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    Clinical Trial Results:
    RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF TAS-102 PLUS BEST SUPPORTIVE CARE (BSC) VERSUS PLACEBO PLUS BSC IN PATIENTS WITH METASTATIC COLORECTAL CANCER REFRACTORY TO STANDARD CHEMOTHERAPIES

    Summary
    EudraCT number
    		 2012-000109-66
    Trial protocol
    		 GB   DE   SE   AT   ES   IE   CZ   BE   IT  
    Global end of trial date
    23 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2017
    First version publication date
    01 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TPU-TAS-102-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01607957
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Taiho Oncology, Inc.
    Sponsor organisation address
    101 Carnegie Center, Suite 101, Princeton, United States, NJ 08540
    Public contact
    Robert Winkler, MD, Taiho Oncology, Inc., 001 609/455.3893, rwinkler@taihooncology.com
    Scientific contact
    Robert Winkler, MD, Taiho Oncology, Inc., 001 609/455.3893, rwinkler@taihooncology.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
    31 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Objectives: To compare the following endpoints for the TAS-102 (experimental) arm with the placebo (control) arm in patients with refractory metastatic colorectal cancer: Primary �� Overall survival (OS) Key Secondary �� Progression-free survival (PFS) �� Safety and tolerability Other Secondary �� Time to treatment failure (TTF) �� Overall response rate (ORR) �� Disease control rate (DCR) �� Duration of response (DR) �� Subgroup analysis by KRAS status on OS and PFS Exploratory (Pharmacokinetic assessments performed at selected sites) �� To explore the effect of intrinsic and extrinsic factors on the pharmacokinetics (PK) of TAS-102 �� To explore the relationship between plasma concentrations of TAS-102 components (FTD and TPI) and safety and efficacy parameters
    Protection of trial subjects
    The study was conducted in accordance with Good Clinical Practices (GCP), ICH Guidelines, the ethical principles that have their origin in the Declaration of Helsinki, and all applicable regulatory requirements. The Investigator (according to applicable regulatory requirements) or a person designated by the Investigator and under the Investigator’s responsibility fully informed patients of all pertinent aspects of the clinical trial. All participants were informed to the fullest extent possible about the study in a language and in terms they are able to understand. Prior to participation in the trial, the written ICF was signed and personally dated by the patient or by the patient’s legal representative and by the person who conducted the ICF discussion. A copy of the signed and dated ICF was provided to the patient. The ICF used had had prior approval by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). An independent data monitoring committee (DMC) monitored the safe conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 A placebo-controlled design was selected for this study since, at the time the study was initiated, there were no standard therapies for patients with metastatic colorectal cancer who had been previously treated with fluoropyrimidines, oxaliplatin, irinotecan, monoclonal anti-VEGF and anti-EGFR antibodies for KRAS wild-type patients, and had become refractory or intolerant to those chemotherapies. Regorafenib became authorised for the treatment of patients with metastatic colorectal cancer in all participating RECOURSE countries (Australia, EU, Japan and the US) only after most of the study enrollment was complete (>80%). Patients in both the TAS-102 and placebo treatment groups received best supportive care in addition to study medication.
    Actual start date of recruitment
    17 Jun 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Spain: 112
    Country: Number of subjects enrolled
    Belgium: 64
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    France: 50
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 108
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    United States: 99
    Country: Number of subjects enrolled
    Japan: 266
    Worldwide total number of subjects
    800
    EEA total number of subjects
    403
    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)
    448
    From 65 to 84 years
    352
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 800 patients were randomized at a total of 101 study centers in 13 countries United States (21), Japan (20), Spain (11), Italy (9), Germany (8), Belgium (6), France (6), Australia (5), United Kingdom (5), Austria (4), Ireland (3), Sweden (2), Czech Republic (1). The first patient was randomized on 17 June 2012 and the last on 08 October 2013.

    Pre-assignment
    Screening details
    		 A total of 1002 patients provided signed informed consent for participation in the study. Of these, 800 were randomized and 202 (20%) did not meet eligibility criteria and were not randomised (ie, screen failures).

