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    Clinical Trial Results:
    AN OPEN-LABEL, MULTICENTER PHASE 1/2 STUDY OF SURUFATINIB IN COMBINATION WITH GEMCITABINE IN PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS

    Summary
    EudraCT number
    		 2021-003602-41
    Trial protocol
    		 IT   DE   ES   DK  
    Global end of trial date
    25 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Nov 2023
    First version publication date
    11 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2020-012-GLOB2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05093322
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HUTCHMED Limited
    Sponsor organisation address
    Building 4, 720 Cailun Road China (Shanghai) Pilot Free Trade Zone, Shanghai, China, 201203
    Public contact
    Mark Woods, HUTCHMED Limited, 0044 7467 414995, markw@hutch-med.com
    Scientific contact
    Marjo Hahka-Kemppinen, HUTCHMED Limited, +358 40 842 5802, marjoh@hutch-med.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002750-PIP01-19
    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
    25 Apr 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the maximum tolerated dose and/or recommended Phase 2 dose of surufatinib, and to evaluate the safety and tolerability of surufatinib in combination with gemcitabine in pediatric patients with recurrent or refractory solid tumors or lymphoma.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, consensus, and ethical principles derived from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonization Good Clinical Practice guidelines, and applicable regulations and guidelines governing clinical study conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Mar 2022
    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: 4
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    13
    EEA total number of subjects
    4
    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)
    5
    Adolescents (12-17 years)
    7
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase 1/2 open-label study was conducted in pediatric, adolescent, and young adult patients with recurrent or refractory solid tumors at 8 study sites.

    Pre-assignment
    Screening details
    		 This study consisted of a screening period (up to 28 days), followed by a treatment phase (Cycle 1: 35 days and subsequent cycles: 21 days) and safety follow-up period (up to 30 days). A total of 13 patients were enrolled in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose Level 1
    Arm description
    		 Participants received surufatinib 120 milligram/meter square (mg/m^2) oral capsule once daily (QD) as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine 1000 mg/m^2/dose intravenous (IV) infusion on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until progressive disease (PD), unacceptable toxicity, or death; whichever came first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 120 mg/m^2 oral capsule was administered QD in all treatment cycles until PD, unacceptable toxicity, or death; whichever came first.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2/dose IV infusion was administered over a period of 90 minutes on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until PD, unacceptable toxicity, or death; whichever came first.

    Arm title
    		 Dose Level 2
    Arm description
    		 Participants received surufatinib 160 mg/m^2 oral capsule QD as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine 1000 mg/m^2/dose IV infusion on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until PD, unacceptable toxicity, or death; whichever came first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 160 mg/m^2 oral capsule was administered QD in all treatment cycles until PD, unacceptable toxicity, or death; whichever came first.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2/dose IV infusion was administered over a period of 90 minutes on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until PD, unacceptable toxicity, or death; whichever came first.

    Number of subjects in period 1
    		Dose Level 1 Dose Level 2
    Started
    10
    3
    Completed
    0
    0
    Not completed
    10
    3
         Death
    6
    2
         Unspecified
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose Level 1
    Reporting group description
    		 Participants received surufatinib 120 milligram/meter square (mg/m^2) oral capsule once daily (QD) as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine 1000 mg/m^2/dose intravenous (IV) infusion on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until progressive disease (PD), unacceptable toxicity, or death; whichever came first.

    Reporting group title
    Dose Level 2
    Reporting group description
    		 Participants received surufatinib 160 mg/m^2 oral capsule QD as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine 1000 mg/m^2/dose IV infusion on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until PD, unacceptable toxicity, or death; whichever came first.

    Reporting group values
    		 Dose Level 1 Dose Level 2 Total
    Number of subjects
    		 10 3 13
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.8 ± 5.55 13.7 ± 2.89 -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 6 2 8
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 2 3
        Not Hispanic or Latino
    		 9 1 10
    Race
    Units: Subjects
        Black or African American
    		 2 0 2
        White
    		 7 2 9
        Not Reported
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Dose Level 1
    Reporting group description
    		 Participants received surufatinib 120 milligram/meter square (mg/m^2) oral capsule once daily (QD) as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine 1000 mg/m^2/dose intravenous (IV) infusion on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until progressive disease (PD), unacceptable toxicity, or death; whichever came first.

    Reporting group title
    Dose Level 2
    Reporting group description
    		 Participants received surufatinib 160 mg/m^2 oral capsule QD as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine 1000 mg/m^2/dose IV infusion on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until PD, unacceptable toxicity, or death; whichever came first.

