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    Clinical Trial Results:
    A Single-Arm, Open-Label, Phase 1/2 Study of ZN-d5 for the Treatment of Relapsed or Refractory Light Chain (AL) Amyloidosis

    Summary
    EudraCT number
    		 2021-003008-42
    Trial protocol
    		 GR   IT   CY  
    Global end of trial date
    14 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Feb 2025
    First version publication date
    22 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZN-d5-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05199337
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zentalis
    Sponsor organisation address
    Science Center Drive, Suite 200, San Diego, United States, 10275
    Public contact
    Regulatory Affairs, K-Group Alpha, Inc, +1 732-666-5002, risrani@zentalis.com
    Scientific contact
    Regulatory Affairs, K-Group Alpha, Inc, +1 6096199909, afrederick@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 Oct 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part A: •To determine the safety, tolerability, and maximum tolerated dose of ZN d5 •To determine the recommended phase 2 dose of ZN d5 Part B: •To assess the response to ZN d5 in subjects with RRAL with and without the t(11;14) translocation
    Protection of trial subjects
    Subject confidentiality and privacy were held in trust by the participating Investigators, their staff, and the Sponsor(s) and its service providers. This confidentiality was extended to cover testing of biological samples in addition to the clinical information relating to subjects. Therefore, the study protocol, documentation, data, and all other information generated were held in confidence. Personal details of subjects were treated as confidential by the Investigator and staff at Sponsor’s CRO, and handling of personal data was in compliance with applicable privacy laws. All research activities were conducted in a private setting. The study monitor, other authorized representatives of the Sponsor (including but not limited to the CRO), representatives of the IRB/IEC, study research monitor, and regulatory agencies, and/or the pharmaceutical company supplying the study product inspected all documents and records required to be maintained by the Investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this study, including records that identified the subject by name. The clinical study site permitted access to such records. The study subject’s contact information was securely stored at each clinical site for internal use during the study. At the end of the study, all records continued to be kept in a secure location for as long a period as dictated by applicable laws, the reviewing IRB/IEC, institutional policies, or Sponsor requirements. Study subject research data, which were for purposes of statistical analysis and scientific reporting, were transmitted to, and stored at, the Sponsor’s service providers. This generally did not include the subject’s contact or identifying information. Rather, individual subjects and their research data were identified by a unique study identification number.
    Background therapy
    		 Standard AL amyloidosis supportive treatments to manage underlying organ system dysfunction were permitted, except for interventions considered treatments for AL amyloidosis (including systemic corticosteroids and tetracycline antibiotics) and contraindicated medications.
    Evidence for comparator
    		 The study did not include a comparator.
    Actual start date of recruitment
    01 Nov 2021
    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: 2
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    18
    EEA total number of subjects
    8
    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)
    10
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Up to approximately 159 subjects with RRAL were planned to be enrolled, including up to approximately 27 subjects in dose escalation and up to 24 subjects in dose optimization during Part A. A total of 18 subjects were enrolled in the study.

    Pre-assignment
    Screening details
    		 Enrolled in this study were subjects with RRAL who had progression of disease after 1 to 3 prior lines of therapy. Additional criteria for inclusion included age ≥18 years (or the minimum legal age, whichever was greater), a biopsy confirmed diagnosis of AL amyloidosis requiring treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ZN-d5 400 mg QD Empty Stomach
    Arm description
    		 Bayesian Optimal Interval dose-escalation arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-d5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ZN-d5 was provided as 25 mg and 100 mg tablets. The initial dose cohort received 400 mg QD ZN-d5 administered orally on an empty stomach.

    Arm title
    		 ZN-d5 200 mg QD With Food
    Arm description
    		 Bayesian Optimal Interval dose-escalation arm. Second dose cohort received 200 mg QD ZN-d5 administered orally with food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-d5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ZN-d5 was provided as 25 mg and 100 mg tablets. The second dose cohort received 200 mg QD ZN-d5 administered orally with food.

    Arm title
    		 ZN-d5 400 mg QD With Food
    Arm description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-d5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ZN-d5 was provided as 25 mg and 100 mg tablets. The third dose cohort received 400 mg QD ZN-d5 administered orally with food.

    Arm title
    		 ZN-d5 800 mg QD With Food
    Arm description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-d5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ZN-d5 was provided as 25 mg and 100 mg tablets. The third dose cohort received 800 mg QD ZN-d5 administered orally with food.

