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    Clinical Trial Results:
    Multicentric Single Arm Phase II Clinical Trial, to Evaluate Safety and Efficacy of the Combination of Olaparib and PLD for Platinum Resistant Ovarian Primary Peritoneal Carcinoma, and Fallopian Tube Cancer Patients.

    Summary
    EudraCT number
    		 2016-004850-14
    Trial protocol
    		 ES  
    Global end of trial date
    27 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2023
    First version publication date
    31 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GEICO-1601
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03161132
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español de Investigación en Cáncer de Ovario (GEICO)
    Sponsor organisation address
    C/ Santa Engracia 151, Planta 5ª oficina 2, Madrid, Spain, 28003
    Public contact
    Contact point designated by the Sponsor, MFAR Clinical Research, investigacion@mfar.net
    Scientific contact
    Contact point designated by the Sponsor, MFAR Clinical Research, 0034 93 434 44 12, investigacion@mfar.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
    27 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of the addition of Olaparib to PLD in platinum resistant advanced ovarian cancer patients plus maintenance with Olaparib. The primary endpoint is 6 months progression-free survival rate (PFS6m).
    Protection of trial subjects
    The trial already safety measures to ensure protection of enrolled patients
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 3 screening failures 1 died before receiving the study treatment

    Period 1
    Period 1 title
    Overal study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Single arm, non-randomized, non blided phase II clinical trial

    Arms
    Arm title
    		 Experimental arm
    Arm description
    		 Pegylated liposomal doxorubicin (PLD) was administered as an intravenous infusion at 30 mg/m2 iv for up to 6 cycles (every 28 days). Olaparib was administered orally at 300 mg two-times per day until objective disease progression if in the Investigator’s opinion they were benefiting from treatment and they did not meet any other discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated liposomal doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated liposomal doxorubicin (PLD) was administered as an intravenous infusion at 30 mg/m2 iv for up to 6 cycles (every 28 days).

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Olaparib was administered orally at 300 mg two-times per day until objective disease progression if in the Investigator’s opinion they were benefiting from treatment and they did not meet any other discontinuation criteria.

    Number of subjects in period 1
    		Experimental arm
    Started
    31
    Completed
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental arm
    Reporting group description
    		 Pegylated liposomal doxorubicin (PLD) was administered as an intravenous infusion at 30 mg/m2 iv for up to 6 cycles (every 28 days). Olaparib was administered orally at 300 mg two-times per day until objective disease progression if in the Investigator’s opinion they were benefiting from treatment and they did not meet any other discontinuation criteria.

    Reporting group values
    		 Experimental arm Total
    Number of subjects
    		 31 31
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 31 31
        Male
    		 0 0
    ECOG PS
    Measure Description: Describes a patients's level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working...). The scale ranges from 0 (Fully active, able to carry on all predisease performance without restriction) to 5 (Dead)
    Units: Subjects
        ECOG PS 0
    		 10 10
        ECOG PS 1
    		 21 21
    Histological subtype
    Measure Description: Describes the histology subtype of tumor, the type of cells from which the tumor has arisen.
    Units: Subjects
        Serous
    		 27 27
        Endometrioid
    		 3 3
        Mixed
    		 1 1
    BRCA status
    Measure Description: BRCA1 and BRCA2 are two tumor suppressor genes. Mutations in BRCA genes have been correlated with sensitization to treatments such as olaparib.
    Units: Subjects
        Native
    		 26 26
        Mutant
    		 5 5
    Previous bevacizumab
    Measure Description: Bevacizumab is indicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian. Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth.
    Units: Subjects
        Yes
    		 19 19
        No
    		 12 12
    Cancer antigen 125 (CA-125)
    Measure Description: CA-125 is a blood biomarker that is used to monitor certain cancers during and after treatment. The CA-125 blood levels are used to evaluate response to treatment. Increasing values may indicate worsening of the disease.
    Units: Subjects
        Basal lower than 2 upper limit normal (ULN)
    		 7 7
        Basal higher than 2 upper limit normal (ULN)
    		 24 24
    Neutrophil to lymphocyte ratio (NLR)
    Measure Description: NLR in blood is an indirect measure of the immune system condition and elevated values may indicate pathological processess such as cancer, atherosclerosis, infection, inflammation or others. Patients with cancer and an NLR above the defined cutoff have consistently been found to have worse outcomes than patients with a lower NLR across cancer types. High NLR values have been previously correlated with poor prognosis in platinum-sensitive ovarian cancer
    Units: Subjects
        < 2
    		 11 11
        ≥ 2
    		 20 20
    lymphocyte to monocyte ratio (LMR)
    Measure Description: LMR in blood can indicate systemic inflammatory responses and have proved to be related with the survival of cancer patients.
    Units: Subjects
        < 4
    		 20 20
        ≥ 4
    		 11 11
    Platelet to lymphocytes ratio
    Measure Description: PLR in blood can indicate systemic inflammatory responses and have proved to be related with the survival of cancer patients
    Units: Subjects
        < 125
    		 13 13
        ≥ 125
    		 18 18
    Initial dose of PLD
    Measure Description: The study treatment scheduled was modified after inclusion of a first set of patients. PLD dose was reduced from 40 mg/m2 to 30 mg/m2.
    Units: Subjects
        40 mg/m2
    		 17 17
        30 mg/m2
    		 14 14
    Total previous lines
    Measure Description: Number of previous treatment lines received for ovarian cancer for each patient.
    Units: Number of previous lines
        median (full range (min-max))
    		 2 (1 to 5) -
    Previous platinum lines
    ] Measure Description: Number of previous treatment lines containing platinum chemotherapeutics received for ovarian cancer for each patient
    Units: Number of previous platinum lines
        median (full range (min-max))
    		 2 (1 to 4) -

