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    Clinical Trial Results:
    “Neo-Adjuvant Treatment with the CDK4,6 inhibitor Palbociclib in HER2-positive and ER-positive breast cancer: effect on Ki67 and apoptosis before, during and after treatment“

    Summary
    EudraCT number
    		 2014-001984-11
    Trial protocol
    		 IT  
    Global end of trial date
    10 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2022
    First version publication date
    06 Jul 2022
    Other versions
    Summary report(s)
    		 Napher2 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    FM-14-B01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02530424
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    FONDAZIONE MICHELANGELO
    Sponsor organisation address
    Via Agostino Bertani 14, milano, Italy,
    Public contact
    Clinical Operation, Michelangelo Tech S.r.l, +39 0287086420, clinical.operation@fondazionemichelangelo.org
    Scientific contact
    Clinical Operation, Michelangelo Tech S.r.l, +39 0287086420, clinical.operation@fondazionemichelangelo.org
    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
    07 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    . Characterize changes of Ki67 from baseline before therapy and at 2 weeks and at surgery (approximately 22 weeks after start of neoadjuvant therapy with HPPF). . Characterize changes in apoptosis from baseline before therapy and at surgery (approximately 22 weeks after start of neoadjuvant therapy with HPPF). . Study the tolerability profile of the combination
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed. Also, all participants gave written informed consent before data collection began.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 May 2015
    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
    Italy: 103
    Worldwide total number of subjects
    103
    EEA total number of subjects
    103
    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)
    90
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First Patient Enrolled: 14 May 2015; Last Patient Enrolled: 16 Feb 2018; Country: Italy.

    Pre-assignment
    Screening details
    		 Female patients aged 18 years or older with histologically confirmed invasive unilateral breast cancer ER+, PgR known (positive for cohort C) suitable for neoadjuvant treatment. HER2 status centrally confirmed (HER2 3+ or neu amplified for cohorts A and B; HER2 1+/2+ without amplification for cohort C); Ki67 > 20% for cohort C; ECOG 0 or 1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A
    Arm description
    		 Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    8 mg/kg loading dose IV, then 6 mg/kg IV q.3 wks (repeat for a total of 6 administrations)

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    840 mg loading dose IV, then 420 mg IV q. 3 wks (repeat for a total of 6 administrations)

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    125 mg po q.d. x 21 q. 4 wks (= 1 cycle; repeat for a total of 5 cycles)

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose (total administrations including the additional one = 6)

    Arm title
    		 Cohort B
    Arm description
    		 Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified receive Trastuzumab+Pertuzumab+Palbociclib (HPP)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    8 mg/kg loading dose IV, then 6 mg/kg IV q.3 wks (repeat for a total of 6 administrations)

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    840 mg loading dose IV, then 420 mg IV q. 3 wks (repeat for a total of 6 administrations)

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    125 mg po q.d. x 21 q. 4 wks (= 1 cycle; repeat for a total of 5 cycles)

    Arm title
    		 Cohort C
    Arm description
    		 Patients with ER positive tumors (> 10%), PgR positive, HER2 1+/2+ (without amplification) and Ki67 > 20% receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    8 mg/kg loading dose IV, then 6 mg/kg IV q.3 wks (repeat for a total of 6 administrations)

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    840 mg loading dose IV, then 420 mg IV q. 3 wks (repeat for a total of 6 administrations)

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    125 mg po q.d. x 21 q. 4 wks (= 1 cycle; repeat for a total of 5 cycles)

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose (total administrations including the additional one = 6)

    Number of subjects in period 1
    		Cohort A Cohort B Cohort C
    Started
    36
    39
    28
    Completed
    30
    26
    23
    Not completed
    6
    13
    5
         Not eligible
    6
    13
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)

    Reporting group title
    Cohort B
    Reporting group description
    		 Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified receive Trastuzumab+Pertuzumab+Palbociclib (HPP)

    Reporting group title
    Cohort C
    Reporting group description
    		 Patients with ER positive tumors (> 10%), PgR positive, HER2 1+/2+ (without amplification) and Ki67 > 20% receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)

