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    Clinical Trial Results:
    A Phase 1/2 Dose Escalation and Dose Expansion Study of ZN-c3 in Combination with Gemcitabine in Adult and Pediatric Subjects with Relapsed or Refractory Osteosarcoma

    Summary
    EudraCT number
    		 2021-000021-27
    Trial protocol
    		 DE   ES   NL  
    Global end of trial date
    07 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Oct 2024
    First version publication date
    09 Oct 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ZN-c3-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04833582
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    K-Group Beta
    Sponsor organisation address
    10275 Science Center Dr, Suite 200 , San Diego, United States, CA 92121
    Public contact
    VP Regulatory Affairs, K-Group Beta, +1 732-666-5002, risrani@zentalis.com
    Scientific contact
    VP Regulatory Affairs, K-Group Beta, +1 732-666-5002, risrani@zentalis.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
    02 Aug 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Mar 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase 1: - To investigate the safety and tolerability, including identification of the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ZN-c3 in combination with gemcitabine Phase 2: - To evaluate the clinical activity of WEE1 inhibition by ZN-c3 in combination with gemcitabine in subjects with relapsed/refractory osteosarcoma as assessed by the event-free survival (EFS) at 18 weeks, per response evaluation criteria in solid tumors RECIST Guideline version 1.1
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Conference on Harmonization Guidelines.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    20 Aug 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    31
    EEA total number of subjects
    6
    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)
    5
    Adults (18-64 years)
    25
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Phase I Subject screening occurred in France and the USA from August 2021 up to including June 2023. First patient signed consent on 20 August 2021 and last patient consented in USA on 26 June 2023. 10 sites were recruiting subjects. The study did not start in Spain and the Netherlands. It was decided not to conduct the phase 2 part of the study.

    Pre-assignment
    Screening details
    		 A total of 40 subject were screened after consent. One subject screen failed. 8 subjects were not enrolled in the study due to various reasons. (e.g. full cohort or at the decision of the investigator)

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ZN-c3 150mg QD + Gemcitabine 800mg/m2
    Arm description
    		 treatment cycles of 21 days with ZN-c3 150mg daily dose in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-c3
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose of ZN-c3 was 150 mg daily continuous dosing Subjects took ZN-c3 in 21-day cycles (± 3 days) with food.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The gemcitabine dose was 800 mg/m2 administered intravenously over 30 minutes (or per institutional standard) on Days 1 and 8 of a 21-day cycle

    Arm title
    		 ZN-c3 200mg QD + Gemcitabine 1000mg/m2
    Arm description
    		 treatment cycles of 21 days with ZN-c3 200mg daily dose in combination with gemcitabine 1000mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-c3
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose of ZN-c3 was 200 mg daily continuous dosing. Subjects took ZN-c3 in 21-day cycles (± 3 days) with food.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The gemcitabine dose was 1000 mg/m2 administered intravenously over 30 minutes (or per institutional standard) on Days 1 and 8 of a 21-day cycle

    Arm title
    		 ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2
    Arm description
    		 treatment cycles of 21 days with ZN-c3 150mg given intermittent 5 days on and 2 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-c3
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    treatment cycles of 21 days with ZN-c3 150mg given intermittent 5 days on and 2 days off.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The gemcitabine dose was 800 mg/m2 administered intravenously over 30 minutes (or per institutional standard) on Days 1 and 8 of a 21-day cycle

    Arm title
    		 ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2
    Arm description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off in combination with gemcitabine 675mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-c3
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The gemcitabine dose was 675 mg/m2 administered intravenously over 30 minutes (or per institutional standard) on Days 1 and 8 of a 21-day cycle

    Arm title
    		 ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2
    Arm description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The gemcitabine dose was 800 mg/m2 administered intravenously over 30 minutes (or per institutional standard) on Days 1 and 8 of a 21-day cycle

    Investigational medicinal product name
    ZN-c3
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off.

