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    Clinical Trial Results:
    A Phase 1b/2 Dose Escalation/Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of GS-4224 in Subjects With Advanced Solid Tumors

    Summary
    EudraCT number
    		 2019-004605-27
    Trial protocol
    		 PL  
    Global end of trial date
    30 Mar 2021

    Results information
    Results version number
    		 v1
    This version publication date
    18 Apr 2022
    First version publication date
    18 Apr 2022
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-494-5484
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04049617
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    30 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to characterize the safety and tolerability of GS-4224 and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of GS-4224 in participants with advanced solid tumors.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Aug 2019
    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
    New Zealand: 12
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    18
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    11
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in New Zealand and the United States. The first participant was screened on 26 August 2019. The last study visit occurred on 30 March 2021.

    Pre-assignment
    Screening details
    		 29 participants were screened. The participants took part in the Phase 1 (Dose Escalation) of the study only. No participants were enrolled in the Phase 1 Cohort 5 and Cohort 2 substudy and the study was terminated due to sponsor decision before the planned Dose Expansion Phase 2 started.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: GS-4224 400 mg (Phase 1)
    Arm description
    		 Participants received GS-4224 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 21 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-4224
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg administered once daily for approximately 21 weeks

    Arm title
    		 Cohort 2: GS-4224 700 mg (Phase 1)
    Arm description
    		 Participants received GS-4224 700 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-4224
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    700 mg administered once daily for approximately 10 weeks

    Arm title
    		 Cohort 3: GS-4224 1000 mg (Phase 1)
    Arm description
    		 Participants received GS-4224 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-4224
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg administered once daily for approximately 39 weeks

    Arm title
    		 Cohort 4: GS-4224 1500 mg (Phase 1)
    Arm description
    		 Participants received GS-4224 1500 mg once daily for 21 days of each cycle (observed maximum duration was approximately 19 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-4224
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1500 mg administered once daily for approximately 19 weeks

    Arm title
    		 Cohort 1 Substudy: GS-4224 400 mg (Phase 1)
    Arm description
    		 Participants received GS-4224 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-4224
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg administered once daily for approximately 39 weeks

    Arm title
    		 Cohort 3 Substudy: GS-4224 1000 mg (Phase 1)
    Arm description
    		 Participants received GS-4224 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-4224
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg administered once daily for approximately 10 weeks

    Number of subjects in period 1
    		Cohort 1: GS-4224 400 mg (Phase 1) Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1 Substudy: GS-4224 400 mg (Phase 1) Cohort 3 Substudy: GS-4224 1000 mg (Phase 1)
    Started
    3
    3
    6
    3
    2
    1
    Completed
    3
    3
    5
    1
    2
    0
    Not completed
    0
    0
    1
    2
    0
    1
         Death
    -
    -
    -
    -
    -
    1
         Adverse event
    -
    -
    -
    1
    -
    -
         Withdrew consent
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: GS-4224 400 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 21 weeks).

    Reporting group title
    Cohort 2: GS-4224 700 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 700 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks).

    Reporting group title
    Cohort 3: GS-4224 1000 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks).

    Reporting group title
    Cohort 4: GS-4224 1500 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1500 mg once daily for 21 days of each cycle (observed maximum duration was approximately 19 weeks).

    Reporting group title
    Cohort 1 Substudy: GS-4224 400 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks).

    Reporting group title
    Cohort 3 Substudy: GS-4224 1000 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks).

    Reporting group values
    		 Cohort 1: GS-4224 400 mg (Phase 1) Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1 Substudy: GS-4224 400 mg (Phase 1) Cohort 3 Substudy: GS-4224 1000 mg (Phase 1) Total
    Number of subjects
    		 3 3 6 3 2 1 18
    Age categorical
    Units: Subjects
    Age continuous
    9999= not reached due to less number of participants
    Units: years
        arithmetic mean (standard deviation)
    		 55.3 ( 28.29 ) 65.3 ( 15.53 ) 61.2 ( 5.67 ) 70.0 ( 11.53 ) 64.0 ( 12.73 ) 42.0 ( 9999 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 0 2 0 0 0 3
        Male
    		 2 3 4 3 2 1 15

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: GS-4224 400 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 21 weeks).

