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    Clinical Trial Results:
    A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects with Advanced Cancer

    Summary
    EudraCT number
    		 2015-004486-86
    Trial protocol
    		 GB  
    Global end of trial date
    28 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Oct 2021
    First version publication date
    08 Oct 2021
    Other versions
    Summary report(s)
    		 SRA737-01 CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    SRA737-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02797964
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sierra Oncology, Inc.
    Sponsor organisation address
    1820 Gateway Drive, San Mateo, United States,
    Public contact
    Clinical Trial Information, Sierra Oncology, Inc., +1 604558-6575, pnadolny@sierraoncology.com
    Scientific contact
    Clinical Trial Information, Sierra Oncology, Inc., adye@sierraoncology.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
    19 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) To establish the safety profile of SRA737. 2) To determine the maximum tolerated dose with 1 or more schedules of administrations of SRA737. 3) To propose a recommended Phase 2 dose and schedule of SRA737. 4) To evaluate the preliminary efficacy of SRA737 including efficacy in prospectively-selected genetically-defined subjects enrolled into indication-specific expansion cohorts.
    Protection of trial subjects
    Ethics review and approval, informed consent, cohort review prior to enrolling new dose level cohort, dose modification in the event of toxicity, safety assessments including adverse events, clinical laboratory assessments, electrocardiograms, echocardiograms, vital signs, and physical examinations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jul 2016
    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
    United Kingdom: 107
    Worldwide total number of subjects
    107
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    56
    From 65 to 84 years
    50
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening evaluations were carried out within 28 days before the first dose of SRA737, with the exception of pre-existing results for HPV status and tumor profiling from archival tumor tissue, which may have been carried out during pre-screening without time restriction.

    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
    		 Colorectal Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SRA737
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SRA737 was supplied as its citrate salt dispersed in a polyethylene glycol (PEG) semi solid formulation in capsules for oral administration, daily in 28 day cycles.

    Arm title
    		 High Grade Serous Ovarian Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SRA737
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SRA737 was supplied as its citrate salt dispersed in a polyethylene glycol (PEG) semi solid formulation in capsules for oral administration, daily in 28 day cycles.

    Arm title
    		 Non Small Cell Lung Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SRA737
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SRA737 was supplied as its citrate salt dispersed in a polyethylene glycol (PEG) semi solid formulation in capsules for oral administration, daily in 28 day cycles.

    Arm title
    		 Metastatic Castration Resistant Prostate Cancer
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SRA737
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SRA737 was supplied as its citrate salt dispersed in a polyethylene glycol (PEG) semi solid formulation in capsules for oral administration, daily in 28 day cycles.

    Arm title
    		 Head and Neck Squamous Cell Carcinoma
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SRA737
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SRA737 was supplied as its citrate salt dispersed in a polyethylene glycol (PEG) semi solid formulation in capsules for oral administration, daily in 28 day cycles.

    Arm title
    		 Other Tumor Type
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SRA737
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SRA737 was supplied as its citrate salt dispersed in a polyethylene glycol (PEG) semi solid formulation in capsules for oral administration, daily in 28 day cycles.

    Number of subjects in period 1
    		Colorectal Cancer High Grade Serous Ovarian Cancer Non Small Cell Lung Cancer Metastatic Castration Resistant Prostate Cancer Head and Neck Squamous Cell Carcinoma Other Tumor Type
    Started
    32
    37
    10
    16
    4
    8
    Completed
    32
    37
    10
    16
    4
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Colorectal Cancer
    Reporting group description
    		 -

    Reporting group title
    High Grade Serous Ovarian Cancer
    Reporting group description
    		 -

    Reporting group title
    Non Small Cell Lung Cancer
    Reporting group description
    		 -

    Reporting group title
    Metastatic Castration Resistant Prostate Cancer
    Reporting group description
    		 -

    Reporting group title
    Head and Neck Squamous Cell Carcinoma
    Reporting group description
    		 -

    Reporting group title
    Other Tumor Type
    Reporting group description
    		 -

    Reporting group values
    		 Colorectal Cancer High Grade Serous Ovarian Cancer Non Small Cell Lung Cancer Metastatic Castration Resistant Prostate Cancer Head and Neck Squamous Cell Carcinoma Other Tumor Type Total
    Number of subjects
    		 32 37 10 16 4 8 107
    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
        arithmetic mean (standard deviation)
    		 61.3 ( 12.05 ) 60.6 ( 9.81 ) 64.4 ( 9.11 ) 68.3 ( 6.76 ) 63.0 ( 6.06 ) 58.4 ( 6.46 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 37 6 0 0 4 61
        Male
    		 18 0 4 16 4 4 46
    Subject analysis sets

