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    Clinical Trial Results:
    A Phase 1/2 Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Gemcitabine plus Cisplatin or Gemcitabine Alone in Subjects with Advanced Cancer

    Summary
    EudraCT number
    		 2015-004467-36
    Trial protocol
    		 GB   ES  
    Global end of trial date
    08 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Nov 2021
    First version publication date
    25 Nov 2021
    Other versions
    Summary report(s)
    		 SRA737-02 CSR synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    SRA737-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02797977
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sierra Oncology, Inc.
    Sponsor organisation address
    1820 Gateway Drive Suite 110 , San Mateo, CA , United States, 94404
    Public contact
    Clinical Trial Information, Sierra Oncology, Inc., +1 604558-6575, sarbour@sierraoncology.com
    Scientific contact
    Clinical Trial Information, Sierra Oncology, Inc., +1 604558-6575, sarbour@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
    14 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) To establish the safety profile of SRA737 administered in combination with gemcitabine +/- cisplatin. 2) To determine the maximum tolerated dose (MTD) of SRA737 administered in combination with gemcitabine 3) To define a recommended Phase 2 dose (RP2D) of SRA737 in combination with gemcitabine
    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
    27 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
    Spain: 36
    Country: Number of subjects enrolled
    United Kingdom: 117
    Worldwide total number of subjects
    153
    EEA total number of subjects
    36
    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)
    96
    From 65 to 84 years
    57
    85 years and over
    0

    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
    No

    Arm title
    		 Stage 1 Dose Escalation
    Arm description
    		 Stage 1 Dose Escalation included subjects with solid tumors who were treated in 3 different dose level cohorts of SRA737 (mg) plus gemcitabine (mg/m2) plus cisplatin (mg/m2): 20|600|80 (3 subjects), 20|875|80 (5 subjects) and 20|1250|80 (2 subjects).
    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. in Stage 1, SRA737 was taken PO approximately 24 and 48 hours after the end of the Day 1 and Day 8 gemcitabine infusions (ie, on Days 2, 3, 9, and 10). In Stage 2, SRA737 was taken PO approximately 24 and 48 hours after the end of the Day 1, 8, and 15 gemcitabine infusions (ie, on Days 2, 3, 9, 10, 16, and 17).

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cisplatin was administered IV over 2 hours following gemcitabine on Day 1 of each 21-day cycle

    Arm title
    		 Stage 2 Dose Escalation
    Arm description
    		 Stage 2 included subjects with solid tumors who were treated in 14 different dose level cohorts of SRA737 plus gemcitabine with SRA737 doses ranging from 20 to 600 mg and gemcitabine doses ranging from 50 to 300 mg/m2. Two subjects who were concurrently enrolled in both Stage 2 Dose Escalation and Stage 2 Cohort Expansion groups.
    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.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Arm title
    		 Stage 2 Anogenital Cancer
    Arm description
    		 This subset of Cohort Expansion patients with anogenital cancer also includes 1 Dose Escalation subject with anogenital cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.
    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.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Arm title
    		 Stage 2 Cervical Cancer
    Arm description
    		 This subset of Cohort Expansion patients with cervical cancer includes 1 concurrently-enrolled Dose Escalation/Expansion subject with cervical cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.
    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.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Arm title
    		 Stage 2 HGSOC
    Arm description
    		 This is a subset of Cohort Expansion patients with high-grade serous ovarian cancer (HGSOC). The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.
    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.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Arm title
    		 Stage 2 Rectal Cancer
    Arm description
    		 This is a subset of Dose Escalation patients with rectal cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.
    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.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Arm title
    		 Stage 2 SCLC
    Arm description
    		 This is a subset of Cohort Expansion patients with small cell lung cancer (SCLC). The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.
    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.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Arm title
    		 Stage 2 STS
    Arm description
    		 This subset of Cohort Expansion patients with soft tissue sarcoma (STS) includes 1 concurrently-enrolled Dose Escalation/Expansion subject with STS. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.
    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.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Arm title
    		 Stage 2 Urothelial Cancer
    Arm description
    		 This is a subset of Cohort Expansion patients with urothelial cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.
    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.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Arm title
    		 Overall Stage 1 and Stage 2
    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. in Stage 1, SRA737 was taken PO approximately 24 and 48 hours after the end of the Day 1 and Day 8 gemcitabine infusions (ie, on Days 2, 3, 9, and 10). In Stage 2, SRA737 was taken PO approximately 24 and 48 hours after the end of the Day 1, 8, and 15 gemcitabine infusions (ie, on Days 2, 3, 9, 10, 16, and 17).