    Primary: Number of Patients With Dose-Limiting Toxicities (DLT)

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    End point title
    		 Number of Patients With Dose-Limiting Toxicities (DLT) [1]
    End point description
    A DLT was defined as any of following events that were attributable to study treatment (at least possibly related). Adverse events (AE) were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. • Any Grade 3 or greater nonhematological toxicity. • Grade 3 liver enzyme elevation. • Cases of Hy’s law. • Any Grade 2 nonhematological toxicity that persisted for >= 7 days. • Any Grade 4 hypertension. • Grade 3 corrected QT interval prolongation > 500 millisecond. • Grade 4 thrombocytopenia for > 7 days. • Grade 3 thrombocytopenia with clinically significant bleeding. • Grade 4 neutropenia that lasted for > 7 days. • Myelosuppression that caused a delay of > 7 days in the start of Cycle 2. DLT evaluable set included all patients enrolled in dose escalation phase of study who received at least 80% of surufatinib dose and both doses of gemcitabine during DLT evaluation period or who discontinued treatment due to a DLT.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug (Day 1) up to Day 35 of Cycle 1.
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    8
    3
    Units: patients
    0
    2
    No statistical analyses for this end point

    Primary: Number of Patients With Treatment Emergent Adverse Events (TEAEs) by Severity

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    End point title
    		 Number of Patients With Treatment Emergent Adverse Events (TEAEs) by Severity [2]
    End point description
    The AEs were graded using the NCI CTCAE version 5.0. The CTCAE displays Grades 1 through 5 where, Grade 1= mild, Grade 2= moderate, Grade 3= Severe, Grade 4= life-threatening consequences and Grade 5= death. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks
    Notes
    [2] - 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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    10
    3
    Units: patients
        Grade 1
    0
    0
        Grade 2
    1
    1
        Grade 3
    4
    2
        Grade 4
    3
    0
        Grade 5
    2
    0
    No statistical analyses for this end point

    Primary: Number of Patients with Clinically Significant Physical Examination Abnormalities

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    End point title
    		 Number of Patients with Clinically Significant Physical Examination Abnormalities [3]
    End point description
    Physical examination included patient height, weight, and general condition, as well as an examination of the head, heart, chest (including the lungs), abdomen, extremities, skin, lymph nodes, nervous system, and additional areas/systems as clinically indicated. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    10
    3
    Units: patients
    6
    1
    No statistical analyses for this end point

    Primary: Number of Patients with Clinically Significant Vital Signs Abnormalities

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    End point title
    		 Number of Patients with Clinically Significant Vital Signs Abnormalities [4]
    End point description
    Vital signs included systolic blood pressure (BP), diastolic BP, heart rate, height, weight, respiratory rate, and body temperature. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    10
    3
    Units: patients
    0
    0
    No statistical analyses for this end point

    Primary: Number of Patients with Clinically Significant Laboratory Abnormalities

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    End point title
    		 Number of Patients with Clinically Significant Laboratory Abnormalities [5]
    End point description
    Blood and urine samples were collected to determine the clinical chemistry, hematology, and urinalysis laboratory abnormalities. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    10
    3
    Units: patients
    0
    1
    No statistical analyses for this end point

    Primary: Number of Patients with Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities

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    End point title
    		 Number of Patients with Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities [6]
    End point description
    Standard 12-lead ECGs were performed after the patient rested for 5 to 10 minutes. The ECG parameters included heart rate, PR interval, RR interval, QT interval, QTcF, and QRS interval from the triplicate 12-lead ECG. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks
    Notes
    [6] - 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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    10
    3
    Units: patients
    1
    0
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    The ORR was defined as the percentage of patients with a best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST version 1.1 progression, death, or withdrawal of consent. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    10
    3
    Units: percentage of patients
        number (confidence interval 95%)
    0 (0.0 to 30.8)
    0 (0.0 to 70.8)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    The DCR was defined as the percentage of patients with a BOR of CR, PR, or stable disease as determined by the investigator using RECIST version 1.1. Stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    10
    3
    Units: percentage of patients
        number (confidence interval 95%)
    20.0 (2.5 to 55.6)
    0 (0.0 to 70.8)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    The TTR was defined as the time from the start of study treatment until the date of the first occurrence of PR or CR for responders only. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [7] - No responders in this study.
    [8] - No responders in this study.
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    The DoR was defined as the time from the first occurrence of PR or CR whichever came first, until disease progression or death. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - No responders in this study.
    [10] - No responders in this study.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    The PFS was defined as the time from the start of study treatment until the first radiographic documentation of objective progression as assessed by the investigator using RECIST version 1.1 or death from any cause. The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine. Here, 99999= The upper limit of 95% confidence interval could not be estimated either due to insufficient number of PFS events or not sufficient follow-up time at the time of the analysis.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    10
    3
    Units: months
        median (confidence interval 95%)
    1.8 (0.7 to 99999)
    1.5 (1.1 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Patients Who Performed Taste and Palatability Survey of Surufatinib