    Reporting group values
    		 Cohort A Cohort B Cohort C Total
    Number of subjects
    		 36 39 28 103
    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)
    		 50.3 ( 10.3 ) 48.5 ( 11.8 ) 51.2 ( 12.3 ) -
    Gender categorical
    Units: Subjects
        Women
    		 36 39 28 103
    Race
    Units: Subjects
        caucasian
    		 36 39 28 103
    T stage
    Units: Subjects
        T1c
    		 2 2 2 6
        T2
    		 24 28 21 73
        T3
    		 7 8 4 19
        T4d
    		 3 1 1 5
    Axillary lymph nodes status
    Units: Subjects
        N0
    		 17 14 11 42
        N1
    		 15 24 15 54
        N2
    		 3 1 2 6
        Missing
    		 1 0 0 1
    Histology
    Units: Subjects
        Ductal invasive
    		 34 35 25 94
        Lobular invasive
    		 1 0 2 3
        Other
    		 1 4 1 6
    Tumour grade
    Units: Subjects
        G2
    		 12 18 13 43
        G3
    		 19 20 10 49
        GX
    		 4 1 5 10
        Missing
    		 1 0 0 1
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 63.2 ( 14.2 ) 67.7 ( 14.8 ) 64.4 ( 10.9 ) -
    Largest Breast Lesion diameter by palpation
    Units: centimetre
        arithmetic mean (standard deviation)
    		 4.3 ( 1.6 ) 4.1 ( 1.7 ) 4.1 ( 2.0 ) -
    Axillary largest diameter by palpation
    Units: centimetre
        arithmetic mean (standard deviation)
    		 2.0 ( 0.7 ) 1.9 ( 0.9 ) 1.7 ( 0.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)

    Reporting group title
    Cohort B
    Reporting group description
    		 Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified receive Trastuzumab+Pertuzumab+Palbociclib (HPP)

    Reporting group title
    Cohort C
    Reporting group description
    		 Patients with ER positive tumors (> 10%), PgR positive, HER2 1+/2+ (without amplification) and Ki67 > 20% receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)

    Primary: Ki67 values

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    End point title
    		 Ki67 values [1]
    End point description
    Changes of Ki67 from baseline before therapy and at 2 weeks
    End point type
    Primary
    End point timeframe
    At week 2
    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: All objectives for efficacy and safety were assessed separately for each study cohort. No comparative analyses were planned
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    25
    25
    23
    Units: percent
        median (confidence interval 95%)
    -24.0 (-31.0 to -17.1)
    -25.7 (-31.7 to -19.6)
    -29.5 (-35.5 to -23.5)
    No statistical analyses for this end point

    Primary: Ki67 values

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    End point title
    		 Ki67 values [2]
    End point description
    Changes of Ki67 from baseline before therapy and at surgery
    End point type
    Primary
    End point timeframe
    At surgery (approximately 22 weeks after start of neoadjuvant therapy)
    Notes
    [2] - 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: All objectives for efficacy and safety were assessed separately for each study cohort. No comparative analyses were planned
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    25
    25
    23
    Units: percent
        median (confidence interval 95%)
    -10.9 (-19.3 to -2.6)
    -9.5 (-18.2 to -0.9)
    -19.3 (-24.5 to 14.0)
    No statistical analyses for this end point

    Primary: Apoptosis

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    End point title
    		 Apoptosis [3]
    End point description
    Changes from baseline before therapy and at 2 weeks
    End point type
    Primary
    End point timeframe
    At baseline and at 2 weeks
    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: All objectives for efficacy and safety were assessed separately for each study cohort. No comparative analyses were planned
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    25
    25
    23
    Units: percent
        median (confidence interval 95%)
    -0.5 (-0.9 to -0.1)
    -0.0 (-0.7 to 0.7)
    -0.6 (-1.3 to -0.0)
    No statistical analyses for this end point

    Secondary: Pathological Complete Response

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    End point title
    		 Pathological Complete Response
    End point description
    Absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
    End point type
    Secondary
    End point timeframe
    At surgery
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    30
    23
    26
    Units: subject
        Yes
    8
    0
    5
        No
    22
    23
    21
    No statistical analyses for this end point