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    In Stage 1, gemcitabine was administered IV over 30 minutes on Days 1 and 8 of each 21-day cycle. In Stage 2, gemcitabine was administered IV over 30 minutes on Days 1, 8 and 15.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cisplatin was administered IV over 2 hours following gemcitabine on Day 1 of each 21-day cycle

    Number of subjects in period 1
    		Stage 1 Dose Escalation Stage 2 Dose Escalation Stage 2 Anogenital Cancer Stage 2 Cervical Cancer Stage 2 HGSOC Stage 2 Rectal Cancer Stage 2 SCLC Stage 2 STS Stage 2 Urothelial Cancer Overall Stage 1 and Stage 2
    Started
    10
    58
    15
    12
    24
    15
    22
    11
    4
    153
    Completed
    10
    58
    15
    12
    24
    15
    22
    11
    4
    153

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Stage 1 Dose Escalation
    Reporting group description
    		 Stage 1 Dose Escalation included subjects with solid tumors who were treated in 3 different dose level cohorts of SRA737 (mg) plus gemcitabine (mg/m2) plus cisplatin (mg/m2): 20|600|80 (3 subjects), 20|875|80 (5 subjects) and 20|1250|80 (2 subjects).

    Reporting group title
    Stage 2 Dose Escalation
    Reporting group description
    		 Stage 2 included subjects with solid tumors who were treated in 14 different dose level cohorts of SRA737 plus gemcitabine with SRA737 doses ranging from 20 to 600 mg and gemcitabine doses ranging from 50 to 300 mg/m2. Two subjects who were concurrently enrolled in both Stage 2 Dose Escalation and Stage 2 Cohort Expansion groups.

    Reporting group title
    Stage 2 Anogenital Cancer
    Reporting group description
    		 This subset of Cohort Expansion patients with anogenital cancer also includes 1 Dose Escalation subject with anogenital cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 Cervical Cancer
    Reporting group description
    		 This subset of Cohort Expansion patients with cervical cancer includes 1 concurrently-enrolled Dose Escalation/Expansion subject with cervical cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 HGSOC
    Reporting group description
    		 This is a subset of Cohort Expansion patients with high-grade serous ovarian cancer (HGSOC). The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 Rectal Cancer
    Reporting group description
    		 This is a subset of Dose Escalation patients with rectal cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 SCLC
    Reporting group description
    		 This is a subset of Cohort Expansion patients with small cell lung cancer (SCLC). The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 STS
    Reporting group description
    		 This subset of Cohort Expansion patients with soft tissue sarcoma (STS) includes 1 concurrently-enrolled Dose Escalation/Expansion subject with STS. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 Urothelial Cancer
    Reporting group description
    		 This is a subset of Cohort Expansion patients with urothelial cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Overall Stage 1 and Stage 2
    Reporting group description
    		 -

    Reporting group values
    		 Stage 1 Dose Escalation Stage 2 Dose Escalation Stage 2 Anogenital Cancer Stage 2 Cervical Cancer Stage 2 HGSOC Stage 2 Rectal Cancer Stage 2 SCLC Stage 2 STS Stage 2 Urothelial Cancer Overall Stage 1 and Stage 2 Total
    Number of subjects
    		 10 58 15 12 24 15 22 11 4 153
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.9 ± 12.63 61.0 ± 12.35 61.3 ± 8.60 49.4 ± 13.47 61.6 ± 8.76 61.8 ± 11.38 60.5 ± 8.91 57.5 ± 15.58 61.5 ± 7.85 59.9 ± 11.49 -
    Gender categorical
    Units: Subjects
        Female
    		 4 32 11 12 24 4 8 7 1 91 91
        Male
    		 6 26 4 0 0 11 14 4 3 62 62
    Subject analysis sets

    Subject analysis set title
    Safety Evaluable Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737, gemcitabine, or cisplatin. Subjects who received the single dose for PK evaluation but never received study treatment during the treatment phase are also included in this population.