    Period 1
    Period 1 title
    Baseline Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental Arm
    Arm description
    		 TAS-102 plus Best supportive care (BSC)
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAS-102
    Investigational medicinal product code
    TAS-102
    Other name
    Lonsurf
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAS-102 was supplied as an immediate-release film coated tablet in 2 strengths (expressed as FTD (trifluridine) content): • 15-mg white, round tablet containing 15 mg FTD and 7.065 mg TPI (tipiracil hydrochloride) as active ingredients. • 20-mg pale-red, round tablet containing 20 mg FTD and 9.420 mg TPI as active ingredients. TAS-102 dosing was based on body surface area (BSA). The starting dose was 35 mg/m2/dose administered twice daily (BID) after morning and evening meals for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest (1 treatment cycle), repeated every 4 weeks.

    Arm title
    		 Control Arm
    Arm description
    		 Placebo plus best supportive care (BSC)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    NA
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Manufactured to look identical to the TAS-102 15-mg (white, round) and 20-mg (pale-red, round) tablets.

    Number of subjects in period 1
    		Experimental Arm Control Arm
    Started
    534
    266
    Completed
    534
    266
    Period 2
    Period 2 title
    On-treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    TAS-102 tablets (15-mg / 20-mg) and the corresponding placebo tablets were identical in appearance and were packaged in identical containers. Unblinding of the study treatment by the Investigator was not to occur unless needed to manage a patient’s medical condition. In this emergency, the Investigator could unblind the patient by calling the IWRS to obtain the patient’s treatments. If unblinding occurred, the Investigator was not to disclose the unblinding information.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental arm
    Arm description
    		 TAS-102 plus Best supportive care (BSC)
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAS-102
    Investigational medicinal product code
    TAS-102
    Other name
    Lonsurf
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAS-102 was supplied as an immediate-release film coated tablet in 2 strengths (expressed as FTD content): • 15-mg white, round tablet containing 15 mg FTD and 7.065 mg TPI as active ingredients. • 20-mg pale-red, round tablet containing 20 mg FTD and 9.420 mg TPI as active ingredients. TAS-102 dosing was based on body surface are (BSA). The starting dose was 35 mg/m2/dose administered twice daily (BID) after morning and evening meals for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest (1 treatment cycle), repeated every 4 weeks.

    Arm title
    		 Control arm
    Arm description
    		 Placebo plus best supportive care (BSC)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Manufactured to look identical to the TAS-102 15-mg (white, round) and 20-mg (pale-red, round) tablets.

    Number of subjects in period 2 [1]
    		Experimental arm Control arm
    Started
    533
    265
    Completed
    496
    263
    Not completed
    37
    2
         Continued study treatment
    37
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Number of subjects starting the on-treatment period does not include 1 patient in each arm (TAS-102 and placebo) that was not treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental Arm
    Reporting group description
    		 TAS-102 plus Best supportive care (BSC)

    Reporting group title
    Control Arm
    Reporting group description
    		 Placebo plus best supportive care (BSC)

    Reporting group values
    		 Experimental Arm Control Arm Total
    Number of subjects
    		 534 266 800
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 63 (27 to 82) 63 (27 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 208 101 309
        Male
    		 326 165 491

    End points

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    End points reporting groups
    Reporting group title
    Experimental Arm
    Reporting group description
    		 TAS-102 plus Best supportive care (BSC)

    Reporting group title
    Control Arm
    Reporting group description
    		 Placebo plus best supportive care (BSC)
    Reporting group title
    Experimental arm
    Reporting group description
    		 TAS-102 plus Best supportive care (BSC)

    Reporting group title
    Control arm
    Reporting group description
    		 Placebo plus best supportive care (BSC)

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Tumour assessments were performed throughout the study based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, 2009. Computed tomography (CT) scans were performed at the end of every 8 weeks until disease progression. If a patient discontinued study medication for reasons other than radiologic disease progression (eg, with intolerable side effects), the patient was followed for tumour response until radiologic disease progression or initiation of new anticancer therapy (whichever occurred first). All patients were followed for survival at scheduled 8-week time intervals until death. Patients were followed until 12 months after the first dose of study medication for the last patient randomised, even if consent for study participation had been withdrawn.
    End point type
    Primary
    End point timeframe
    Overall survival data: 24 January 2014 (observation of the 571st death in the study) The time from the date of randomization to the death date.
    End point values
    		 Experimental arm Control arm
    Number of subjects analysed
    533
    265
    Units: months
        median (confidence interval 95%)
    7.1 (6.5 to 7.8)
    5.3 (4.6 to 6)
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    Experimental arm v Control arm
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Stratified log-rank test p-value
    Confidence interval
    Notes
    [1] - (1-sided and 2-sided)