    Arm title
    		 ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2
    Arm description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 4 days on and 3 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-c3
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    treatment cycles of 21 days with ZN-c3 200mg given intermittent 4 days on and 3 days off.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The gemcitabine dose was 800 mg/m2 administered intravenously over 30 minutes (or per institutional standard) on Days 1 and 8 of a 21-day cycle

    Number of subjects in period 1
    		ZN-c3 150mg QD + Gemcitabine 800mg/m2 ZN-c3 200mg QD + Gemcitabine 1000mg/m2 ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2
    Started
    5
    9
    6
    6
    3
    2
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    5
    9
    6
    6
    3
    2
         Consent withdrawn by subject
    1
    1
    1
    1
    -
    -
         death
    1
    5
    4
    2
    1
    2
         study terminated by sponsor
    2
    1
    1
    3
    2
    -
         subject decision
    -
    2
    -
    -
    -
    -
         Lost to follow-up
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ZN-c3 150mg QD + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 150mg daily dose in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD + Gemcitabine 1000mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg daily dose in combination with gemcitabine 1000mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 150mg given intermittent 5 days on and 2 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off in combination with gemcitabine 675mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 4 days on and 3 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group values
    		 ZN-c3 150mg QD + Gemcitabine 800mg/m2 ZN-c3 200mg QD + Gemcitabine 1000mg/m2 ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2 Total
    Number of subjects
    		 5 9 6 6 3 2 31
    Age categorical
    Age of subjects per category
    Units: Subjects
        Adolescents (12-17 years)
    		 1 3 0 1 0 0 5
        Adults (18-64 years)
    		 4 5 6 5 3 2 25
        From 65-84 years
    		 0 1 0 0 0 0 1
    Gender categorical
    Units: Subjects
        Female
    		 2 4 1 4 3 1 15
        Male
    		 3 5 5 2 0 1 16
    race
    Units: Subjects
        white
    		 3 5 3 3 2 0 16
        asian
    		 1 1 0 1 0 0 3
        black or African American
    		 0 2 1 0 0 0 3
        other
    		 0 0 0 1 0 0 1
        not reported
    		 1 1 2 1 1 2 8
    Region of Enrollment
    Units: Subjects
        USA
    		 5 9 4 5 2 25
        France
    		 0 0 2 1 1 2 6
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set includes all subjects who received at least 1 dose of study drug (either ZN-c3 or gemcitabine). This analysis set was used for subject disposition, demographics and baseline characteristics, study drug exposure and dose modifications, and safety and clinical activity analyses (unless otherwise noted). The Full Analysis Set includes all 31 enrolled subjects.

    Subject analysis set title
    DLT-Evaluable Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    DLT-Evaluable Set: The DLT-Evaluable Set includes all subjects in the Full Analysis Set, excluding those for whom the cumulative dose of ZN-c3 was <75% in Cycle 1 for reasons other than AEs. This analysis set is applicable to Phase 1 only and was used to summarize DLTs. The DLT-Evaluable Set includes 29 subjects

    Subject analysis set title
    Response-Evaluable Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Response-Evaluable Set includes all subjects in the Full Analysis Set who had measurable disease at baseline and at least 1 postbaseline disease assessment

    Subject analysis sets values
    		 Full Analysis Set DLT-Evaluable Set Response-Evaluable Set
    Number of subjects
    31
    29
    28
    Age categorical
    Age of subjects per category
    Units: Subjects
        Adolescents (12-17 years)
    5
    5
    5
        Adults (18-64 years)
    25
    24
    23
        From 65-84 years
    1
    0
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    15
    14
    15
        Male
    16
    15
    13
    race
    Units: Subjects
        white
    16
    16
    16
        asian
    3
    3
    2
        black or African American
    3
    2
    2
        other
    1
    1
    1
        not reported
    8
    7
    7
    Region of Enrollment
    Units: Subjects
        USA
    25
        France
    6

    End points

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    End points reporting groups
    Reporting group title
    ZN-c3 150mg QD + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 150mg daily dose in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD + Gemcitabine 1000mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg daily dose in combination with gemcitabine 1000mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 150mg given intermittent 5 days on and 2 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off in combination with gemcitabine 675mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 4 days on and 3 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set includes all subjects who received at least 1 dose of study drug (either ZN-c3 or gemcitabine). This analysis set was used for subject disposition, demographics and baseline characteristics, study drug exposure and dose modifications, and safety and clinical activity analyses (unless otherwise noted). The Full Analysis Set includes all 31 enrolled subjects.