    End points

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    End points reporting groups
    Reporting group title
    Experimental arm
    Reporting group description
    		 Pegylated liposomal doxorubicin (PLD) was administered as an intravenous infusion at 30 mg/m2 iv for up to 6 cycles (every 28 days). Olaparib was administered orally at 300 mg two-times per day until objective disease progression if in the Investigator’s opinion they were benefiting from treatment and they did not meet any other discontinuation criteria.

    Subject analysis set title
    Experimental arm
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Pegylated liposomal doxorubicin (PLD) was administered as an intravenous infusion at 30 mg/m2 iv for up to 6 cycles (every 28 days). Olaparib was administered orally at 300 mg two-times per day until objective disease progression if in the Investigator’s opinion they were benefiting from treatment and they did not meet any other discontinuation criteria.

    Primary: Progression-free Survival

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    End point title
    		 Progression-free Survival [1]
    End point description
    Proportion of pacients with no progression of disease at 6 months after start of treatment with Olaparib plus PLD
    End point type
    Primary
    End point timeframe
    6 months
    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: Single arm study, no compaison apply. The comparison is established indirectly with the state of the art and previous clinical trials.
    End point values
    		 Experimental arm
    Number of subjects analysed
    31
    Units: Percentage of patients free of event
        number (confidence interval 95%)
    47 (32 to 69)
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Proportion of patients with tumor size reduction. Response duration is measured from the time of initial response until documented tumor progression. The Objective Response Rate (ORR) is defined as the sum of partial responses plus complete responses according to RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    31
    Units: Patients
        Partial response (PR)
    9
        Stable disease (SD)
    15
        Progressive disease (PD)
    6
        Not evaluable (NE)
    1
    No statistical analyses for this end point

    Secondary: Disease Control Rate

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    End point title
    		 Disease Control Rate
    End point description
    Proportion of patients who have achieved complete response, partial response and stable disease of 8 or more months according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    31
    Units: Patients
        Yes
    10
        No
    20
        NE
    1
    No statistical analyses for this end point

    Secondary: Response to Treatment Rate According CA-125 Levels

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    End point title
    		 Response to Treatment Rate According CA-125 Levels
    End point description
    Proportion of patients who have achieved a response according to CA-125: and it has occurred if there is at least a 50% reduction in CA-125 levels from a pretreatment sample.
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    31
    Units: Patients
        Responders
    10
        Non responders
    14
        NE
    7
    No statistical analyses for this end point

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Time from the date of the first dose of study treatment to the date of objective disease progression or death (in the absence of progression) regardless of whether the subject withdraws from study treatment or receives another anticancer therapy prior to progression.
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    31
    Units: Months
    median (confidence interval 95%)
        Overall study, intention to treat (ITT)
    5.8 (4.4 to 9.7)
        PLD 30 mg/m2
    5.8 (4.4 to 100000)
        PLD 40 mg/m2
    5.4 (4 to 13.2)
        BRCA native
    5.4 (4 to 12)
        BRCA mutated
    6.5 (5.3 to 100000)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Time from inclusion until death of any cause.
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    31
    Units: Months
    median (confidence interval 95%)
        Overall study, intention to treat (ITT)
    14.5 (9.9 to 100000)
        BRCA wt
    12.2 (10.6 to 100000)
        BRCA mutated
    21.3 (12.5 to 100000)
    No statistical analyses for this end point