    Secondary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    End point type
    Secondary
    End point timeframe
    All clinical data except overall survival: 31 January 2014 The time (in months) from the date of randomization until the date of the investigator-assessed radiological disease progression or death due to any cause.
    End point values
    		 Experimental arm Control arm
    Number of subjects analysed
    533
    265
    Units: Months
        median (confidence interval 95%)
    2 (1.9 to 2.1)
    1.7 (1.7 to 1.8)
    Statistical analysis title
    		 Progression-Free Survival
    Comparison groups
    Experimental arm v Control arm
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Stratified log-rank test p-value
    Confidence interval
    Notes
    [2] - (1-sided and 2-sided)

    Secondary: Safety and Tolerability

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    End point title
    		 Safety and Tolerability
    End point description
    End point type
    Secondary
    End point timeframe
    All clinical data except overall survival: 31 January 2014 The time from when patient signs ICF through the period of patient follow-up (30 days after the last dose of study medication or until the start of new antitumor therapy, whichever is earlier)
    End point values
    		 Experimental arm Control arm
    Number of subjects analysed
    533
    265
    Units: Percentage
    number (not applicable)
        Any adverse event (AE)
    98.3
    93.2
        Any treatment-related AE
    85.7
    54.7
        Any ≥Grade 3 AE
    69.4
    51.7
        Any treatment-related ≥Grade 3 AE
    49
    9.8
        Any serious AE (SAE)
    29.6
    33.6
        Any AE resulting in discontinuation
    10.3
    13.6
        Any AE with outcome of death
    3.2
    11.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs will be reported from the time a patient signs informed consent through the period of patient follow-up (30 days after the last dose of study medication or until the start of new antitumor therapy, whichever is earlier).
    Adverse event reporting additional description
    Document all AEs in the source documents. Documentation should include onset and resolution/stabilization dates, severity/grade, relationship to study medication, and outcome of the event. All AEs should be entered in the CRF within 10 business days or as soon as possible from the time the Investigator first becomes aware of them.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    Experimental Arm
    Reporting group description
    		 TAS-102 plus Best supportive care (BSC)

    Reporting group title
    Control Arm
    Reporting group description
    		 Placebo plus best supportive care (BSC)

