
    26
    Units: ng/mL
    median (full range (min-max))
        Cmax Fasted
    57.6 (45.2 to 131)
    424 (182 to 638)
    585 (127 to 3100)
        Cmax Fed
    71.1 (21.3 to 102)
    393 (177 to 1210)
    746 (198 to 2640)
    No statistical analyses for this end point

    Secondary: Food Effect on PK of Rucaparib - AUC Last (Part 1 and Part 3)

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    End point title
    		 Food Effect on PK of Rucaparib - AUC Last (Part 1 and Part 3)
    End point description
    AUC last = Area under the plasma concentration-time curve from time 0 to the last recorded observation. The effect of food on rucaparib PK parameters was assessed over a 24-hour period in blood samples from a subset of patients. Patients were given a single dose of 40 mg or 300 mg rucaparib (Part 1), or 600 mg rucaparib (Part 3) with and without a high-fat meal on Day -7 or Cycle 1 Day 1. On each day, patients underwent blood sampling for PK at the specified time points. Analysis Population Description: A subset of patients treated with either 40 mg, 300 mg, or 600 mg rucaparib. For the 40 mg and 300 mg arms, the number analyzed at Day 1 and Day 15 differs from the overall number based on number of evaluable samples collected at each time point.
    End point type
    Secondary
    End point timeframe
    Day -7 to Cycle 1 Day 1, or approximately 7 days
    End point values
    		 Rucaparib 40 mg QD Rucaparib 300 mg QD Rucaparib 600 mg BID
    Number of subjects analysed
    3 [23]
    6 [24]
    26
    Units: hr*ng/mL
    median (full range (min-max))
        AUC Last Fasted
    468 (347 to 1410)
    5410 (2390 to 8680)
    7050 (1110 to 33000)
        AUC Last Fed
    794 (415 to 1170)
    6000 (2670 to 12100)
    10900 (1990 to 40400)
    Notes
    [23] - Fasted = 3 patients analyzed, Fed = 2 patients analyzed
    [24] - Fasted = 6 patients analyzed, Fed = 5 patients analyzed
    No statistical analyses for this end point

    Secondary: QTcF Value Change From Baseline (Part 1)

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    End point title
    		 QTcF Value Change From Baseline (Part 1)
    End point description
    QTcF value change from baseline by daily dose corrected using Fridericia's method (QTcF). To evaluate the effects of rucaparib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Screening, on Cycle 1 Day -1, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 1 Day 22, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient. Analysis Population Description: Safety population - Consists of all Part 1 patients who received at least one dose of rucaparib. One patient in the 40 mg dose group had no Baseline evaluation and was excluded from analyses of change from Baseline.
    End point type
    Secondary
    End point timeframe
    Screening to End of Treatment, up to approximately 15 months
    End point values
    		 Rucaparib 40 mg QD Rucaparib 80 mg QD Rucaparib 160 mg QD Rucaparib 300 mg QD Rucaparib 500 mg QD Rucaparib 240 mg BID Rucaparib 360 mg BID Rucaparib 480 mg BID Rucaparib 600 mg BID Rucaparib 840 mg BID
    Number of subjects analysed
    5
    3
    4
    9
    4
    3
    8
    9
    7
    3
    Units: Participants
        QTcF Change from Baseline <30 msec
    5
    3
    4
    9
    3
    3
    8
    9
    7
    3
        QTcF Change from Baseline ≥30 to <60 msec
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
        QTcF Change from Baseline ≥60 msec
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    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 first dose of study drug and within 28 days after last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Part 1 (Phase 1)
    Reporting group description
    		 Rucaparib 40 to 500 mg QD, followed by 240 to 840 mg BID, for continuous 21-day cycles.

    Reporting group title
    Part 2A (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles.

    Reporting group title
    Part 2B (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles.

    Reporting group title
    Part 3 (Phase 2)
    Reporting group description
    		 Rucaparib 600 mg BID for 21-day cycles.

