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    Clinical Trial Results:
    A phase 2, randomized, open label study to evaluate the efficacy, safety, pharmacodynamics, pharmacokinetics of the anti-ALK-1 MAB PF-03446962 in combination with best supportive care vs. best supportive care alone in adult patients with advanced hepatocellular carcinoma.

    Summary
    EudraCT number
    2013-001426-26
    Trial protocol
    IT   ES  
    Global end of trial date
    09 Jul 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    25 May 2016
    First version publication date
    21 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A8471005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01911273
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    ClinicalTrials.gov Call Centre, Pfizer Inc, +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    ClinicalTrials.gov Call Centre, Pfizer Inc, +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    09 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine whether overall survival (OS) of PF-03446962 plus best supportive care (BSC) is superior to OS of BSC in subjects with advanced HCC following sorafenib failure.
    Protection of trial subjects
    The study was conducted in accordance with legal and regulatory requirements, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International Conference on Harmonization [ICH] 1996), and the Declaration of Helsinki (World Medical Association, 1996 & 2008 versions). In addition, the study was conducted in accordance with the protocol, the ICH guideline on GCP, and applicable local regulatory requirements and laws.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Scientific research
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 3
    Worldwide total number of subjects
    3
    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)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Only 3 subjects were randomized under the open-lable study design: 1 subject in Arm A (PF-03446962 plus BSC) and 2 in Arm B (BSC alone). The 2 subjects randomized to Arm B (BSC alone) withdrew the consent after being aware of the assigned arm.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    PF-03446962 plus BSC
    Arm description
    PF-03446962 7 milligram per kilogram (mg/kg) was administered intravenously (IV) as 1-hour infusion every two weeks (q2w) plus BSC.
    Arm type
    Active comparator

    Investigational medicinal product name
    PF-03446962
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    PF-03446962 7 mg/kg was administered IV as 1-hour infusion q2w plus BSC.

    Arm title
    BSC alone
    Arm description
    BSC might vary depending on the subject's signs and symptoms, site current practice, and country practice and might include medications and supportive measures deemed necessary to palliate disease-related symptoms and improve quality of life.
    Arm type
    best supportive care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    PF-03446962 plus BSC BSC alone
    Started
    1
    2
    Premature termination of the study
    0
    0
    Completed
    0
    0
    Not completed
    1
    2
         Premature termination of the study
    1
    -
         Consent withdrawn by subject
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-03446962 plus BSC
    Reporting group description
    PF-03446962 7 milligram per kilogram (mg/kg) was administered intravenously (IV) as 1-hour infusion every two weeks (q2w) plus BSC.

    Reporting group title
    BSC alone
    Reporting group description
    BSC might vary depending on the subject's signs and symptoms, site current practice, and country practice and might include medications and supportive measures deemed necessary to palliate disease-related symptoms and improve quality of life.

    Reporting group values
    PF-03446962 plus BSC BSC alone Total
    Number of subjects
    1 2 3
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    1 2 3
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    1 0 1
        Male
    0 2 2

    End points

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    End points reporting groups
    Reporting group title
    PF-03446962 plus BSC
    Reporting group description
    PF-03446962 7 milligram per kilogram (mg/kg) was administered intravenously (IV) as 1-hour infusion every two weeks (q2w) plus BSC.

    Reporting group title
    BSC alone
    Reporting group description
    BSC might vary depending on the subject's signs and symptoms, site current practice, and country practice and might include medications and supportive measures deemed necessary to palliate disease-related symptoms and improve quality of life.

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS) [1]
    End point description
    OS was the duration from date of randomization to date of death due to any cause. For subjects who are alive, overall survival was censored at the last contact. Death was determined from adverse event (AE) data where outcome was death or from follow-up contact data where the subject current status was death. Analysis population description: Full analysis set (FAS) included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Primary
    End point timeframe
    From first randomization to date of death from any cause, whichever came first, assessed up to 24 months after last subject randomization.
    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: Insufficient data available to conduct adequate analysis due to premature termination of the study.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [2]
    2 [3]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [2] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [3] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    No statistical analyses for this end point

    Secondary: Time to Tumor Progression (TTP)