    Arm title
    		 ZN-d5 600 mg BID With Food
    Arm description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZN-d5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ZN-d5 was provided as 25 mg and 100 mg tablets. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food. BID dosing was allowed for the 1200 mg cohort (administered as 600 mg BID), as well as at lower dose levels per Sponsor approval. ZN-d5 was administered daily and continuously, in 28-day treatment cycles, with no interruption during or between cycles.

    Number of subjects in period 1
    		ZN-d5 400 mg QD Empty Stomach ZN-d5 200 mg QD With Food ZN-d5 400 mg QD With Food ZN-d5 800 mg QD With Food ZN-d5 600 mg BID With Food
    Started
    3
    5
    3
    3
    4
    Completed
    0
    0
    0
    0
    0
    Not completed
    3
    5
    3
    3
    4
         Adverse event, serious fatal
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    1
    -
    -
         Study Terminated By Sponsor
    -
    1
    1
    1
    1
         Adverse event, non-fatal
    -
    -
    -
    1
    -
         Investigator Discretion
    1
    3
    1
    1
    2
         Disease Progression
    1
    1
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ZN-d5 400 mg QD Empty Stomach
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm.

    Reporting group title
    ZN-d5 200 mg QD With Food
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm. Second dose cohort received 200 mg QD ZN-d5 administered orally with food.

    Reporting group title
    ZN-d5 400 mg QD With Food
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.

    Reporting group title
    ZN-d5 800 mg QD With Food
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.

    Reporting group title
    ZN-d5 600 mg BID With Food
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.

    Reporting group values
    		 ZN-d5 400 mg QD Empty Stomach ZN-d5 200 mg QD With Food ZN-d5 400 mg QD With Food ZN-d5 800 mg QD With Food ZN-d5 600 mg BID With Food Total
    Number of subjects
    		 3 5 3 3 4 18
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 2 4 1 2 1 10
        From 65-84 years
    		 1 1 2 1 3 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.3 ( 9.61 ) 61.6 ( 7.54 ) 67.0 ( 9.17 ) 62.3 ( 4.04 ) 70.8 ( 9.91 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 1 0 2 6
        Male
    		 2 3 2 3 2 12

    End points

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    End points reporting groups
    Reporting group title
    ZN-d5 400 mg QD Empty Stomach
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm.

    Reporting group title
    ZN-d5 200 mg QD With Food
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm. Second dose cohort received 200 mg QD ZN-d5 administered orally with food.

    Reporting group title
    ZN-d5 400 mg QD With Food
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.

    Reporting group title
    ZN-d5 800 mg QD With Food
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.

    Reporting group title
    ZN-d5 600 mg BID With Food
    Reporting group description
    		 Bayesian Optimal Interval dose-escalation arm. Dose escalations continued up to a daily dose of 1200 mg ZN-d5 administered with food.

    Primary: Dose-limiting toxicities

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    End point title
    		 Dose-limiting toxicities [1]
    End point description
    End point type
    Primary
    End point timeframe
    Through Cycle 1, Day 28
    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: All subjects were DLT-evaluable and no DLTs were identified, hence no data to report as there were no DLTs.
    End point values
    		 ZN-d5 400 mg QD Empty Stomach ZN-d5 200 mg QD With Food ZN-d5 400 mg QD With Food ZN-d5 800 mg QD With Food ZN-d5 600 mg BID With Food
    Number of subjects analysed
    3
    5
    3
    3
    4
    Units: Subjects
        Dose-limiting toxicities
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Incidence and severity of AEs

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    End point title
    		 Incidence and severity of AEs
    End point description
    End point type
    Primary
    End point timeframe
    From the first dose through EOT or initiation of subsequent therapy
    End point values
    		 ZN-d5 400 mg QD Empty Stomach ZN-d5 200 mg QD With Food ZN-d5 400 mg QD With Food ZN-d5 800 mg QD With Food ZN-d5 600 mg BID With Food
    Number of subjects analysed
    3
    5
    3
    3
    4
    Units: Subjects
        TEAE
    2
    5
    3
    3
    3
        Study drug-related TEAE
    2
    3
    3
    3
    2
        Grade ≥3 TEAE
    2
    3
    1
    1
    1
        TEAE study drug interruption and/or modification
    0
    2
    3
    1
    1
        TEAE leading to study drug discontinuation
    1
    0
    0
    1
    0
        Serious TEAE
    1
    1
    0
    1
    0
        Fatal AE
    0
    0
    0
    0
    0
    Statistical analysis title
    		 All Enrolled Subjects
    Statistical analysis description
    All subjects who signed an Informed Consent Form for the study, met all inclusion criteria, and were enrolled
    Comparison groups
    ZN-d5 400 mg QD Empty Stomach v ZN-d5 200 mg QD With Food v ZN-d5 400 mg QD With Food v ZN-d5 800 mg QD With Food v ZN-d5 600 mg BID With Food
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 18
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AE and SAE Reporting Periods began at the time a study subject signed an ICF and ended 30 days after the last dose of study drug or at the start of subsequent disease therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Empty Stomach: 400 mg/day
    Reporting group description
    		 -