    Serious adverse events
    		 Part 1 (Phase 1) Part 2A (Phase 2) Part 2B (Phase 2) Part 3 (Phase 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 56 (37.50%)
    19 / 42 (45.24%)
    3 / 12 (25.00%)
    9 / 26 (34.62%)
         number of deaths (all causes)
    4
    4
    1
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell type acute leukaemia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    7 / 56 (12.50%)
    4 / 42 (9.52%)
    1 / 12 (8.33%)
    3 / 26 (11.54%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
    0 / 3
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract stoma complication
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal fistula
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 (Phase 1) Part 2A (Phase 2) Part 2B (Phase 2) Part 3 (Phase 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 56 (98.21%)
    41 / 42 (97.62%)
    12 / 12 (100.00%)
    26 / 26 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    10 / 56 (17.86%)
    5 / 42 (11.90%)
    1 / 12 (8.33%)
    4 / 26 (15.38%)
         occurrences all number
    11
    6
    1
    4
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 56 (3.57%)
    2 / 42 (4.76%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    2
    7
    2
    0
    Hypertension
         subjects affected / exposed
    1 / 56 (1.79%)
    4 / 42 (9.52%)
    2 / 12 (16.67%)
    1 / 26 (3.85%)
         occurrences all number
    1
    8
    3
    1
    Lymphoedema
         subjects affected / exposed
    2 / 56 (3.57%)
    1 / 42 (2.38%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    3
    7
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 56 (3.57%)
    13 / 42 (30.95%)
    1 / 12 (8.33%)
    2 / 26 (7.69%)
         occurrences all number
    2
    49
    2
    3
    Axillary pain
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Chest pain
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Chills
         subjects affected / exposed
    1 / 56 (1.79%)
    5 / 42 (11.90%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    5
    1
    0
    Early satiety
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Fatigue
         subjects affected / exposed
    28 / 56 (50.00%)
    30 / 42 (71.43%)
    6 / 12 (50.00%)
    14 / 26 (53.85%)
         occurrences all number
    48
    85
    8
    29
    Influenza like illness
         subjects affected / exposed
    2 / 56 (3.57%)
    5 / 42 (11.90%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    8
    2
    0
    Injection site bruising
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    2 / 56 (3.57%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    4
    2
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    5
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
    5 / 26 (19.23%)
         occurrences all number
    4
    6
    0
    6
    Peripheral swelling
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    4
    0
    2
    Pyrexia
         subjects affected / exposed
    9 / 56 (16.07%)
    5 / 42 (11.90%)
    3 / 12 (25.00%)
    3 / 26 (11.54%)
         occurrences all number
    11
    13
    4
    4
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 56 (1.79%)
    5 / 42 (11.90%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    6
    0
    0
    Vaginal discharge
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 56 (21.43%)
    10 / 42 (23.81%)
    2 / 12 (16.67%)
    4 / 26 (15.38%)
         occurrences all number
    13
    18
    2
    5
    Dysphonia
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    11 / 56 (19.64%)
    11 / 42 (26.19%)
    1 / 12 (8.33%)
    4 / 26 (15.38%)
         occurrences all number
    16
    16
    1
    4
    Dyspnoea exertional
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    0
    3
    Hypoxia
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Nasal discomfort
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    7 / 56 (12.50%)
    7 / 42 (16.67%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    7
    12
    1
    1
    Pleural effusion
         subjects affected / exposed
    5 / 56 (8.93%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    5
    2
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    3 / 56 (5.36%)
    6 / 42 (14.29%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    5
    7
    0
    2
    Depressed mood
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Depression
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    12
    0
    0
    Insomnia
         subjects affected / exposed
    6 / 56 (10.71%)
    6 / 42 (14.29%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    6
    14
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 56 (16.07%)
    24 / 42 (57.14%)
    2 / 12 (16.67%)
    6 / 26 (23.08%)
         occurrences all number
    15
    53
    11
    18