    Subject analysis set title
    Response Evaluable Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Response Evaluable Population (REP) included all enrolled subjects who satisfy all of the following conditions: 1. Measurable disease and assessment at baseline 2. Received at least 75% of 1 cycle of study medication, based on dosing information 3. At least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death

    Subject analysis set title
    Safety Evaluable Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects received at least one dose of SRA737 are included in the Safety Evaluable Population.

    Subject analysis sets values
    		 Response Evaluable Population Safety Evaluable Population
    Number of subjects
    81
    107
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.8 ( 9.70 )
    62.2 ( 10.04 )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Colorectal Cancer
    Reporting group description
    		 -

    Reporting group title
    High Grade Serous Ovarian Cancer
    Reporting group description
    		 -

    Reporting group title
    Non Small Cell Lung Cancer
    Reporting group description
    		 -

    Reporting group title
    Metastatic Castration Resistant Prostate Cancer
    Reporting group description
    		 -

    Reporting group title
    Head and Neck Squamous Cell Carcinoma
    Reporting group description
    		 -

    Reporting group title
    Other Tumor Type
    Reporting group description
    		 -

    Subject analysis set title
    Response Evaluable Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Response Evaluable Population (REP) included all enrolled subjects who satisfy all of the following conditions: 1. Measurable disease and assessment at baseline 2. Received at least 75% of 1 cycle of study medication, based on dosing information 3. At least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death

    Subject analysis set title
    Safety Evaluable Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects received at least one dose of SRA737 are included in the Safety Evaluable Population.

    Primary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR) [1] [2]
    End point description
    The disease control rate (DCR) was defined as the number of subjects achieving complete response (CR) + partial response (PR) + stable disease (SD) per RECIST 1.1 criteria. Since no subjects achieved CR or PR in this study, the DCR represents the proportion of subjects in each group who achieved SD.
    End point type
    Primary
    End point timeframe
    Radiographic tumor assessments were performed every 2 cycles of therapy.
    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: The DCR was calculated for each tumor-type subgroup.
    [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: DCR was analyzed for each tumor-type subgroup.
    End point values
    		 Colorectal Cancer High Grade Serous Ovarian Cancer Non Small Cell Lung Cancer Metastatic Castration Resistant Prostate Cancer Head and Neck Squamous Cell Carcinoma Response Evaluable Population
    Number of subjects analysed
    25
    26
    8
    13
    4
    81
    Units: Subjects
    8
    11
    3
    8
    3
    34
    No statistical analyses for this end point

    Primary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP) [3] [4]
    End point description
    Time to progression (TTP) was defined as the time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1, or if the subject did not experience disease progression, to the last imaging assessment. TTP was analyzed using the K–M method. The median value is reported without a measure of dispersion since the 95% CI could not be estimated due to insufficient number of participants with events.
    End point type
    Primary
    End point timeframe
    Radiographic tumor assessments were performed every 2 cycles of therapy. Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy.
    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: TTP was analyzed using the Kaplan-Meier method. The output included count and percentage of subjects with death or censored outcome. Median OS and 95% CI based on log-log transformation were provided for tumor-type subgroups.
    [4] - 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: TTP was analyzed for each tumor-type subgroup.
    End point values
    		 Colorectal Cancer High Grade Serous Ovarian Cancer Non Small Cell Lung Cancer Metastatic Castration Resistant Prostate Cancer Head and Neck Squamous Cell Carcinoma Response Evaluable Population
    Number of subjects analysed
    24
    26
    8
    13
    4
    81
    Units: Months
        number (not applicable)
    1.87
    1.94
    1.87
    3.02
    3.78
    1.87
    No statistical analyses for this end point

