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    Clinical Trial Results:
    Single arm feasibility of multi-maintenance olaparib after disease recurrence in participants with platinum sensitive BRCAm high grade serous ovarian cancer

    Summary
    EudraCT number
    		 2015-003883-36
    Trial protocol
    		 GB  
    Global end of trial date
    31 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jul 2023
    First version publication date
    26 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CFTSp104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02855697
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Christie NHS Foundation Trust
    Sponsor organisation address
    550 Wilmslow Road, Manchester, United Kingdom, M20 4BX
    Public contact
    Clare Griffin, The Christie NHS Foundation Trust, +44 01614468280, the-christie.sponsoredresearch@nhs.net
    Scientific contact
    Clare Griffin, The Christie NHS Foundation Trust, +44 01614468280, the-christie.sponsoredresearch@nhs.net
    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
    17 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine the feasibility of administering a second course of maintenance olaparib for more than 6 months (26 weeks) to participants with recurrent platinum-sensitive HGS/EOC who have been previously treated with olaparib.
    Protection of trial subjects
    The trial will be conducted in accordance with the principles of good clinical practice (GCP) and the Declaration of Helsinki. The sponsor and MCTU will ensure that the study protocol, participant information sheet, participant consent from, GP letter and submitted supporting documents have been approved by the research ethics committee(s) prior to any subject recruitment. The Principal Investigator will update participants whenever new information becomes available that might affect the participant’s willingness to continue in the trial. Participants will be assigned a unique ID at registration that will be used throughout the trial and any personal data recorded will be regarded as confidential and will not be released into the public domain. Investigator and site staff must not provide any participant-identifying data to the MCTU during the course of the trial, and any identifying data received by the MCTU will be redacted or destroyed. All investigators and site staff involved with the trial must comply with the requirements of the Data Protection Act 1998 with regard to the collection, storage, processing and disclosure of personal information and will uphold the Act’s core principles.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 27
    Worldwide total number of subjects
    27
    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)
    22
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 27 participants with a known pathogenic/likely pathogenic germline BRCA1/2 mutation were recruited. All patients were recruited prior to rechallenge platinum chemotherapy. Patients recruited at EP1 had never been treated with a PARPi. Patients recruited at EP2 had received a first maintenance course of olaparib immediately prior to trial enrolment

    Pre-assignment
    Screening details
    		 Screening assessments included a CT scan of the abdomen and pelvis, ECOG performance status, ECG, safety laboratory assessments (including haemotology, clinical chemistry, CA125, renal function test and coagulation parameters), pregnancy testing and a standard examination of height, weight, pulse rate, blood pressure and temperature.

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

    Arms
    Arm title
    		 Second maintenance olaparib
    Arm description
    		 Subjects who were intended to receive a second maintenance dose of olaparib whilst on trial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Olaparib will be provided as tablets, marked with 100mg or 150mg. The recommended dose is 300 mg taken twice daily (bd), equivalent to a total daily dose of 600 mg.

    Number of subjects in period 1
    		Second maintenance olaparib
    Started
    27
    Completed
    27

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (trial period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (trial period) Total
    Number of subjects
    		 27 27
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 22 22
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 27 27
        Male
    		 0 0
    ECOG performance status
    Units: Subjects
        00
    		 21 21
        01
    		 6 6
    Germline BRCA1/2 mutation
    Units: Subjects
        BRCA1
    		 22 22
        BRCA2
    		 5 5
    Histology
    Units: Subjects
        Serous
    		 27 27
        Endometrioid
    		 0 0
    FIGO (2014) stage
    Units: Subjects
        I-II
    		 4 4
        III
    		 18 18
        IV
    		 5 5
    Prior lines of platinum chemotherapy before trial entry
    Units: Subjects
        01
    		 6 6
        02
    		 9 9
        More than or equal to 3
    		 12 12
    Prior bevacizumab therapy
    Units: Subjects
        None
    		 16 16
        First line
    		 6 6
        Second line/recurrent disease
    		 5 5
    Progression-free interval prior to platinum 1
    Units: Subjects
        6–12 months
    		 17 17
        >12 months
    		 10 10

    End points

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    End points reporting groups
    Reporting group title
    Second maintenance olaparib
    Reporting group description
    		 Subjects who were intended to receive a second maintenance dose of olaparib whilst on trial.