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 56 (23.21%)
    22 / 42 (52.38%)
    2 / 12 (16.67%)
    6 / 26 (23.08%)
         occurrences all number
    15
    40
    3
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    8 / 56 (14.29%)
    10 / 42 (23.81%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    9
    16
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    8
    2
    0
    Blood cholesterol increased
         subjects affected / exposed
    5 / 56 (8.93%)
    3 / 42 (7.14%)
    2 / 12 (16.67%)
    3 / 26 (11.54%)
         occurrences all number
    7
    5
    3
    3
    Blood creatinine increased
         subjects affected / exposed
    5 / 56 (8.93%)
    15 / 42 (35.71%)
    6 / 12 (50.00%)
    3 / 26 (11.54%)
         occurrences all number
    6
    34
    16
    4
    Blood potassium increased
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood urea increased
         subjects affected / exposed
    3 / 56 (5.36%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    6 / 56 (10.71%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    11
    15
    0
    9
    Platelet count decreased
         subjects affected / exposed
    4 / 56 (7.14%)
    7 / 42 (16.67%)
    2 / 12 (16.67%)
    2 / 26 (7.69%)
         occurrences all number
    5
    18
    2
    7
    Transaminases increased
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    0
    2
    Weight decreased
         subjects affected / exposed
    3 / 56 (5.36%)
    8 / 42 (19.05%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    3
    11
    1
    2
    White blood cell count decreased
         subjects affected / exposed
    5 / 56 (8.93%)
    5 / 42 (11.90%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    12
    20
    0
    2
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 56 (16.07%)
    9 / 42 (21.43%)
    1 / 12 (8.33%)
    6 / 26 (23.08%)
         occurrences all number
    11
    15
    1
    6
    Dysgeusia
         subjects affected / exposed
    8 / 56 (14.29%)
    17 / 42 (40.48%)
    2 / 12 (16.67%)
    5 / 26 (19.23%)
         occurrences all number
    10
    34
    2
    7
    Headache
         subjects affected / exposed
    11 / 56 (19.64%)
    20 / 42 (47.62%)
    2 / 12 (16.67%)
    2 / 26 (7.69%)
         occurrences all number
    13
    38
    3
    2
    Lethargy
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    3 / 12 (25.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    6
    1
    Neuropathy peripheral
         subjects affected / exposed
    2 / 56 (3.57%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Paraesthesia
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    3
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 56 (32.14%)
    30 / 42 (71.43%)
    8 / 12 (66.67%)
    6 / 26 (23.08%)
         occurrences all number
    42
    149
    32
    38
    Leukopenia
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Lymphopenia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Neutropenia
         subjects affected / exposed
    6 / 56 (10.71%)
    9 / 42 (21.43%)
    2 / 12 (16.67%)
    3 / 26 (11.54%)
         occurrences all number
    14
    22
    5
    8
    Thrombocytopenia
         subjects affected / exposed
    4 / 56 (7.14%)
    8 / 42 (19.05%)
    4 / 12 (33.33%)
    3 / 26 (11.54%)
         occurrences all number
    8
    22
    13
    14
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 42 (4.76%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    4 / 56 (7.14%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    4
    3
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    3
    1
    0
    2
    Abdominal distension
         subjects affected / exposed
    8 / 56 (14.29%)
    11 / 42 (26.19%)
    0 / 12 (0.00%)
    4 / 26 (15.38%)
         occurrences all number
    9
    18
    0
    5
    Abdominal pain
         subjects affected / exposed
    14 / 56 (25.00%)
    20 / 42 (47.62%)
    5 / 12 (41.67%)
    4 / 26 (15.38%)
         occurrences all number
    22
    51
    7
    6
    Abdominal pain lower
         subjects affected / exposed
    2 / 56 (3.57%)
    6 / 42 (14.29%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    2
    7
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    7 / 56 (12.50%)
    5 / 42 (11.90%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    9
    9
    2
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Ascites
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    4
    3
    0
    1
    Constipation
         subjects affected / exposed
    14 / 56 (25.00%)
    22 / 42 (52.38%)
    7 / 12 (58.33%)
    7 / 26 (26.92%)
         occurrences all number
    16
    33
    11
    9
    Diarrhoea
         subjects affected / exposed
    13 / 56 (23.21%)
    17 / 42 (40.48%)
    3 / 12 (25.00%)
    4 / 26 (15.38%)
         occurrences all number