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS) [5] [6]
    End point description
    Progression free survival (PFS) was defined as time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1 or death, whichever happened first. PFS was analyzed using the K–M method. The median value is reported without a measure of dispersion since the 95% CI could not be estimated due to insufficient number of participants with events.
    End point type
    Primary
    End point timeframe
    Radiographic tumor assessments were performed every 2 cycles of therapy. Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy.
    Notes
    [5] - 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: PFS was analyzed using the Kaplan-Meier method. The output included count and percentage of subjects with death or censored outcome. Median OS and 95% CI based on log-log transformation were provided for tumor-type subgroups.
    [6] - 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: PFS was analyzed for each tumor-type subgroup.
    End point values
    		 Colorectal Cancer High Grade Serous Ovarian Cancer Non Small Cell Lung Cancer Metastatic Castration Resistant Prostate Cancer Head and Neck Squamous Cell Carcinoma Response Evaluable Population
    Number of subjects analysed
    24
    26
    8
    13
    4
    81
    Units: Months
        number (not applicable)
    1.84
    1.94
    1.76
    3.02
    3.55
    1.87
    No statistical analyses for this end point

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [7] [8]
    End point description
    Overall survival (OS) was defined as time from Cycle 1 Day 1 to the date of death (or date last known to be alive). OS was analyzed using the K–M method. The median value is reported for 3 tumor type subgroups and without a measure of dispersion since the median survival and/or 95% CI could not be estimated in some cases due to insufficient number of participants with events.
    End point type
    Primary
    End point timeframe
    Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy.
    Notes
    [7] - 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: OS was analyzed using the Kaplan-Meier method. The output included count and percentage of subjects with death or censored outcome. Median OS and 95% CI based on log-log transformation were provided for tumor-type subgroups.
    [8] - 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: OS was analyzed for each tumor-type subgroup.
    End point values
    		 Colorectal Cancer High Grade Serous Ovarian Cancer Non Small Cell Lung Cancer Response Evaluable Population
    Number of subjects analysed
    24
    26
    8
    81
    Units: Months
        number (not applicable)
    5.72
    6.93
    6.08
    6.93
    No statistical analyses for this end point

    Primary: Maximum Tolerated Dose (MTD)

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    End point title
    		 Maximum Tolerated Dose (MTD) [9]
    End point description
    End point type
    Primary
    End point timeframe
    Cycle 1 (28 days) in the Dose Escalation Phase
    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: The MTD of SRA737 was defined as the highest dose at which ≤ 33% of subjects have a DLT in a cohort of up to 6 subjects during the dose escalation phase.
    End point values
    		 Safety Evaluable Population
    Number of subjects analysed
    18 [10]
    Units: mg, QD
        number (not applicable)
    1000
    Notes
    [10] - In the Dose Escalation Phase, a total of 18 subjects were enrolled into 8 daily dose levels
    No statistical analyses for this end point

    Primary: Recommended Phase 2 Dose (RP2D)

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    End point title
    		 Recommended Phase 2 Dose (RP2D) [11]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 30 days after last dose of SRA737
    Notes
    [11] - 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: The RP2D of SRA737 was defined by the Cohort Review Committee at the end of the study and took all clinically relevant toxicity, PK and PDn data into account.
    End point values
    		 Safety Evaluable Population
    Number of subjects analysed
    107
    Units: mg QD
        number (not applicable)
    800
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) were reported until the safety Follow up (SFU) visit, 30 days after the last dose of SRA737 or prior to the initiation of a new anticancer treatment, whichever came first.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Safety Evaluable Population
    Reporting group description
    		 The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