    Subject analysis set title
    Response Evaluable Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Response Evaluable Population (REP) is the primary population used for efficacy analyses. The REP includes all enrolled subjects who satisfy all of the following conditions: 1. Have measurable disease assessment at baseline (for inclusion in Expansion Cohorts, subjects also need to meet the appropriate protocol criteria for genetically defined tumor) 2. Received at least 75% (Stage 1) or 83% (Stage 2) of SRA737 in Cycle 1 3. Have at least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death

    Subject analysis sets values
    		 Safety Evaluable Population Response Evaluable Population
    Number of subjects
    153
    105
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.9 ± 11.49
    ±
    Gender categorical
    Units: Subjects
        Female
    91
        Male
    62

    End points

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    End points reporting groups
    Reporting group title
    Stage 1 Dose Escalation
    Reporting group description
    		 Stage 1 Dose Escalation included subjects with solid tumors who were treated in 3 different dose level cohorts of SRA737 (mg) plus gemcitabine (mg/m2) plus cisplatin (mg/m2): 20|600|80 (3 subjects), 20|875|80 (5 subjects) and 20|1250|80 (2 subjects).

    Reporting group title
    Stage 2 Dose Escalation
    Reporting group description
    		 Stage 2 included subjects with solid tumors who were treated in 14 different dose level cohorts of SRA737 plus gemcitabine with SRA737 doses ranging from 20 to 600 mg and gemcitabine doses ranging from 50 to 300 mg/m2. Two subjects who were concurrently enrolled in both Stage 2 Dose Escalation and Stage 2 Cohort Expansion groups.

    Reporting group title
    Stage 2 Anogenital Cancer
    Reporting group description
    		 This subset of Cohort Expansion patients with anogenital cancer also includes 1 Dose Escalation subject with anogenital cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 Cervical Cancer
    Reporting group description
    		 This subset of Cohort Expansion patients with cervical cancer includes 1 concurrently-enrolled Dose Escalation/Expansion subject with cervical cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 HGSOC
    Reporting group description
    		 This is a subset of Cohort Expansion patients with high-grade serous ovarian cancer (HGSOC). The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 Rectal Cancer
    Reporting group description
    		 This is a subset of Dose Escalation patients with rectal cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 SCLC
    Reporting group description
    		 This is a subset of Cohort Expansion patients with small cell lung cancer (SCLC). The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 STS
    Reporting group description
    		 This subset of Cohort Expansion patients with soft tissue sarcoma (STS) includes 1 concurrently-enrolled Dose Escalation/Expansion subject with STS. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Stage 2 Urothelial Cancer
    Reporting group description
    		 This is a subset of Cohort Expansion patients with urothelial cancer. The majority of subjects in Stage 2 received doses of at least 500 mg SRA737 + 250 mg/m2 gemcitabine, which was ultimately determined to be the RP2D.

    Reporting group title
    Overall Stage 1 and Stage 2
    Reporting group description
    		 -

    Subject analysis set title
    Safety Evaluable Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737, gemcitabine, or cisplatin. Subjects who received the single dose for PK evaluation but never received study treatment during the treatment phase are also included in this population.

    Subject analysis set title
    Response Evaluable Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Response Evaluable Population (REP) is the primary population used for efficacy analyses. The REP includes all enrolled subjects who satisfy all of the following conditions: 1. Have measurable disease assessment at baseline (for inclusion in Expansion Cohorts, subjects also need to meet the appropriate protocol criteria for genetically defined tumor) 2. Received at least 75% (Stage 1) or 83% (Stage 2) of SRA737 in Cycle 1 3. Have at least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death

    Primary: Stage 2 Recommended Phase 2 Dose (RP2D)

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    End point title
    		 Stage 2 Recommended Phase 2 Dose (RP2D) [1] [2]
    End point description
    The recommended phase 2 dose (RP2D) of SRA737 combined with 250 mg/m2 gemcitabine.
    End point type
    Primary
    End point timeframe
    Stage 2 Dose Escalation Phase
    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 RP2D of SRA737 + LDG 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.
    [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: The RP2D of SRA737 + LDG 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
    		 Stage 2 Dose Escalation
    Number of subjects analysed
    58
    Units: mg
        number (not applicable)
    500
    No statistical analyses for this end point

    Secondary: Stage 2 Objective Response Rate (ORR)

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    End point title
    		 Stage 2 Objective Response Rate (ORR) [3]
    End point description
    The objective response rate (ORR) was defined as the number of subjects achieving CR + PR, including unconfirmed responses. Since no subjects achieved CR in this study, the ORR represents the proportion of subjects in each group who achieved PR.
    End point type
    Secondary
    End point timeframe
    Radiographic tumor assessments were performed every 2 cycles of therapy.
    Notes
    [3] - 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: ORR was analyzed for each tumor-type subgroup.
    End point values
    		 Stage 2 Anogenital Cancer Stage 2 Cervical Cancer Stage 2 HGSOC Stage 2 Rectal Cancer Stage 2 SCLC Stage 2 STS Stage 2 Urothelial Cancer
    Number of subjects analysed
    12
    6
    15
    10
    9
    9
    4
    Units: Patients
    3
    1
    1
    1
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Stage 2 Disease Control rate (DCR)