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    End point title
    Time to Tumor Progression (TTP)
    End point description
    TTP was defined as the time from first randomization to date of first documentation of objective tumor progression. If tumor progession data included more than (>) 1 date, the first date was to be used. TTP (in months) was calculated as first event date or last known progression-free date minus the first randomization date plus 1 divided by 30.4. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease per Respones Evaluation Criteria in Solid Tumors [RECIST]). Analysis population description: FAS included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Screening and every 8 weeks by calendar thereafter, up to 24 months after last subject randomization.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [4]
    2 [5]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [4] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [5] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS was defined as the time from randomization to first documentation of objective tumor progression or to death due to any cause, whichever occured first. If tumor progression data included >1 date, the first date was to be used. PFS (in months) was calculated as first event date minus first randomization date plus 1 divided by 30.4. Analysis population description: FAS included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Screening and every 8 weeks by calendar thereafter, up to 24 months after last subject randomization.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [6]
    2 [7]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [6] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [7] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) - Percentage of Participants With Objective Response

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    End point title
    Objective Response Rate (ORR) - Percentage of Participants With Objective Response
    End point description
    ORR was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.1, relative to all randomized participants. CR were those that persisted on repeat imaging study more than or equal to (>=) 4 weeks after initial documentation of response. PR was defined as >=30% decrease in the sum of diameters of target lesions and non CR/non PD to non-target lesions. Participants who did not have on study radiographic tumor re-evaluation or who died, progressed or dropped out for any reason prior to reaching a CR or PR were to be counted as non-responders in the assessment of ORR. A participant who initially met the criteria for a PR and then subsequently became a confirmed CR, was to be assigned a best response of CR. Analysis population description: FAS included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Screening and every 8 weeks by calendar thereafter, up to 24 months after last subject randomization.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [8]
    2 [9]
    Units: Percentage of Subjects
        number (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [8] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [9] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    No statistical analyses for this end point

    Secondary: Duration of Response (DR)

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    End point title
    Duration of Response (DR)
    End point description
    DR was defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. If tumor progression data included >1 date, the first date was to be used. DR (in months) was calculated as the end date for DR minus date of first CR or PR that was subsequently confirmed plus 1 divided by 30.4. CR was defined as disapperance of all target lesions and non-target, if any. PR was defined as >=30% decrease in the sum of diameters of target lesions and non CR/non PD to non-target lesions. Analysis population description: Subgroup of subjects with objective response. Since objective response was not assessed in any of the subjects, ideally the number of subjects analyzed field should be 0 and the reason was insufficient data available to conduct adequate analysis due to premature termination of the study.
    End point type
    Secondary
    End point timeframe
    From first randomization to date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months after last subject randomization
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [10] - No data displayed because Outcome Measure has zero total subjects analyzed.
    [11] - No data displayed because Outcome Measure has zero total subjects analyzed.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Disease Control Rate (DCR) at 16 Weeks

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    End point title
    Percentage of Subjects with Disease Control Rate (DCR) at 16 Weeks
    End point description
    DCR was defined as the proportion of subjects with confirmed CR or confirmed PR or a best response of stable disease (SD) >=16 weeks according to RECIST, relative to all randomized subjects. CR was defined as disapperance of all target lesions. PR was defined as >=30% decrease in the sum of diameters of target lesions and non CR/non PD to non-target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Analysis population description: FAS included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    From first randomization to date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months after last participant randomization.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [12]
    2 [13]
    Units: Percentage of Participants
        number (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [12] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [13] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire (FACT-Hep)