    Serious adverse events
    		 Safety Evaluable Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 107 (44.86%)
         number of deaths (all causes)
    18
         number of deaths resulting from adverse events
    8
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    10 / 107 (9.35%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 7
    Pyrexia
         subjects affected / exposed
    4 / 107 (3.74%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Biopsy liver
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Vomiting
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    4 / 107 (3.74%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Evaluable Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 107 (99.07%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    54 / 107 (50.47%)
         occurrences all number
    85
    Pyrexia
         subjects affected / exposed
    13 / 107 (12.15%)
         occurrences all number
    13
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    19 / 107 (17.76%)
         occurrences all number
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 107 (7.48%)
         occurrences all number
    9
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    18 / 107 (16.82%)
         occurrences all number
    22
    Aspartate aminotransferase increased
         subjects affected / exposed
    14 / 107 (13.08%)
         occurrences all number
    21
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 107 (10.28%)
         occurrences all number
    19
    Lymphocyte count decreased
         subjects affected / exposed
    10 / 107 (9.35%)
         occurrences all number
    32
    Blood creatinine increased
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    9
    Electrocardiogram QT prolonged
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    10
    White blood cell count decreased
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    24
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Platelet count decreased
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    14
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 107 (12.15%)
         occurrences all number
    13
    Lethargy
         subjects affected / exposed
    9 / 107 (8.41%)
         occurrences all number
    14
    Dysgeusia
         subjects affected / exposed
    8 / 107 (7.48%)
         occurrences all number
    9
    Dizziness
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    25 / 107 (23.36%)
         occurrences all number
    48
    Neutropenia
         subjects affected / exposed
    16 / 107 (14.95%)
         occurrences all number
    34
    Thrombocytopenia
         subjects affected / exposed
    9 / 107 (8.41%)
         occurrences all number
    16
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    74 / 107 (69.16%)
         occurrences all number
    131
    Nausea
         subjects affected / exposed
    72 / 107 (67.29%)
         occurrences all number
    125
    Vomiting
         subjects affected / exposed
    56 / 107 (52.34%)
         occurrences all number
    94
    Constipation
         subjects affected / exposed
    19 / 107 (17.76%)
         occurrences all number
    26
    Abdominal pain
         subjects affected / exposed
    17 / 107 (15.89%)
         occurrences all number
    23
    Abdominal distension
         subjects affected / exposed
    11 / 107 (10.28%)
         occurrences all number
    17
    Dyspepsia
         subjects affected / exposed
    10 / 107 (9.35%)
         occurrences all number
    11
    Abdominal pain upper
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    7
    Ascites
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    11 / 107 (10.28%)
         occurrences all number
    11
    Rash
         subjects affected / exposed
    11 / 107 (10.28%)
         occurrences all number
    18
    Rash maculo-papular
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    8
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    12 / 107 (11.21%)
         occurrences all number
    15
    Oral candidiasis
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    7
    Cellulitis
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    8
    Lower respiratory tract infection
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 107 (24.30%)
         occurrences all number
    36
    Hypokalaemia
         subjects affected / exposed
    8 / 107 (7.48%)
         occurrences all number
    9
    Hypomagnesaemia
         subjects affected / exposed
    8 / 107 (7.48%)
         occurrences all number
    9
    Hyponatraemia
         subjects affected / exposed
    8 / 107 (7.48%)
         occurrences all number
    21

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2016
    Addition of QTc exclusion criteria and amendments to contraceptive advice (prior to enrolment of subjects).
    05 Dec 2016
    The study was amended to assess preliminary efficacy in all subjects including 40 additional biomarker selected and indication specific subjects with tumors anticipated to be sensitive to inhibition of Chk1. Enrollment to Dose Escalation Phase and Cohort Expansion Phase was allowed to begin in parallel, prior to completion of the Dose Escalation Phase. Requirement was added for tumor tissue (archival or fresh biopsy) for tumor profiling.
    10 Feb 2017
    Clarification of the frequency of bone scans for subjects with prostate cancer. In addition, a clarification was provided for the microsatellite instability (MSI) testing criteria and ECG data collection.
    18 May 2017
    Removal of the maximum number of prior regimens criteria for subjects participating in the Cohort Expansion Phase and circulating tumor cells requirement for metastatic castration resistant prostate cancer (mCRPC) subjects.
    14 Sep 2017
    Increase the size of each indication specific cohort in the Cohort Expansion Phase from 8 to 20. The title of the study was changed from “Phase 1” to “Phase 1/2” to appropriately describe the current study design. The cohort enrolling subjects with squamous cell carcinoma of the head and neck (HNSCC) was amended to also include squamous cell carcinoma of the anus (SCCA). The schedule of assessments for PK sampling, central ECGs, and troponin were adjusted to improve coverage of relevant time points and reduce burden on subjects. Addition that the sponsor may choose to refine or select particular genomic profile requirements in expansion cohorts based on observations of tumor response and clinical benefit in the ongoing study and/or other emerging clinical and nonclinical data.
    10 Jan 2018
    Added a specific expansion cohort of approximately 20 subjects with high grade serous ovarian cancer (HGSOC) with CCNE1 gene amplification. This is in addition to the expansion cohort of subjects with HGSOC.
    27 Jun 2018
    The requirements for enrollment in the 2 expansion cohorts for subjects with HGSOC were revised. One cohort will enroll subjects with platinum resistant or refractory disease who are BRCA1 or BRCA2 mutant and the second will include subjects with platinum resistant or refractory disease who are BRCA1 and BRCA2 wild type. The size of both HGSOC cohorts was increased from the previous 20 subjects; the BRCA mutant cohort to 30 subjects and the BRCA wild type cohort to 35 subjects.

    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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