    Subject analysis set title
    DLT-Evaluable Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    DLT-Evaluable Set: The DLT-Evaluable Set includes all subjects in the Full Analysis Set, excluding those for whom the cumulative dose of ZN-c3 was <75% in Cycle 1 for reasons other than AEs. This analysis set is applicable to Phase 1 only and was used to summarize DLTs. The DLT-Evaluable Set includes 29 subjects

    Subject analysis set title
    Response-Evaluable Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Response-Evaluable Set includes all subjects in the Full Analysis Set who had measurable disease at baseline and at least 1 postbaseline disease assessment

    Primary: Incidence and severity of DLTs in DLT-evaluable subjects during Cycle 1 of Phase 1

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    End point title
    		 Incidence and severity of DLTs in DLT-evaluable subjects during Cycle 1 of Phase 1 [1]
    End point description
    Objective Phase 1: To investigate the safety and tolerability, MTD, and RP2D of ZN-c3 in combination with gemcitabine.
    End point type
    Primary
    End point timeframe
    analysis after 1 cycle (21 days)
    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: No statistical analysis performed for this endpoint. this is a safety endpoint and it is a listing of occurring DLT events
    End point values
    		 ZN-c3 150mg QD + Gemcitabine 800mg/m2 ZN-c3 200mg QD + Gemcitabine 1000mg/m2 ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2 DLT-Evaluable Set
    Number of subjects analysed
    5
    7
    6
    6
    3
    2
    29
    Units: events
    2
    3
    0
    2
    2
    1
    10
    No statistical analyses for this end point

    Secondary: Clinical activity: o According to RECIST v1.1 and clinical criteria: ΕFS

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    End point title
    		 Clinical activity: o According to RECIST v1.1 and clinical criteria: ΕFS
    End point description
    Efficacy analyses are based on the Response-Evaluable Set, which had 28 subjects (5 pediatric subjects and 23 adult subjects). EFS Event-Free Survival for all subjects (adult and pediatric). presented in weeks
    End point type
    Secondary
    End point timeframe
    up to 12 months after ZN-c3 treatment
    End point values
    		 ZN-c3 150mg QD + Gemcitabine 800mg/m2 ZN-c3 200mg QD + Gemcitabine 1000mg/m2 ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2 Response-Evaluable Set
    Number of subjects analysed
    5
    7
    5
    6
    3
    2
    28
    Units: weeks
        median (full range (min-max))
    12.9 (7.0 to 26.1)
    37.1 (6.0 to 37.1)
    8.1 (6.3 to 26.3)
    21.4 (6.6 to 43.3)
    9.1 (6.3 to 68.9)
    12.5 (3.7 to 21.3)
    12.9 (3.7 to 68.9)
    No statistical analyses for this end point

    Secondary: Clinical activity: o According to RECIST v1.1 and clinical criteria: OS (median and at 12 months)

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    End point title
    		 Clinical activity: o According to RECIST v1.1 and clinical criteria: OS (median and at 12 months)
    End point description
    Efficacy analyses are based on the Response-Evaluable Set, which had 28 subjects (5 pediatric subjects and 23 adult subjects). OS overall Survival for all subjects (adult and pediatric). Only presented for the total for 28 Subjects, as some timepoints in the various dosing groups were not evaluable.
    End point type
    Secondary
    End point timeframe
    up to 12 months after last dose of ZN-c3
    End point values
    		 Response-Evaluable Set
    Number of subjects analysed
    28
    Units: months
        median (full range (min-max))
    11.5 (0.8 to 22.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days after the last dose
    Adverse event reporting additional description
    SAE presented when occurrence >1 subject (Except for cardiac arrest). Relatedness to Zn-c3 and or gemcitabine. TEAEs are defined as AEs that occur or worsen from the first dose of study drug to 30 days after the last dose of study drug. The Non SAE presented are all defined as related to ZN-c3 and occurrence >10% of total subjects
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    ZN-c3 150mg QD + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 150mg daily dose in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD + Gemcitabine 1000mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg daily dose in combination with gemcitabine 1000mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 150mg given intermittent 5 days on and 2 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off in combination with gemcitabine 675mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 5 days on and 2 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Reporting group title
    ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2
    Reporting group description
    		 treatment cycles of 21 days with ZN-c3 200mg given intermittent 4 days on and 3 days off in combination with gemcitabine 800mg/m2, until progression of disease or any of the withdrawal criteria included in the protocol are met