    Reporting group title
    Cohort 2: GS-4224 700 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 700 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks).

    Reporting group title
    Cohort 3: GS-4224 1000 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks).

    Reporting group title
    Cohort 4: GS-4224 1500 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1500 mg once daily for 21 days of each cycle (observed maximum duration was approximately 19 weeks).

    Reporting group title
    Cohort 1 Substudy: GS-4224 400 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks).

    Reporting group title
    Cohort 3 Substudy: GS-4224 1000 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks).

    Subject analysis set title
    Cohort 1: GS-4224 400 mg (Phase 1)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK Analysis Set included participants in the Safety Analysis Set who had received the study drug and have at least 1 sample with detectable drug concentration. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1.

    Primary: Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase

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    End point title
    		 Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase [1]
    End point description
    DLT: any toxicity defined as follows:•Grade ≥4 neutropenia•Grade ≥3 neutropenia with fever•Grade ≥3 thrombocytopenia•Grade ≥2 bleeding •Grade ≥3 anemia•Grade ≥3 or higher non-hematologic toxicity (excluding Grade 3 nausea or emesis or Grade 3 diarrhea)•Grade ≥2 non-hematologic treatment-emergent adverse event that in the opinion of the investigator is of potential clinical significance•Treatment interruption of ≥7days due to unresolved toxicity•Any toxicity event that precludes further administration of GS-4224•Any Grade 3 or Grade 4 elevation in aspartate aminotransferase or alanine aminotransferase associated with a Grade 2 elevation in bilirubin lasting ≥7days•An immune-related adverse event for which immunotherapy should be permanently discontinued.Safety Analysis Set included data from all participants who received at least 1 dose of study treatment, with treatment assignments designated according to the actual treatment received.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 21
    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 was planned.
    End point values
    		 Cohort 1: GS-4224 400 mg (Phase 1) Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1 Substudy: GS-4224 400 mg (Phase 1) Cohort 3 Substudy: GS-4224 1000 mg (Phase 1)
    Number of subjects analysed
    3
    3
    6
    3
    2
    1
    Units: participants
    0
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameter: AUCtau of GS-4224 During the Dose Escalation Phase

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    End point title
    		 Pharmacokinetic (PK) Parameter: AUCtau of GS-4224 During the Dose Escalation Phase [2]
    End point description
    AUCtau was defined as area under the concentration-time curve from time zero to the end of the dosing interval. PK Analysis Set included participants in the Safety Analysis Set who had received the study drug and have at least 1 sample with detectable drug concentration. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1. PK data were not collected for Cohort 3 Substudy group due to discontinuation of the development program.
    End point type
    Secondary
    End point timeframe
    Intensive PK: Predose, 0-24 hours (h) post dose (400-1500 mg cohorts) on C1D1 & D15 C=Cycle Day=Day
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1: GS-4224 400 mg (Phase 1)
    Number of subjects analysed
    3
    6
    3
    5
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        C1D1
    8703.8 ( 3717.93 )
    12241.8 ( 2793.17 )
    19132.6 ( 596.64 )
    6543.1 ( 1783.07 )
        C1D15
    13508.4 ( 3126.80 )
    19380.8 ( 5261.89 )
    27664.5 ( 7758.37 )
    9269.8 ( 2693.53 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Cmax of GS-4224 During the Dose Escalation Phase

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    End point title
    		 PK Parameter: Cmax of GS-4224 During the Dose Escalation Phase [3]
    End point description
    Cmax was defined as the maximum observed drug concentration. Participants in PK Analysis Set were analyzed. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1. PK data were not collected for Cohort 3 Substudy group due to discontinuation of the development program.
    End point type
    Secondary
    End point timeframe
    Intensive PK: Predose, 0-24 hours (h) post dose (400-1500 mg cohorts) on C1D1 & D15
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1: GS-4224 400 mg (Phase 1)
    Number of subjects analysed
    3
    6
    3
    5
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1D1
    1468.7 ( 497.74 )
    1918.3 ( 377.59 )
    2116.7 ( 55.08 )
    1090.4 ( 355.12 )
        C1D15
    1580.0 ( 245.76 )
    2051.7 ( 686.89 )
    2480.0 ( 278.75 )
    1193.8 ( 605.87 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Ctrough of GS-4224 During the Dose Escalation Phase