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    End point title
    		 Stage 2 Disease Control rate (DCR) [4]
    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 in this study, the DCR represents the proportion of subjects in each group who achieved SD or PR.
    End point type
    Secondary
    End point timeframe
    Radiographic tumor assessments were performed every 2 cycles of therapy.
    Notes
    [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: DCR was analyzed for each tumor-type subgroup.
    End point values
    		 Stage 2 Anogenital Cancer Stage 2 Cervical Cancer Stage 2 HGSOC Stage 2 Rectal Cancer Stage 2 SCLC Stage 2 STS Stage 2 Urothelial Cancer
    Number of subjects analysed
    12
    6
    15
    10
    9
    9
    4
    Units: Patients
    6
    4
    10
    6
    5
    5
    2
    No statistical analyses for this end point

    Secondary: Stage 2 Time to Progression (TTP)

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    End point title
    		 Stage 2 Time to Progression (TTP) [5]
    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
    Secondary
    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] - 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
    		 Stage 2 Anogenital Cancer Stage 2 Cervical Cancer Stage 2 HGSOC Stage 2 Rectal Cancer Stage 2 SCLC Stage 2 STS Stage 2 Urothelial Cancer
    Number of subjects analysed
    12
    6
    15
    10
    9
    9
    4
    Units: Months
        number (not applicable)
    3.6
    3.06
    3.48
    2.83
    2.99
    3.15
    6.51
    No statistical analyses for this end point

    Secondary: Stage 2 Progression Free Survival (PFS)

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    End point title
    		 Stage 2 Progression Free Survival (PFS) [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 for 6 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
    Secondary
    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
    [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
    		 Stage 2 Anogenital Cancer Stage 2 Cervical Cancer Stage 2 HGSOC Stage 2 Rectal Cancer Stage 2 SCLC Stage 2 STS
    Number of subjects analysed
    12
    6
    15
    10
    9
    9
    Units: Months
        number (not applicable)
    3.6
    3.06
    3.48
    2.83
    1.97
    3.15
    No statistical analyses for this end point

    Secondary: Stage 2 Overall Survival (OS)

