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    Clinical Trial Results:
    A Phase 1b-2, Open-Label, Dose Escalation and Expansion Study Evaluating the Safety and Efficacy of Entospletinib (ENTO [GS-9973]) combined with Vincristine (VCR) in Adult Subjects with Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (NHL)

    Summary
    EudraCT number
    		 2015-002731-17
    Trial protocol
    		 HU   GB   ES  
    Global end of trial date
    22 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2018
    First version publication date
    06 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-339-1562
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02568683
    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
    22 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to evaluate the safety of entospletinib (ENTO) with vincristine (VCR) in adults with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL).
    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
    11 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    10
    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)
    0
    Adults (18-64 years)
    4
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States and France. The first participant was screened on 11 February 2016. The last study visit occurred on 22 June 2017.

    Pre-assignment
    Screening details
    		 13 participants were screened.

    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
    		 ENTO 200 mg
    Arm description
    		 ENTO 200 mg + VCR
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablet administered orally twice daily under fasted conditions

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    VCR
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.0 mg/m^2 administered via intravenous infusion every 14 days

    Arm title
    		 ENTO 400 mg
    Arm description
    		 ENTO 400 mg + VCR
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg tablet administered orally twice daily under fasted conditions

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    VCR
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.0 mg/m^2 administered via intravenous infusion every 14 days

    Number of subjects in period 1
    		ENTO 200 mg ENTO 400 mg
    Started
    6
    4
    Completed
    0
    0
    Not completed
    6
    4
         Withdrew Consent
    1
    -
         Study Terminated By Sponsor
    5
    2
         Death
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ENTO 200 mg
    Reporting group description
    		 ENTO 200 mg + VCR

    Reporting group title
    ENTO 400 mg
    Reporting group description
    		 ENTO 400 mg + VCR

    Reporting group values
    		 ENTO 200 mg ENTO 400 mg Total
    Number of subjects
    		 6 4 10
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62 ± 13.6 69 ± 8.1 -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 4
        Male
    		 3 3 6
    Race
    Units: Subjects
        White
    		 4 1 5
        Not Permitted
    		 2 3 5
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 4 1 5
        Not Permitted
    		 2 3 5

    End points

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    End points reporting groups
    Reporting group title
    ENTO 200 mg
    Reporting group description
    		 ENTO 200 mg + VCR

    Reporting group title
    ENTO 400 mg
    Reporting group description
    		 ENTO 400 mg + VCR

    Primary: Occurrence of adverse events and laboratory abnormalities defined as dose limiting toxicities (DLTs) for ENTO in combination with VCR in participants in the dose escalation stage with relapsed or refractory B-cell NHL

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    End point title
    		 Occurrence of adverse events and laboratory abnormalities defined as dose limiting toxicities (DLTs) for ENTO in combination with VCR in participants in the dose escalation stage with relapsed or refractory B-cell NHL [1]
    End point description
    DLT Analysis Set: participants in the Full Analysis Set (participants receiving at least 1 dose of ENTO) who received 37 of 56 Cycle 1 doses of ENTO for dose level 1-4 and completed the full Cycle 1 dose of VCR or who experienced a DLT during the DLT assessment window.
    End point type
    Primary
    End point timeframe
    Up to 28 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 comparison was planned or performed.
    End point values
    		 ENTO 200 mg ENTO 400 mg
    Number of subjects analysed
    6
    3
    Units: participants
        number (not applicable)
    0
    2
    No statistical analyses for this end point

    Secondary: Occurrence of adverse events and laboratory abnormalities not defined as DLTs for ENTO with VCR in participants in the dose escalation stage with relapsed or refractory B-cell NHL

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    End point title
    		 Occurrence of adverse events and laboratory abnormalities not defined as DLTs for ENTO with VCR in participants in the dose escalation stage with relapsed or refractory B-cell NHL
    End point description
    Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 28 days
    End point values
    		 ENTO 200 mg ENTO 400 mg
    Number of subjects analysed
    6
    4
    Units: participants
    number (not applicable)
        AEs not defined as DLTs
    6
    4
        Lab abnormalities not defined as DLTs
    5
    4
    No statistical analyses for this end point

    Secondary: Duration of Exposure to Entospletinib

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    End point title
    		 Duration of Exposure to Entospletinib
    End point description
    Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (maximum: 24 weeks)
    End point values
    		 ENTO 200 mg ENTO 400 mg
    Number of subjects analysed
    6
    4
    Units: weeks
        arithmetic mean (standard deviation)
    17.7 ± 6.09
    4.3 ± 2.68
    No statistical analyses for this end point

    Secondary: Duration of Exposure to Vincristine

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    End point title
    		 Duration of Exposure to Vincristine
    End point description
    Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (maximum: 24 weeks)
    End point values
    		 ENTO 200 mg ENTO 400 mg
    Number of subjects analysed
    6
    4
    Units: doses
        arithmetic mean (standard deviation)
    8.7 ± 3.27
    2.3 ± 1.50
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to the last dose date plus 30 days (maximum exposure: 200 mg ENTO = 24 weeks; 400 mg ENTO = 8 weeks). Any adverse events or deaths occurring outside of this time frame were not included.
    Adverse event reporting additional description
    Safety Analysis Set: all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    ENTO 200 mg
    Reporting group description
    		 ENTO 200 mg + VCR

    Reporting group title
    ENTO 400 mg
    Reporting group description
    		 ENTO 400 mg + VCR

    Serious adverse events
    		 ENTO 200 mg ENTO 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sinus pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ENTO 200 mg ENTO 400 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Feeling drunk
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Ill-defined disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hiccups
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Mental status changes
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Weight decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Ileus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Odynophagia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Groin pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2015
    Revision of the scan frequency during the long term follow-up to align with European Society for Medical Oncology (ESMO) guidelines for follow-up of subjects with diffuse large B-cell lymphoma
    15 Oct 2015
    Updated inclusion criterion for acute toxic effects and added text regarding excluded medications
    18 Feb 2016
    ● Revised study title to include full name of Entospletinib as well as addition of “relapsed or refractory B-cell” ● Standardized dose escalation levels and dose expansion cohort wording ● Removed language regarding R-CHOP, EPOCH, their components, and combination therapy references ● Updated number of subjects participating in the study

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Jun 2017
    Upon review of the clinical data, Gilead decided not to proceed with the dose expansion stage given the minimal treatment effect observed, and the study was terminated. This decision was not based upon any safety concerns.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Because the study was terminated after enrolling only 10 subjects, the planned efficacy analyses were not 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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