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    End point title
    Change From Baseline in Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire (FACT-Hep)
    End point description
    Patient reported outcomes (PROs) were assessed using the FACT-Hep. The FACT-Hep included the FACT-general (FACT-G) and a hepatobiliary module, it consisted of the 27-item FACT-G, which assessed generic health-related quality of life (HRQoL) concerns, and the 18-item hepatobiliary subscale (HS), which assessed disease-specific issues. The questionnaire used a 5 point Likert scale from ‘0’ “not at all” to ‘4’ “very much” regarding how much each item was present in the last 7 days; lower score indicated severer symptom. Eight of the items (lack of energy, pain, weight loss, back pain, fatigue, stomach pain/discomfort, nausea, and jaundice) made up the Fact Hepatobiliary Symptom Index (FHSI 8) were considered to be symptoms specific to hepatobiliary cancer. Analysis population description: FAS included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Screening, Cycle 1 Day1,8; Cycle >=2 Day 1; End of treatment, survival follow-up up to 24 months after last subject randomization.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [14]
    2 [15]
    Units: Unites on Scale
        log mean (standard deviation)
    99999 ± 99999
    99999 ± 99999
    Notes
    [14] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [15] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    No statistical analyses for this end point

    Secondary: Maximum PF-03446962 Serum Concentration (Cmax)

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    End point title
    Maximum PF-03446962 Serum Concentration (Cmax)
    End point description
    Analysis population description: The pharmacokinetic (PK) concentration set consisted of all subjects who were treated and had at least one concentration on at least 1 day of PK assessment.
    End point type
    Secondary
    End point timeframe
    1 hour (after start of infusion) on Day1 of Cycles 1, 2, 4, 6, and 8
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [16]
    0 [17]
    Units: microgram per milliliter (mcg/mL)
        geometric mean (standard deviation)
    99999 ± 99999
    ±
    Notes
    [16] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [17] - No specimen were analyzed
    No statistical analyses for this end point

    Secondary: Trough Serum Concentration of PF-03446962 (Ctrough)

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    End point title
    Trough Serum Concentration of PF-03446962 (Ctrough)
    End point description
    Analysis population description: The PK concentration set consisted of all subjects who were treated and had at least one concentration on at least 1 day of PK assessment.
    End point type
    Secondary
    End point timeframe
    0 hour (predose) on Day 1 of Cycles 1, 2, 4, 6, and 8
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [18]
    0 [19]
    Units: mcg/mL
        geometric mean (standard deviation)
    99999 ± 99999
    ±
    Notes
    [18] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [19] - No specimen were analyzed
    No statistical analyses for this end point

    Secondary: Number of Subjects with Human Anti-Human Antibodies (HAHA)

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    End point title
    Number of Subjects with Human Anti-Human Antibodies (HAHA)
    End point description
    Analysis population description: The immunogenicity assessment consisted of all subjects who had at least 1 sample on at least 1 day of immunogenicity assessment.
    End point type
    Secondary
    End point timeframe
    Cycle 1, 2, 4, 6, 8 Day 1 at 0 hour (pre-dose)
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [20]
    0 [21]
    Units: Subjects
        number (not applicable)
    99999
    Notes
    [20] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [21] - No specimen were analyzed
    No statistical analyses for this end point

    Secondary: Presence of Sensitivity Signature

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    End point title
    Presence of Sensitivity Signature
    End point description
    Tumor molecular characteristics including but not limited to transcriptomic (RNA) signatures of sensitivity. Analysis population description: FAS included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (before infusion), Cycle 4 Day 1 (before infusion), at disease progression/subject withdrawl.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: Percentage
        number (not applicable)
    Notes
    [22] - No data displayed because Outcome Measure has zero total subjects analyzed.
    [23] - No data displayed because Outcome Measure has zero total subjects analyzed.
    No statistical analyses for this end point

    Secondary: Ratio to Baseline of Serum Circulating Protein Concentration

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    End point title
    Ratio to Baseline of Serum Circulating Protein Concentration
    End point description
    Protein involved TGFB1, VEGF-A, VEGF-C, PIGF, Endoglin, BMP-9, VEGFR1, VEGFR2, VEGFr3, Ang-2, VEGF-D, CD54, CD106, and CCL2. Tumor molecular characteristics including but not limited to transcriptomic (ribonucleic acid) signatures of efficacy. Analysis population description: FAS included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (before infusion), Cycle 4 Day 1 (before infusion), at disease progression/subject withdrawl.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [24]
    0 [25]
    Units: Percentage
        number (not applicable)
    99999
    Notes
    [24] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [25] - No data displayed because Outcome Measure has zero total subjects analyzed.
    No statistical analyses for this end point