    Serious adverse events
    		 Experimental Arm Control Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    158 / 533 (29.64%)
    89 / 265 (33.58%)
         number of deaths (all causes)
    368
    212
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (inc cysts and polps)
         subjects affected / exposed
    6 / 533 (1.13%)
    7 / 265 (2.64%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 533 (0.19%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    27 / 533 (5.07%)
    16 / 265 (6.04%)
         occurrences causally related to treatment / all
    3 / 27
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Repiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    15 / 533 (2.81%)
    12 / 265 (4.53%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Investigations
         subjects affected / exposed
    5 / 533 (0.94%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    10 / 533 (1.88%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    4 / 533 (0.75%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    9 / 533 (1.69%)
    10 / 265 (3.77%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    28 / 533 (5.25%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    26 / 28
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye disorders
         subjects affected / exposed
    1 / 533 (0.19%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    40 / 533 (7.50%)
    26 / 265 (9.81%)
         occurrences causally related to treatment / all
    12 / 40
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    19 / 533 (3.56%)
    13 / 265 (4.91%)
         occurrences causally related to treatment / all
    1 / 19
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    13 / 533 (2.44%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    6 / 533 (1.13%)
    6 / 265 (2.26%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and Infestations
         subjects affected / exposed
    24 / 533 (4.50%)
    12 / 265 (4.53%)
         occurrences causally related to treatment / all
    9 / 24
    1 / 12
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    8 / 533 (1.50%)
    7 / 265 (2.64%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental Arm Control Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    524 / 533 (98.31%)
    247 / 265 (93.21%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (inc cysts and polps)
         subjects affected / exposed
    46 / 533 (8.63%)
    35 / 265 (13.21%)
         occurrences all number
    46
    35
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    51 / 533 (9.57%)
    25 / 265 (9.43%)
         occurrences all number
    51
    25
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    1 / 533 (0.19%)
    0 / 265 (0.00%)
         occurrences all number
    7
    0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    373 / 533 (69.98%)
    141 / 265 (53.21%)
         occurrences all number
    373
    141
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    2 / 533 (0.38%)
    1 / 265 (0.38%)
         occurrences all number
    2
    1
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    12 / 533 (2.25%)
    4 / 265 (1.51%)
         occurrences all number
    12
    4
    Respiratory, thoracic and mediastinal disorders
    Respiritory, thoracic and mediastinal disorders
         subjects affected / exposed
    142 / 533 (26.64%)
    80 / 265 (30.19%)
         occurrences all number
    142
    80
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    50 / 533 (9.38%)
    42 / 265 (15.85%)
         occurrences all number
    50
    42
    Investigations
    Investigations
         subjects affected / exposed
    291 / 533 (54.60%)
    92 / 265 (34.72%)
         occurrences all number
    291
    92
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    26 / 533 (4.88%)
    7 / 265 (2.64%)
         occurrences all number
    26
    7
    Congenital, familial and genetic disorders
    Congenital, familial and genetic disorders
         subjects affected / exposed
    0 / 533 (0.00%)
    1 / 265 (0.38%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    21 / 533 (3.94%)
    12 / 265 (4.53%)
         occurrences all number
    21
    12
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    113 / 533 (21.20%)
    52 / 265 (19.62%)
         occurrences all number
    113
    52
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    304 / 533 (57.04%)
    29 / 265 (10.94%)
         occurrences all number
    304
    29
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    11 / 533 (2.06%)
    1 / 265 (0.38%)
         occurrences all number
    11
    1
    Eye disorders
    Eye disorders
         subjects affected / exposed
    18 / 533 (3.38%)
    5 / 265 (1.89%)
         occurrences all number
    18
    5
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    413 / 533 (77.49%)
    161 / 265 (60.75%)
         occurrences all number
    413
    161
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    55 / 533 (10.32%)
    28 / 265 (10.57%)
         occurrences all number
    55
    28
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    127 / 533 (23.83%)
    48 / 265 (18.11%)
         occurrences all number
    127
    48
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    70 / 533 (13.13%)
    30 / 265 (11.32%)
         occurrences all number
    70
    30
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    0 / 533 (0.00%)
    1 / 265 (0.38%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    117 / 533 (21.95%)
    55 / 265 (20.75%)
         occurrences all number
    117
    55
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    144 / 533 (27.02%)
    42 / 265 (15.85%)
         occurrences all number
    144
    42
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    248 / 533 (46.53%)
    104 / 265 (39.25%)
         occurrences all number
    248
    104

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Mar 2012
    • v1.0 - ROW, v2.0 Japan • Names of Sponsor’s Medical Monitors updated/added. • Clarification of the following: stratification variables; duration of survival follow-up; duration of baseline period; definition of end of treatment; definition of non-target lesions; definition of best overall response; definition of population evaluable for tumour response; and size of population for PK analysis. • Modification of Inclusion Criterion #8 to specify that verification of adequate organ function should be based on laboratory data obtained within 7 days prior to Day 1 of Cycle 1; and specified an exception to requirement of total serum bilirubin of ≤1.5 mg/dL (ie, except for Grade 1 hyperbilirubinaemia due solely to a medical diagnosis of Gilbert’s syndrome). • Addition of Exclusion Criterion #1j for patients with autoimmune disorders and/or requiring immunosuppressive therapy • Specified requirement for fractionation (direct/indirect) in case of elevation of total bilirubin.
    22 Apr 2012
    • v2.0 ROW, v3.0 Japan • Addition of mobile phone number of Medical Monitor for Japan. • Removal of carbon dioxide from required serum chemistry tests.
    13 Nov 2012
    • v3.0 ROW, v4.0 Japan, v4.0 Sweden, v5.0 Germany • Addition of generic name and updated chemical name for TPI • Clarification of timing of end of treatment assessments of ECG, urinalysis, and tumour measurements. • Modification of Exclusion Criterion #4 regarding unresolved toxicities associated with prior therapies. • Addition of a caution statement when using human thymidine analogues concomitantly with TAS-102. • Clarification of procedures to be followed in case of need to break the study blind.

    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.
    NA
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