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    End point title
    		 PK Parameter: Ctrough of GS-4224 During the Dose Escalation Phase [4]
    End point description
    Ctrough is defined as the observed concentration at the end of the dosing interval. Participants in the PK Analysis Set were analyzed. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1. PK data were not collected for Cohort 3 Substudy group due to discontinuation of the development program.
    End point type
    Secondary
    End point timeframe
    Intensive PK: Predose, 0-24 hours (h) post dose (400-1500 mg cohorts) on C1D1 & D15
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1: GS-4224 400 mg (Phase 1)
    Number of subjects analysed
    3
    6
    3
    5
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1D1
    56.2 ( 18.05 )
    111.9 ( 43.92 )
    180.3 ( 21.50 )
    40.3 ( 9.80 )
        C1D15
    198.7 ( 57.98 )
    318.5 ( 88.44 )
    472.7 ( 112.88 )
    109.8 ( 35.61 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Tmax of GS-4224 During the Dose Escalation Phase

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    End point title
    		 PK Parameter: Tmax of GS-4224 During the Dose Escalation Phase [5]
    End point description
    Tmax is defined as the time to maximum observed concentration. Participants in PK Analysis Set were analyzed. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1. PK data were not collected for Cohort 3 Substudy group due to discontinuation of the development program.
    End point type
    Secondary
    End point timeframe
    Intensive PK: Predose, 0-24 hours (h) post dose (400-1500 mg cohorts) on C1D1 & D15
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned.
    End point values
    		 Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1: GS-4224 400 mg (Phase 1)
    Number of subjects analysed
    3
    6
    3
    5
    Units: hours
    median (inter-quartile range (Q1-Q3))
        C1D1
    1.53 (1.00 to 2.50)
    1.52 (1.00 to 1.65)
    2.50 (2.50 to 6.00)
    1.00 (1.00 to 1.02)
        C1D15
    1.50 (1.00 to 1.50)
    1.51 (1.00 to 2.50)
    4.00 (1.50 to 5.95)
    1.50 (1.00 to 2.02)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-Cause Mortality: Enrollment up to 46.1 weeks; Adverse Events: First dose date up to last dose (maximum: 39.1 weeks) plus 30 days
    Adverse event reporting additional description
    All-Cause Mortality: All Enrolled Analysis Set included all participants who received a study identification number in the study after screening. Adverse Events: Safety Analysis Set included data from all participants who received at least 1 dose of study treatment, with treatment assignments designated according to the actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Cohort 1: GS-4224 400 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 21 weeks).

    Reporting group title
    Cohort 2: GS-4224 700 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 700 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks).

    Reporting group title
    Cohort 3: GS-4224 1000 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks).

    Reporting group title
    Cohort 4: GS-4224 1500 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1500 mg once daily for 21 days of each cycle (observed maximum duration was approximately 19 weeks).

    Reporting group title
    Cohort 1 Substudy: GS-4224 400 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks).

    Reporting group title
    Cohort 3 Substudy: GS-4224 1000 mg (Phase 1)
    Reporting group description
    		 Participants received GS-4224 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks).