    Subject analysis set title
    Olaparib 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patents who received a first maintenance course of olaparib used for post hoc analysis

    Subject analysis set title
    Olaparib 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received a second maintenance course of olaparib used for post hoc analysis

    Primary: The proportion of patients who received a second maintenance course of olaparib

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    End point title
    		 The proportion of patients who received a second maintenance course of olaparib [1]
    End point description
    End point type
    Primary
    End point timeframe
    For Entry Point 1, the timeframe was from screening until the second instance of progressive disease. For patients at Entry Point 2 the timeframe was from screening until the first instance of disease progression.
    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 analyses were performed for this end-point due to the results being a count i.e number of patients
    End point values
    		 Second maintenance olaparib
    Number of subjects analysed
    19 [2]
    Units: Number of patients
    12
    Notes
    [2] - 19 patients received at least one dose of platinum 2 and were evaluable for the co-primary outcomes
    No statistical analyses for this end point

    Primary: The proportion of patients who received a second course of olaparib for ≥6 months

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    End point title
    		 The proportion of patients who received a second course of olaparib for ≥6 months [3]
    End point description
    End point type
    Primary
    End point timeframe
    From starting point of olaparib second course until their 6th month of treatment or greater.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed for this end-point due to the results being a count i.e number of patients
    End point values
    		 Second maintenance olaparib
    Number of subjects analysed
    12 [4]
    Units: Number of patients
    4
    Notes
    [4] - Patients who received a second course of olaparib
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Secondary
    End point timeframe
    The time interval between cycle 1 day 1 of the first maintenance course of olaparib to the date of clinical or RECIST defined progression or death, whichever occurred first
    End point values
    		 Second maintenance olaparib
    Number of subjects analysed
    19 [5]
    Units: month
        median (confidence interval 95%)
    8.7 (4.7 to 12.2)
    Notes
    [5] - Patients eligible for platinum 2
    No statistical analyses for this end point

    Secondary: Time to first subsequent therapy

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    End point title
    		 Time to first subsequent therapy
    End point description
    End point type
    Secondary
    End point timeframe
    The time interval between cycle 1 day 1 of the first maintenance course of olaparib to cycle 1 day 1 of platinum 2 or death, whichever occurred first.
    End point values
    		 Second maintenance olaparib
    Number of subjects analysed
    19 [6]
    Units: month
        median (confidence interval 95%)
    11.8 (6.9 to 18.5)
    Notes
    [6] - Patients eligible for platinum 2
    No statistical analyses for this end point

    Secondary: Progression free survival 2

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    End point title
    		 Progression free survival 2
    End point description
    End point type
    Secondary
    End point timeframe
    The time interval between cycle 1 day 1 of the first maintenance course of olaparib to the date of clinical or RECIST-defined progression or death following platinum 2, whichever occurred first.
    End point values
    		 Second maintenance olaparib
    Number of subjects analysed
    19 [7]
    Units: month
        median (confidence interval 95%)
    17.4 (13.6 to 24.7)
    Notes
    [7] - Patients eligible for platinum 2 following progression on their first course of olaparib
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    The time interval from cycle 1 day 1 of the first maintenance course of olaparib to the date of death.
    End point values
    		 Second maintenance olaparib
    Number of subjects analysed
    14 [8]
    Units: month
        median (confidence interval 95%)
    30.5 (17.5 to 43.6)
    Notes
    [8] - Patients whose follow up data could be obtained
    No statistical analyses for this end point