    Reporting group title
    With Food: 200 mg/day
    Reporting group description
    		 -

    Reporting group title
    With Food: 400 mg/day
    Reporting group description
    		 -

    Reporting group title
    With Food: 800 mg/day
    Reporting group description
    		 -

    Reporting group title
    With Food: 600 mg/day (BID)
    Reporting group description
    		 -

    Serious adverse events
    		 Empty Stomach: 400 mg/day With Food: 200 mg/day With Food: 400 mg/day With Food: 800 mg/day With Food: 600 mg/day (BID)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    2
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Myocarditis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Empty Stomach: 400 mg/day With Food: 200 mg/day With Food: 400 mg/day With Food: 800 mg/day With Food: 600 mg/day (BID)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 4 (75.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Bowen's disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    2
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Mucosal ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Localised oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Bartholin's cyst
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Breast enlargement
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Upper respiratory tract irritation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Investigations
    Holotranscobalamin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Troponin T increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Human metapneumovirus test positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Depressed level of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia macrocytic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    3 / 4 (75.00%)
         occurrences all number
    4
    1
    3
    7
    5
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    2
    3
    0
    0
    Lip ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Change of bowel habit
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    5
    0
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Renal cyst
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Folate deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2022
    - Clarified the starting dose cohort and escalation cohorts for Part A. - Added text in section 6.1.2. to allow administration of ZN-d5 with a meal based on findings from the food effect study (ZN-d5-002). - Added a secondary efficacy endpoint in Part B to better assess hematological response and progression. - Removed the bone marrow plasma cell requirement at baseline because we have clarified that any subject with a diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) is excluded from the study, and the bone marrow plasma cell count above or below 30% does not affect the diagnosis. - Deleted timing of bone marrow function assessment to include eligible patients and align with body of protocol. Edited platelet count criteria to include eligible antibody light chain (AL) amyloidosis patients who would otherwise be excluded. - Clarified that subjects with any type of multiple myeloma will be excluded. - Plasma cell counts were removed as an eligibility criterion. - A specific exclusion of subjects with HIV is not needed, although most HIV subjects will be unable to participate because of prohibited concomitant medications. - p-GP inhibitors are allowed to be used with caution during ZN-d5 treatment. - More detailed dosing interruption criteria and suggested dose reduction levels could provide more accurate instructions to clinical site. - Specific B cell count assessments at some time points were removed, as the counts at the other designated time points are sufficient to evaluate potential biomarkers. Removed biomarker assessment considering this assessment does not provide useful biomarker information. - There will be no ZN-d5 concentration in blood before dosing; thus it is unnecessary to collect a pharmacokinetic (PK) sample at Screening. - ORR is replaced with HRR across the document as HRR is a term of convention to assess response.
    30 Jun 2023
    - Part A was initially designed to evaluate the safety and identify the RP2D of ZN-d5 for patients with relapsed/refractory light chain (AL) amyloidosis. Part A is updated to allow for the evaluation of intermediate doses based on emerging clinical and PK data and to include a more robust assessment of PK, safety, and efficacy data at additional dose levels (rather than only the initially presumed RP2D) to support dose optimization. The study duration and patient enrollment is updated to accommodate for time required to enroll subjects into these cohorts. - Study is modified to allow the opportunity for a one-time intrasubject dose escalation to a dose that has been deemed safe by the SRC. Subjects must be on their current dose of ZN-d5 for at least 4 months without treatment related adverse events leading to a dose interruption, reduction, or discontinuation, and must obtain Sponsor approval. This option provides patients, particularly those enrolled in early dose levels, with the potential of a greater benefit:risk ratio. - A 60-day washout for prior therapeutic antibodies (eg, daratumumab) was considered too long of a treatment interruption for patients with active, relapsed/refractory disease. - The previous toxicity monitoring section was designed to evaluate events using a Bayesian design in predefined increments of 10 patients. To facilitate improved and timely assessment of potential AEs associated with the use of ZN-d5/BCL2 inhibitors, we used the Toxicity Monitoring Criteria section to establish AESIs that require immediate reporting and therefore evaluation by the Sponsor. - DLT criteria were updated to be more conservative per FDA request.

    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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