    Serious adverse events
    		 Cohort 1: GS-4224 400 mg (Phase 1) Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1 Substudy: GS-4224 400 mg (Phase 1) Cohort 3 Substudy: GS-4224 1000 mg (Phase 1)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (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 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Norovirus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    		 Cohort 1: GS-4224 400 mg (Phase 1) Cohort 2: GS-4224 700 mg (Phase 1) Cohort 3: GS-4224 1000 mg (Phase 1) Cohort 4: GS-4224 1500 mg (Phase 1) Cohort 1 Substudy: GS-4224 400 mg (Phase 1) Cohort 3 Substudy: GS-4224 1000 mg (Phase 1)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    2 / 2 (100.00%)
    0 / 1 (0.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Ageusia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    4 / 6 (66.67%)
    2 / 3 (66.67%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    6
    3
    4
    2
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    4 / 6 (66.67%)
    2 / 3 (66.67%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    5
    2
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    2 / 3 (66.67%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    3
    3
    0
    0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hepatobiliary disorders
    Gallbladder obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    Intertrigo
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Postoperative wound infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2019
    The protocol was amended in response to comments received from FDA on 30 May 2019 and 05 June 2019, and the pre-IND meeting (comments received April 15, 2019) regarding this study protocol.
    12 Aug 2019
    The protocol was amended to provide clarification for the Phase 1b starting dose rationale, assessment time points and the addition of non-small cell lung cancer (NSCLC) in the Phase 2 dose expansion basket cohort B1.
    04 May 2020
    • The protocol was amended to include updated higher dose GS-4224 tablet strengths (200 mg and 500 mg) and the addition of a new formulation for 100 mg strength tablets. • Language in the protocol was updated to allow up to 12 participants to enroll in one of the of the biopsy substudy cohorts. The number of planned participants for Phase 1b and total for the study were adjusted for the 6 additional participants. • Updates were also made to the acid-reducing agent restrictions following a preliminary study on the effects of acid reducing agents on the absorption of GS-4224. Additionally, requirements for positron emission tomography computed tomography (PET-CT) scans for participants with classical Hodgkin’s lymphoma (cHL) as well as Lugano response assessment requirements for cHL were added throughout the protocol.
    07 Aug 2020
    • The protocol was amended to include a new dose level (1500 mg) in the dose-escalation portion of the study. The protocol’s rationale for dose selection was updated to include the safety information for the added 1500-mg dose level. Protocol language was also updated to reflect the change in the number of subjects that will be enrolled in Phase 1b and the study overall due to the addition of the new dose level. • The protocol was amended to allow for Phase 1b biopsy substudy subjects receiving GS-4224 at a dose level below that which has been deemed to be safe by the study review team (SRT) to receive, at the investigator’s discretion, GS-4224 at the highest dose deemed to be safe by the SRT after completing posttreatment biopsy and Cycle 2. • Appendix 5 (Pregnancy Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirements) was updated to align with new guidelines for contraception. • Appendix 8 was added in response to the COVID-19 pandemic and possible future pandemics that may impact the study.
    02 Oct 2020
    • The protocol was amended to include a new dose level (1000 mg twice daily (BID) in the dose-escalation portion of the study. The safety profile has been manageable at doses up to 1000 mg once daily and no dose-limiting toxicities (DLTs) have been observed. Higher doses are being studied and the protocol’s rationale for dose selection was updated to include the safety information for the added 1000 mg twice daily dose level. Protocol language was also updated to reflect the change in the number of participants that will be enrolled in Phase 1b and the study overall due to the addition of the new dose level. • Language in the protocol regarding the administration of GS-4224 was updated as the participants will receive GS-4224 orally once daily in the 400-1500 mg QD cohorts and 1000 mg twice daily in the 1000 mg BID cohort. • The protocol was amended to allow for Phase 1b dose escalation subjects receiving GS-4224 at a dose level below that which has been deemed to be safe by the study review team (SRT) to receive, at the investigator’s discretion, GS-4224 at the highest dose deemed to be safe by the SRT after completing 4 cycles of treatment and Cycle 5 Day 1 scans. • Language in the protocol was updated as pharmacodynamic peripheral blood mononuclear cell (PBMC) collection will be required only at select sites in the 1000 mg BID dose escalation cohort.
    02 Oct 2020
    • Updates were made to collect intensive pharmacokinetics (PK) samples in all participants in Phase 1b dose cohorts between 400–1500 mg QD. In the 1000 mg BID dose escalation cohort, intensive PK will be collected at select sites in at least 6 participants and a 12-hour time point was added. Predose PK samples will be collected on the indicated days in all participants in Phase 1b who have intensive PK collection (all participants in dose cohorts between 400–1500 mg QD and at least 6 participants in 1000 mg BID dose cohort). Additionally, sparse PK will be collected on the indicated days in all participants in Phase 2 and in those who do not have intensive PK collection in Phase 1b.

    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.
    This was a planned Phase 1/2 study. However, Phase 2 was not conducted because the study was closed due to sponsor decision prior to opening the dose expansion cohort. Hence, RP2D and any analyses were not performed for Phase 2 (Dose Expansion Phase)
    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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