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    End point title
    		 Number of Patients Who Performed Taste and Palatability Survey of Surufatinib
    End point description
    The taste and palatability survey was assessed in patients who had taken surufatinib oral suspension. For pediatric patients, their parents completed the taste and palatability survey. Data for the evaluation of taste of surufatinib oral suspension was summarized on a scale of 1 (very bad) through 5 (very nice). The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    End point type
    Secondary
    End point timeframe
    Days 1 and 8 of Cycle 1
    End point values
    		 Dose Level 1 Dose Level 2
    Number of subjects analysed
    2
    0 [11]
    Units: patients
    number (not applicable)
        Cycle 1 Day 1: Very Nice
    0
        Cycle 1 Day 1: Nice
    1
        Cycle 1 Day 1: Not Nice, not Bad
    0
        Cycle 1 Day 1: Bad
    1
        Cycle 1 Day 1: Very Bad
    0
        Cycle 1 Day 8: Very Nice
    0
        Cycle 1 Day 8: Nice
    1
        Cycle 1 Day 8: Not Nice, not Bad
    0
        Cycle 1 Day 8: Bad
    1
        Cycle 1 Day 8: Very Bad
    0
    Notes
    [11] - No patients performed the survey.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs (TEAEs) were collected from the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks
    Adverse event reporting additional description
    The Safety analysis set included all patients who received at least 1 dose of surufatinib or gemcitabine.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Dose Level 1
    Reporting group description
    		 Participants received surufatinib 120 mg/m^2 oral capsule QD as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine 1000 mg/m^2/dose IV infusion on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until PD, unacceptable toxicity, or death; whichever came first.

    Reporting group title
    Dose Level 2
    Reporting group description
    		 Participants received surufatinib 160 mg/m^2 oral capsule QD as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine 1000 mg/m^2/dose IV infusion on Days 15 and 22 of a 35-day Cycle 1 and on Days 1 and 8 of 21-day subsequent cycles until PD, unacceptable toxicity, or death; whichever came first.

    Serious adverse events
    		 Dose Level 1 Dose Level 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    6
    2
         number of deaths resulting from adverse events
    2
    0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Dose Level 1 Dose Level 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 3 (66.67%)
         occurrences all number
    3
    3
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    6
    2
    Fatigue
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 3 (66.67%)
         occurrences all number
    4
    2
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    3
    1
    Asthenia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Gait disturbance
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Injection site pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 3 (66.67%)
         occurrences all number
    5
    2
    Dyspnoea
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 3 (66.67%)
         occurrences all number
    2
    2
    Atelectasis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Epistaxis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Nasal congestion
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Acute respiratory failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Hallucination
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 3 (100.00%)
         occurrences all number
    3
    5
    Neutrophil count decreased
         subjects affected / exposed
    5 / 10 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    9
    1
    Platelet count decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
         occurrences all number
    11
    1
    White blood cell count decreased
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 3 (66.67%)
         occurrences all number
    6
    3
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 3 (66.67%)
         occurrences all number
    4
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    International normalised ratio increased
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    7
    4
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    Weight decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Skin abrasion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Wound dehiscence
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    4
    1
    Pericardial effusion
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
         occurrences all number
    3
    1
    Dizziness
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    Dysgeusia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 10 (60.00%)
    2 / 3 (66.67%)
         occurrences all number
    16
    5
    Eosinophilia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    4
    Leukopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Neutropenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Thrombocytosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    10
    3
    Vomiting
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    6
    3
    Diarrhoea
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
         occurrences all number
    8
    1
    Constipation
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    1
    Abdominal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    Dyspepsia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Oral pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia oral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Skin ulcer
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
         occurrences all number
    6
    3
    Haematuria
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 3 (66.67%)
         occurrences all number
    2
    3
    Muscle spasms
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pain in jaw
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Paronychia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Skin infection
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Bacteraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 3 (66.67%)
         occurrences all number
    5
    3
    Hypocalcaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
         occurrences all number
    7
    1
    Hyperglycaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    2
    Hyperphosphataemia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
         occurrences all number
    11
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    Hypomagnesaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2021
    • Updated patient age limits. • Updated required number of patients for the Part 1 Pharmacokinetic (PK) expansion cohort. • Changed study duration to an estimated 36 months. • Updates to the schedule of PK sample collection. • Updates to the Schedule of Assessments table. • Revised inclusion criteria for reproductive potential. • Revised requirements for contraception. • Specified risks for gemcitabine. • Added a biomarker for evaluation.
    03 Mar 2022
    Administrative updates to update Sponsor’s name.
    24 Jan 2023
    • Added language to indicate that enrollment was halted as of 16 December 2022. Following approval of Amendment 3, patients who were still enrolled were deriving clinical benefit from treatment were allowed to continue to participate in the study. • Revised number of patients in study from “Up to 116 patients” to “Up to 36 patients.” • Updates to the efficacy endpoints.

    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.
    With the withdrawal of the Marketing Authorisation Application for surufatinib, the PIP was discontinued. As such, due to the small number of patients treated in this study, efficacy assessment was limited in this paediatric population.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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