    19
    35
    4
    4
    Dry mouth
         subjects affected / exposed
    4 / 56 (7.14%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
    2 / 26 (7.69%)
         occurrences all number
    6
    3
    1
    2
    Dyspepsia
         subjects affected / exposed
    5 / 56 (8.93%)
    3 / 42 (7.14%)
    2 / 12 (16.67%)
    6 / 26 (23.08%)
         occurrences all number
    7
    3
    3
    6
    Flatulence
         subjects affected / exposed
    1 / 56 (1.79%)
    5 / 42 (11.90%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    8
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 56 (7.14%)
    2 / 42 (4.76%)
    2 / 12 (16.67%)
    2 / 26 (7.69%)
         occurrences all number
    5
    2
    2
    2
    Intestinal obstruction
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Mouth ulceration
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Nausea
         subjects affected / exposed
    30 / 56 (53.57%)
    35 / 42 (83.33%)
    11 / 12 (91.67%)
    11 / 26 (42.31%)
         occurrences all number
    48
    92
    26
    20
    Small intestinal obstruction
         subjects affected / exposed
    1 / 56 (1.79%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    5
    0
    2
    Stomatitis
         subjects affected / exposed
    4 / 56 (7.14%)
    7 / 42 (16.67%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    4
    11
    1
    0
    Tooth disorder
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    24 / 56 (42.86%)
    24 / 42 (57.14%)
    9 / 12 (75.00%)
    9 / 26 (34.62%)
         occurrences all number
    41
    67
    22
    18
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 56 (3.57%)
    8 / 42 (19.05%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    2
    8
    1
    1
    Blister
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Dry skin
         subjects affected / exposed
    2 / 56 (3.57%)
    6 / 42 (14.29%)
    1 / 12 (8.33%)
    2 / 26 (7.69%)
         occurrences all number
    2
    8
    1
    3
    Erythema
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Nail discolouration
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    3
    0
    1
    Photosensitivity reaction
         subjects affected / exposed
    6 / 56 (10.71%)
    5 / 42 (11.90%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    6
    6
    1
    1
    Pruritus
         subjects affected / exposed
    4 / 56 (7.14%)
    6 / 42 (14.29%)
    1 / 12 (8.33%)
    3 / 26 (11.54%)
         occurrences all number
    6
    9
    1
    3
    Rash
         subjects affected / exposed
    3 / 56 (5.36%)
    8 / 42 (19.05%)
    1 / 12 (8.33%)
    3 / 26 (11.54%)
         occurrences all number
    3
    18
    2
    5
    Rash macular
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    7
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin ulcer
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Dysuria
         subjects affected / exposed
    3 / 56 (5.36%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    3
    3
    0
    2
    Micturition urgency
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Proteinuria
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    8
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    3
    1
    1
    Pollakiuria
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 56 (3.57%)
    9 / 42 (21.43%)
    3 / 12 (25.00%)
    3 / 26 (11.54%)
         occurrences all number
    2
    16
    5
    3
    Back pain
         subjects affected / exposed
    5 / 56 (8.93%)
    7 / 42 (16.67%)
    2 / 12 (16.67%)
    4 / 26 (15.38%)
         occurrences all number
    5
    11
    3
    4
    Bone pain
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 42 (7.14%)
    2 / 12 (16.67%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    3
    3
    Muscle spasms
         subjects affected / exposed
    2 / 56 (3.57%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    3
    3
    1
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    4
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    5
    2
    1
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Myalgia
         subjects affected / exposed
    3 / 56 (5.36%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Neck pain
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    3 / 56 (5.36%)
    5 / 42 (11.90%)
    1 / 12 (8.33%)
    2 / 26 (7.69%)
         occurrences all number
    3
    9
    1
    2
    Infections and infestations
    Ear infection
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 42 (0.00%)
    4 / 12 (33.33%)
    1 / 26 (3.85%)
         occurrences all number
    5
    0
    5
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 56 (1.79%)
    5 / 42 (11.90%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    6
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Sepsis