    Serious adverse events
    		 ZN-c3 150mg QD + Gemcitabine 800mg/m2 ZN-c3 200mg QD + Gemcitabine 1000mg/m2 ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    5 / 9 (55.56%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    2 / 2 (100.00%)
         number of deaths (all causes)
    1
    5
    4
    2
    1
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
    Additional description: Thrombocytopenia includes the preferred terms Platelet count decreased and Thrombocytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
    Additional description: Neutropenia includes the preferred terms Neutropenia, Neutrophil count decreased, and Neutrophil percentage decreased.
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ZN-c3 150mg QD + Gemcitabine 800mg/m2 ZN-c3 200mg QD + Gemcitabine 1000mg/m2 ZN-c3 150mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 675mg/m2 ZN-c3 200mg QD 5:2 + Gemcitabine 800mg/m2 ZN-c3 200mg QD 4:3 + Gemcitabine 800mg/m2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    9 / 9 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    2 / 2 (100.00%)
    Blood and lymphatic system disorders
    Thrombocytopenia
    Additional description: Thrombocytopenia includes the preferred terms Platelet count decreased and Thrombocytopenia.
         subjects affected / exposed
    2 / 5 (40.00%)
    6 / 9 (66.67%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    3 / 3 (100.00%)
    1 / 2 (50.00%)
         occurrences all number
    4
    24
    3
    8
    10
    1
    Neutropenia
    Additional description: Neutropenia includes the preferred terms Neutropenia, Neutrophil count decreased, and Neutrophil percentage decreased.
         subjects affected / exposed
    1 / 5 (20.00%)
    4 / 9 (44.44%)
    0 / 6 (0.00%)
    4 / 6 (66.67%)
    3 / 3 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    8
    14
    0
    15
    13
    0
    Anaemia
    Additional description: Anaemia includes the preferred terms Anaemia, Haematocrit decreased, Haemoglobin decreased, and RBC count decreased
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 9 (33.33%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 3 (66.67%)
    1 / 2 (50.00%)
         occurrences all number
    8
    14
    3
    4
    7
    1
    Leukopenia
    Additional description: Leukopenia includes the preferred terms Leukopenia and WBC count decreased.
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 9 (44.44%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 3 (66.67%)
    0 / 2 (0.00%)
         occurrences all number
    12
    29
    2
    15
    18
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 5 (20.00%)
    5 / 9 (55.56%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 3 (66.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    8
    3
    12
    2
    0
    Metabolism and nutrition disorders
    Nausea
         subjects affected / exposed
    1 / 5 (20.00%)
    5 / 9 (55.56%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    2
    9
    1
    4
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2022
    in France the protocol was amendment from protocol 4.3 to protocol version 6.0 The main changes in Protocol version 6.0 against Protocol version 4.3 were: Update to inclusion and exclusion criteria Update to contraceptive requirements Update to the schedule of activities Number of study participants Prolongation of study duration period Revised guidance on IMP administration based on food effect evaluation Modification of ZN-c3 and Gemcitabine dosing Implementation of prophylactic treatment with antiemetics (previously introduced by Protocol Clarification Letter) Limitation of blood volume collection Other changes including clarifications and guidance Minor editorial, organizational, and administrative changes

    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.
    Decision was made to terminate the phase I study while some patients were in safety follow up (12 months) The Phase 2 part of this study was never conducted.
    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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