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    End point title
    		 Stage 2 Overall Survival (OS) [7]
    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 1 tumor type subgroup and without a measure of dispersion since the median survival and/or 95% CI could not be estimated in other groups due to insufficient number of participants with events.
    End point type
    Secondary
    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] - 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
    		 Stage 2 SCLC
    Number of subjects analysed
    9
    Units: Months
        number (not applicable)
    3.81
    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 Population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 153 (31.37%)
         number of deaths (all causes)
    10
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Incisional hernia repair
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ureteral stent insertion
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 153 (11.11%)
         occurrences causally related to treatment / all
    8 / 19
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 6
    Oedema peripheral
         subjects affected / exposed
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 153 (3.92%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 153 (2.61%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal stoma output decreased
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Drug administration error
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dysaesthesia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    4 / 153 (2.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Ascites
         subjects affected / exposed
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lip swelling
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 153 (0.65%)
         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 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Swelling face
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 153 (3.27%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    5 / 153 (3.27%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    Bronchitis
         subjects affected / exposed
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 153 (69.28%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    41 / 153 (26.80%)
         occurrences all number
    92
    Aspartate aminotransferase increased
         subjects affected / exposed
    36 / 153 (23.53%)
         occurrences all number
    81
    Platelet count decreased
         subjects affected / exposed
    17 / 153 (11.11%)
         occurrences all number
    59
    Blood alkaline phosphatase increased
         subjects affected / exposed
    15 / 153 (9.80%)
         occurrences all number
    24
    Weight decreased
         subjects affected / exposed
    14 / 153 (9.15%)
         occurrences all number
    16
    White blood cell count decreased
         subjects affected / exposed
    11 / 153 (7.19%)
         occurrences all number
    23
    Blood creatinine increased
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    14
    Neutrophil count decreased
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    31
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 153 (13.73%)
         occurrences all number
    34
    Lethargy
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    17
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    80 / 153 (52.29%)
         occurrences all number
    156
    Pyrexia
         subjects affected / exposed
    44 / 153 (28.76%)
         occurrences all number
    94
    Influenza like illness
         subjects affected / exposed
    23 / 153 (15.03%)
         occurrences all number
    36
    Asthenia
         subjects affected / exposed
    16 / 153 (10.46%)
         occurrences all number
    39
    Oedema peripheral
         subjects affected / exposed
    12 / 153 (7.84%)
         occurrences all number
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    69 / 153 (45.10%)
         occurrences all number
    168
    Neutropenia
         subjects affected / exposed
    52 / 153 (33.99%)
         occurrences all number
    170
    Thrombocytopenia
         subjects affected / exposed
    41 / 153 (26.80%)
         occurrences all number
    100
    Lymphopenia
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    18
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    95 / 153 (62.09%)
         occurrences all number
    213
    Vomiting
         subjects affected / exposed
    84 / 153 (54.90%)
         occurrences all number
    193
    Diarrhoea
         subjects affected / exposed
    73 / 153 (47.71%)
         occurrences all number
    134
    Constipation
         subjects affected / exposed
    41 / 153 (26.80%)
         occurrences all number
    52
    Abdominal pain
         subjects affected / exposed
    21 / 153 (13.73%)
         occurrences all number
    33
    Dyspepsia
         subjects affected / exposed
    14 / 153 (9.15%)
         occurrences all number
    16
    Abdominal distension
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    10
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 153 (14.38%)
         occurrences all number
    25
    Dyspnoea
         subjects affected / exposed
    22 / 153 (14.38%)
         occurrences all number
    34
    Oropharyngeal pain
         subjects affected / exposed
    9 / 153 (5.88%)
         occurrences all number
    13
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    16 / 153 (10.46%)
         occurrences all number
    25
    Rash maculo-papular
         subjects affected / exposed
    13 / 153 (8.50%)
         occurrences all number
    23
    Pruritus
         subjects affected / exposed
    12 / 153 (7.84%)
         occurrences all number
    14
    Dry skin
         subjects affected / exposed
    9 / 153 (5.88%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    26 / 153 (16.99%)
         occurrences all number
    36
    Arthralgia
         subjects affected / exposed
    12 / 153 (7.84%)
         occurrences all number
    15
    Myalgia
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    12
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    21 / 153 (13.73%)
         occurrences all number
    32
    Lower respiratory tract infection
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    11
    Oral candidiasis
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    46 / 153 (30.07%)
         occurrences all number
    75
    Hypokalaemia
         subjects affected / exposed
    13 / 153 (8.50%)
         occurrences all number
    20
    Hypomagnesaemia
         subjects affected / exposed
    13 / 153 (8.50%)
         occurrences all number
    39
    Hyponatraemia
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    19
    Hypoalbuminaemia
         subjects affected / exposed
    9 / 153 (5.88%)
         occurrences all number
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2016
    Addition of hearing impairment and history of allergy to cisplatin or gemcitabine exclusion criteria and amendments to contraceptive advice (made at the request of the MHRA prior to approval)
    11 Oct 2016
    Sponsor change – All sponsor-specific details were updated to reflect the new sponsor Sierra Oncology, Inc. (formerly known as ProNAi Therapeutics, Inc.), including sponsor name, responsibilities, address, emergency contact details, and the protocol title and number.
    05 Dec 2016
    Protocol Amendment v4.0 included changes to the name of the sponsor and investigational product. In addition, the study was amended to focus on assessment of safety and preliminary efficacy in subjects with tumors anticipated to be sensitive to inhibition of Chk1 mainly in the SRA737+gemcitabine combination. Procedures were revised to ensure appropriate subject selection, in accordance with the new and retained study objectives. Protocol Amendment v4.0 removed the Stage 2 expansion cohort of 8 subjects with solid tumors of any type, but retained the Stage 2 expansion cohort of 6 subject with bladder or pancreatic cancer as defined in previous protocol versions.
    17 Feb 2017
    Protocol Amendment v5.0 updated the frequency of bone scans. In addition, clarifications were provided for IMP dosing, tumor biopsies, and laboratory assessments. Protocol Amendment Version 5.0 ended enrollment in Stage 1 of the protocol and initiated Stage 2.
    05 Oct 2017
    Protocol Amendment v6.0 changed the indications in the Stage 2 Cohort Expansion Phase (adding small cell lung cancer, cervical/anogenital cancer, and soft tissue sarcoma; retaining bladder/urothelial cancer; and removing pancreatic cancer) and increased the size of each cohort from 6-8 subjects to approximately 20 subjects. The genetic selection strategy was modified so that the sponsor could choose to refine or select particular genetic 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.

    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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