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    1
    Tooth infection
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 56 (3.57%)
    12 / 42 (28.57%)
    2 / 12 (16.67%)
    2 / 26 (7.69%)
         occurrences all number
    4
    16
    2
    5
    Urinary tract infection
         subjects affected / exposed
    5 / 56 (8.93%)
    8 / 42 (19.05%)
    3 / 12 (25.00%)
    6 / 26 (23.08%)
         occurrences all number
    6
    10
    6
    7
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    1
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 56 (28.57%)
    12 / 42 (28.57%)
    3 / 12 (25.00%)
    10 / 26 (38.46%)
         occurrences all number
    18
    19
    3
    17
    Dehydration
         subjects affected / exposed
    7 / 56 (12.50%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
    2 / 26 (7.69%)
         occurrences all number
    9
    4
    1
    6
    Hypercalcaemia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    4 / 56 (7.14%)
    4 / 42 (9.52%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    4
    10
    1
    1
    Hyperglycaemia
         subjects affected / exposed
    7 / 56 (12.50%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    2 / 26 (7.69%)
         occurrences all number
    15
    2
    1
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    0
    3
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    4
    3
    0
    1
    Hypokalaemia
         subjects affected / exposed
    4 / 56 (7.14%)
    4 / 42 (9.52%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    5
    6
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    4 / 56 (7.14%)
    7 / 42 (16.67%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    5
    15
    3
    0
    Hyponatraemia
         subjects affected / exposed
    5 / 56 (8.93%)
    5 / 42 (11.90%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    6
    7
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    4 / 56 (7.14%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    6
    5
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jan 2012
    Exclusion criteria were revised to apply exclusion for history of clinically significant abnormal ECG to patients in both Parts 1 and 2 of the study. Withdrawal criteria were revised to include absolute QTc measurement > 500 msec as reason for withdrawal.
    23 Apr 2012
    The study design was revised to include an ovarian cancer arm in Part 2 of the study. An optional collection of a fresh or archival tumor tissue sample was added for patients who consented to provide a biopsy sample. Secondary objectives were revised to include an objective for evaluation of antitumor activity in patients with solid tumors enrolling into Part 1 of the study.
    02 Oct 2012
    The dose escalation plan was revised to included evaluation of BID, and possibly TID dosing. The study population for the RP2D expansion cohort was revised to include patients with a solid tumor and a deleterious gBRCA mutation, and the size was increased to up to 15 patients. Health-related quality of life (HRQoL) assessment was added to Part 2 of the study. The option for intrapatient dose escalation was added to Part 1 of the study so that patients may have their dose escalated to a potentially therapeutic level.
    27 Nov 2013
    The RP2D was determined to be 600 mg BID based on safety, PK, and efficacy data from the Phase 1 portion of the study. The breast cancer arm was removed to prioritize development of rucaparib in ovarian cancer patients. Changes to inclusion and exclusion criteria.
    02 Feb 2015
    Part 3 was added to further evaluate the PK of, and the effect of food on, higher dose strength tablets at the RP2D in patients with any advanced solid tumor, inclusive of lymphoma, with evidence of a BRCA mutation.
    27 Apr 2015
    An additional cohort of patients with relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, with evidence of a deleterious BRCA mutation (germline or somatic) who have received at least 3, but no more than 4, prior chemotherapy regimens was included in the Phase 2 part of the study. Initial Part 2 became Part 2A, and the new cohort of patients was enrolled into Part 2B.
    29 Jun 2016
    The protocol was amended to implement more stringent pregnancy testing requirements, birth control measures including criteria for defining females of childbearing potential and to update adverse events of special interest for patient safety. Restrictions regarding concomitant use of medications that are CYP substrates were updated based on nonclinical data. Dose modification criteria were updated to provide management guideline in the event of Grade 3 or Grade 4 ALT/AST elevations.

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

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

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