    Secondary: Health Related Quality of Life

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    End point title
    		 Health Related Quality of Life
    End point description
    Change in patient's quality of life during the study, using the self-reported European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) (EORTC QLQ-C30) and the EORTC ovarian cancer module (EORTC-OV-28). Both scores will be combined to report a final outcome. Values range from 0 to 100. higher values indicate better performance status.
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    31
    Units: Arbitrary units
    median (full range (min-max))
        Baseline
    58.3 (16.7 to 100)
        Week 32
    66.7 (16.7 to 83.3)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0

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    End point title
    		 Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
    End point description
    Frequency, nature and number of patients developing adverse events throughout follow up
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Experimental arm
    Number of subjects analysed
    31
    Units: Patients
        Had at least one treatment-related adverse event
    30
        Had no treatment-related adverse event
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period, approximately 5 years.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Experimental arm
    Reporting group description
    		 Pegylated liposomal doxorubicin (PLD) was administered as an intravenous infusion at 30 mg/m2 iv for up to 6 cycles (every 28 days). Olaparib was administered orally at 300 mg two-times per day until objective disease progression if in the Investigator’s opinion they were benefiting from treatment and they did not meet any other discontinuation criteria.

    Serious adverse events
    		 Experimental arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 31 (35.48%)
         number of deaths (all causes)
    25
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Thromboembolic event - G3
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anemia - G3
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia - G4
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutrophil count decreased - G3
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction - G3
         subjects affected / exposed
    4 / 31 (12.90%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction - G2
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction - G5
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Mucositis oral - G3
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Mucositis oral - G4
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion - G3
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Pyelonephritis- G3
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal insufficiency- G2
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Upper respiratory infection - G2
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 31 (100.00%)
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    17 / 31 (54.84%)
         occurrences all number
    17
    Neutrophil count decrease
         subjects affected / exposed
    15 / 31 (48.39%)
         occurrences all number
    15
    Platelet count decrease
         subjects affected / exposed
    7 / 31 (22.58%)
         occurrences all number
    7
    Lymphocyte count decrease
         subjects affected / exposed
    6 / 31 (19.35%)
         occurrences all number
    6
    General disorders and administration site conditions
    Abdominal pain
         subjects affected / exposed
    6 / 31 (19.35%)
         occurrences all number
    6
    Fatigue
         subjects affected / exposed
    21 / 31 (67.74%)
         occurrences all number
    21
    Headache
         subjects affected / exposed
    4 / 31 (12.90%)
         occurrences all number
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 31 (38.71%)
         occurrences all number
    12
    Diarrhoea
         subjects affected / exposed
    11 / 31 (35.48%)
         occurrences all number
    11
    Intestinal obstruction
         subjects affected / exposed
    4 / 31 (12.90%)
         occurrences all number
    4
    Mucositis oral
         subjects affected / exposed
    8 / 31 (25.81%)
         occurrences all number
    8
    Nausea
         subjects affected / exposed
    22 / 31 (70.97%)
         occurrences all number
    22
    Vomits
         subjects affected / exposed
    17 / 31 (54.84%)
         occurrences all number
    17
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    8 / 31 (25.81%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jan 2019
    - Update of inclusion criteria. - Update of information related to the treatment of toxicities associated with the investigational product.
    25 Feb 2020
    Safety modifications in the IB V16 of January 29, 2019. Necessary modification of protocol V3.1 (19DEC19) and HIP-CI V4.0 (19SEP19).
    13 Jul 2020
    Safety modifications in the IB V18 of January 29, 2020. Necessary modification of protocol V4.0 (18MAR2020) and HIP-CI V5.0 (18MAR2020).
    08 Jan 2021
    Safety modifications in IB V19 of August 6, 2020. Necessary modification of protocol V5.0 (8NOV20) and HIP-CI V6.0 (8NOV2020). Change IP H. Dr. Negrin
    15 Jul 2021
    Update of the olaparib investigator's manual (version 20 of January 21, 2021) that includes new information on the safety of patients treated with this medication. HIP-CI _7.0_08 April 2021. IB-olaparib-edition-20.pdf

    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.
    the sample size was small, and toxicity led to dose reuction in a proportion of patients.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/84468
    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
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