    Post-hoc: Duration of each maintenance course of olaparib

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    End point title
    		 Duration of each maintenance course of olaparib
    End point description
    End point type
    Post-hoc
    End point timeframe
    The timeframe was the duration of each maintenance course of olaparib.
    End point values
    		 Olaparib 1 Olaparib 2
    Number of subjects analysed
    23 [9]
    12 [10]
    Units: month
        arithmetic mean (standard deviation)
    12.1 ± 9.8
    4.4 ± 2.7
    Notes
    [9] - All patients who received a first maintenance course of olaparib whilst on the trial
    [10] - All patients who received a second maintenance course of olaparib
    Statistical analysis title
    		 Olaparib 1 vs olaparib 2 duration
    Statistical analysis description
    To ascertain if there was a significant difference in the mean duration of olaparib 1 and olaparib 2 treatment
    Comparison groups
    Olaparib 1 v Olaparib 2
    Number of subjects included in analysis
    35
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the patient's screening until disease progression on the second course of olaparib or until the patient drops out of the trial.
    Adverse event reporting additional description
    Adverse events were reported for the first and second course of olaparib in addition to any serious adverse events recorded over the duration of the trial.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 -

    Serious adverse events
    		 Single arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 27 (55.56%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    2
    Investigations
    Platelet count decreased
    Additional description: Platelet count decreased
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
    Additional description: Acute coronary syndrome
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    Fever
    Additional description: Fever
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anemia
    Additional description: Anemia
         subjects affected / exposed
    6 / 27 (22.22%)
         occurrences causally related to treatment / all
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    Febrile Neutropenia
    Additional description: Febrile Neutropenia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Eye Infection
    Additional description: Eye Infection
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
    Additional description: Abdominal Pain
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small Intestinal Obstruction
    Additional description: Small Intestinal Obstruction
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion
    Additional description: Pleural Effusion
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
    Additional description: Pneumothorax
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
    Additional description: Acute Kidney Injury
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
    Additional description: Back Pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung Infection
    Additional description: Lung Infection
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
    Additional description: Sepsis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sinusitis
    Additional description: Sinusitis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Single arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 27 (62.96%)
    Investigations
    Platelet Count Decreased
    Additional description: Platelet Count Decreased
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Neutrophil Count Decreased
    Additional description: Neutrophil Count Decreased
         subjects affected / exposed
    8 / 27 (29.63%)
         occurrences all number
    18
    Lymphocyte Count Decreased
    Additional description: Lymphocyte Count Decreased
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Weight Loss
    Additional description: Weight Loss
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Vascular disorders
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
    Additional description: Anemia
         subjects affected / exposed
    7 / 27 (25.93%)
         occurrences all number
    18
    General disorders and administration site conditions
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    10 / 27 (37.04%)
         occurrences all number
    13
    Eye disorders
    Eye Infection
    Additional description: Eye Infection
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal Pain
    Additional description: Abdominal Pain
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    4 / 27 (14.81%)
         occurrences all number
    4
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    6 / 27 (22.22%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
    Additional description: Dyspnea
         subjects affected / exposed
    4 / 27 (14.81%)
         occurrences all number
    4
    Renal and urinary disorders
    Acute Kidney Injury
    Additional description: Acute Kidney Injury
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back Pain
    Additional description: Back Pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Infections and infestations
    Urinary Tract Infection
    Additional description: Urinary Tract Infection
         subjects affected / exposed
    4 / 27 (14.81%)
         occurrences all number
    4
    Lung Infection
    Additional description: Lung Infection
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Anorexia
    Additional description: Anorexia
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Hypomagnesemia
    Additional description: Hypomagnesemia
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2016
    Study documents updated following MHRA commments after initial submission.
    08 Sep 2017
    1. Addition of ctDNA analysis (blood samples) performed by prof Caroline Dive's team 2. archival tumour biopsies can be requested for patients entering at Entry Point 2
    07 Jun 2018
    Protocol was updated to include QP declaration, IB update, PIS/ICF change linked to translational blood collection, clarification of SAE wording, addition of a blood sample collection window (to allow use of bloods taken up to 14 days prior to visit) & addition of archival tumour block collection at entry point 2
    08 Oct 2018
    Change of PI
    18 Jun 2020
    Updated IBs for Olaparib and Cediranib with RSI changes for Olaparib
    07 Jan 2021
    Updated Cediranib IB from edition 22 to 23 and changes o the protocol to incorporate new secondary end point questions
    22 Jun 2021
    Updated Olaparib IB ed 20 with changes added to the protocol and PIS. Updated IRAS form inline with SA#7

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36799931
    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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