    Secondary: Observed Serum Concentration of Circulating Protein

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    End point title
    Observed Serum Concentration of Circulating Protein
    End point description
    Analysis population description: FAS included all randomized subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (before infusion), Cycle 4 Day 1 (before infusion), at disease progression/subject withdrawl.
    End point values
    PF-03446962 plus BSC BSC alone
    Number of subjects analysed
    1 [26]
    0 [27]
    Units: mcg/mL
        number (not applicable)
    99999
    Notes
    [26] - Insufficient data available to conduct adequate analysis due to premature termination of the study.
    [27] - No data displayed because Outcome Measure has zero total subjects analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to 28 days after the last administration of study medication.
    Adverse event reporting additional description
    Three subjects were assigned to receive study treatment, as of study termination date. One subject was assigned to receive PF-03446962 plus BSC treatment and discontinued due to progression of disease; 2 were assigned to receive BSC only treatment and discontinued due to withdrawal of consent.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    PF-03446962 plus BSC
    Reporting group description
    PF-03446962 7 mg/kg was administered IV as 1-hour infusion q2w plus BSC.

    Reporting group title
    BSC alone
    Reporting group description
    BSC might vary depending on the subject's signs and symptoms, site current practice, and country practice and might include medications and supportive measures deemed necessary to palliate disease-related symptoms and improve quality of life.

    Serious adverse events
    PF-03446962 plus BSC BSC alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    PF-03446962 plus BSC BSC alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2013
    1) Section 5.2.5, Dose Reductions: Table 2, “PF 03446962 Dose Modification at Start of Subsequent Cycle” updated to reflect the most common type of toxicities associated with the administration of PF 03446962. 2) In agreement with updated Table 2, amylase and lipase have been added to Appendix 2, List of Laboratory Tests. 3) Schedule of Activities: time of collection of Banked Biospecimens, Blood Sample for Soluble Proteins and HAHA corrected.
    04 Nov 2013
    1) The description of the safety profile of PF 0344962 has been expanded and updated in agreement with the current IB. 2) Some study secondary objectives have been expanded in order to clarify the translational research component of the study. The relevant study endpoints have also been clarified. 3) In order to limit patient burden and to support the identification of mechanism of resistance to PF 0344962, mandatory tumor biopsy collection at the time of disease progression has been limited to those patients randomized to PF 0344962 (Arm A) who progress after showing objective response or stable disease for at least 16 weeks after randomization. 4) The duration of treatment/active observation periods have been clarified in the study design section. 5) Some patient selection criteria have been clarified. Patients with known portal hypertension and untreated high risk esophageal varices have been excluded. Patients with history of any other malignancy in the previous 3 years have also been excluded. 6) Dose Modification Criteria for PF 03446962 have been clarified. 7) Schedule of Activities: inconsistencies between table and footnotes and some protocol sections have been fixed. Some footnotes have been reworded to improve clarity.IRC description has been added. 8) PRO testing on Day 8 of Cycle 1 has been added to Arm B. 9) EoT in non Member States has been defined. 10) Appendix 2 List of Laboratory Tests has been clarified. 11) Appendix 4 List of abbreviations and definitions of terms has been added. 12) Typos and minor inconsistencies have been fixed across the protocol.
    08 Apr 2014
    1) The study design has been changed from open label to double blind in order to minimize the risk of premature dropout from the comparator arm and preserve the integrity of the study. 2) Schedule of Activities and assessment types and frequencies have been made identical in both treatment arms. 3) A statement relevant to failure of targeted agents to show clinical benefit in the 2nd line treatment of HCC has been included upon IRB/health authority request. 4) Timing of adverse events and laboratory abnormalities occurrence has been removed from relevant secondary endpoints since it is not part of the standard safety analysis. 5) Reference to the pathology report and statement has been removed from the protocol with details included in the Study Manual. 6) The description of the Internal Review Committee role has been elaborated. 7) Editorial changes to address typos and align protocol language with updated protocol template have been made.

    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 study was prematurely terminated due to a Sponsor decision not to pursure the clinical development of PF-03446962 as monotherapy in second-line HCC. Primary and secondary objectives were not achived in this study due to the premature termination
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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