    Secondary: Clinical response

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    End point title
    		 Clinical response
    End point description
    Clinical objective response rate
    End point type
    Secondary
    End point timeframe
    At surgery
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    30
    26
    23
    Units: Subject
        Complete response
    15
    9
    3
        Partial response
    14
    14
    15
        Stable disease
    1
    2
    4
        Progressive disease
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study
    Adverse event reporting additional description
    Treatment Emergent Adverse Events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)

    Reporting group title
    Cohort B
    Reporting group description
    		 Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified receive Trastuzumab+Pertuzumab+Palbociclib (HPP)

    Reporting group title
    Cohort C
    Reporting group description
    		 Patients with ER positive tumors (> 10%), PgR positive, HER2 1+/2+ (without amplification) and Ki67 > 20% receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)

    Serious adverse events
    		 Cohort A Cohort B Cohort C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 39 (0.00%)
    0 / 28 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A Cohort B Cohort C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 35 (100.00%)
    38 / 39 (97.44%)
    27 / 28 (96.43%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 39 (7.69%)
    2 / 28 (7.14%)
         occurrences all number
    1
    3
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 39 (7.69%)
    2 / 28 (7.14%)
         occurrences all number
    1
    3
    2
    Vascular disorders
    Hot flush
         subjects affected / exposed
    5 / 35 (14.29%)
    0 / 39 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    5
    0
    3
    Hypertension
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 39 (10.26%)
    3 / 28 (10.71%)
         occurrences all number
    2
    4
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 39 (7.69%)
    4 / 28 (14.29%)
         occurrences all number
    3
    3
    4
    Dysgeusia
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 39 (5.13%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    2
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    11 / 35 (31.43%)
    13 / 39 (33.33%)
    7 / 28 (25.00%)
         occurrences all number
    11
    13
    7
    Pyrexia
         subjects affected / exposed
    4 / 35 (11.43%)
    11 / 39 (28.21%)
    7 / 28 (25.00%)
         occurrences all number
    4
    11
    7
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    24 / 35 (68.57%)
    25 / 39 (64.10%)
    14 / 28 (50.00%)
         occurrences all number
    24
    25
    14
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    26 / 35 (74.29%)
    23 / 39 (58.97%)
    15 / 28 (53.57%)
         occurrences all number
    26
    23
    15
    Stomatitis
         subjects affected / exposed
    5 / 35 (14.29%)
    11 / 39 (28.21%)
    8 / 28 (28.57%)
         occurrences all number
    5
    11
    8
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    8 / 35 (22.86%)
    7 / 39 (17.95%)
    2 / 28 (7.14%)
         occurrences all number
    8
    7
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 35 (5.71%)
    7 / 39 (17.95%)
    2 / 28 (7.14%)
         occurrences all number
    2
    7
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 39 (5.13%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 39 (2.56%)
    3 / 28 (10.71%)
         occurrences all number
    1
    1
    3
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 39 (5.13%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2015
    The protocol was first amended (Protocol Version 2, amendment 1, July 6, 2015) because accumulating data on safety and tolerability of palbociclib in combination with other antineoplastic agents allowed to better clarify intervention with palbociclib in the presence of defined types and grades of adverse events. In addition, patients who experience grade and frequency of adverse events requiring decrease of the palbociclib dose level to 75 mg, if clinically stable and fully recovered from the adverse event, were allowed to re-escalate to 100 mg per investigator’s discretion.
    22 Mar 2016
    A second amendment (amendment 2, Protocol Version 3, March 22, 2016) was activated to allow inclusion of new study cohorts based on available preclinical and clinical literature data. The two new cohorts were Cohort B: Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified who were planned to receive Trastuzumab+Pertuzumab+Palbociclib (HPP) without fulvestrant. Allocation to Cohort B had to be started after completion of recruitment to Cohort A. Cohort C: Patients with ER positive tumors (> 10%), PgR positive, HER2 1+/2+ and Ki67 > 20% who were planned to receive Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF).

    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.
    Due to the somehow slower rate of accrual in Cohort C, the registration of patients in this cohort was discontinued on February 2018 although less than 32 patients were registered.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29326029
    http://www.ncbi.nlm.nih.gov/pubmed/29326028
    http://www.ncbi.nlm.nih.gov/pubmed/35013314
    For support, Contact us.
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