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    Clinical Trial Results:
    Open-label, randomized, multicenter, international, parallel exploratory phase II study, comparing 3 FEC-3 Docetaxel chemotherapy to letrozole + palbociclib combination as neoadjuvant treatment of stage II-IIIA PAM 50 ROR-defined low or intermediate risk Luminal breast cancer, in postmenopausal women.

    Summary
    EudraCT number
    		 2014-002560-33
    Trial protocol
    		 FR   BE  
    Global end of trial date
    25 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Nov 2021
    First version publication date
    05 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UC-0140/1404_CARMINA04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02400567
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France, 75013
    Public contact
    Nourredine AIT-RAHMOUNE, UNICANCER, 33 1 71 93 67 04, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT-RAHMOUNE, UNICANCER, 33 1 71 93 67 04, n.ait-rahmoune@unicancer.fr
    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 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to evaluate the ability of each treatment strategy to provide residual cancer burden (RCB) 0-I histological tumor response at surgery (local assessment) in luminal A node-positive (N+) and luminal B patients subgroup.
    Protection of trial subjects
    In order to ensure the protection of the rights, safety and well-being of trial subjects, this clinical trial was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable local regulatory requirements and laws. Furthermore, independent Ethics Committees in France and Belgium reviewed and gave a favorable opinion to the study documents, including the initial protocol and all subsequent amendments, and all information and documents provided to subjects/patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    France: 174
    Worldwide total number of subjects
    186
    EEA total number of subjects
    186
    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)
    110
    From 65 to 84 years
    76
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 NEOPAL was an international multicentric phase II trial comparing two neoadjuvant treatments, the sequential standard chemotherapy (3 FEC 100-3 Docetaxel 100) with the combination of letrozole plus palbociclib in stage II-IIIA Luminal A N+/Luminal B breast cancer patients.

    Pre-assignment
    Screening details
    		 The study consisted of a screening phase before randomization to establish eligibility, a treatment phase (21-day treatment cycles; 19 weeks), and a long-term follow-up to monitor the residual cancer burden, clinical response, relapse-free survival, invasive disease-free survival, breast conservation therapy, and safety.

    Pre-assignment period milestones
    Number of subjects started
    		 186
    Number of subjects completed
    		 106

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Not meeting inclusion criteria: 13
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    Reason: Number of subjects
    		 Prosigma technical failure: 15
    Reason: Number of subjects
    		 Non-luminal breast cancer: 15
    Reason: Number of subjects
    		 Unknown lymph node status: 16
    Reason: Number of subjects
    		 Node-negative: 19
    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
    		 Palbociclib + letrozole
    Arm description
    		 Patients received palbociclib (125 mg oral) once daily on a discontinuous 3/4 weeks schedule (i.e 21 days of palbociclib followed by 7 days off) up to the day prior to surgery plus letrozole (2.5 mg, oral) daily up to the day prior to surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Palbociclib was administered orally (125mg) once a day for 21 days of every 28-day cycle followed by 7 days off treatment until the day prior to surgery, for about 19 weeks. The medication should have been taken orally with a glass of water, approximately at the same time each day, during a meal, preferably in the morning.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was administered orally (2.5 mg) once a day until the day prior to surgery, for about 19 weeks.

    Arm title
    		 FEC100-Docetaxel
    Arm description
    		 Patients received the standard chemotherapy consisting of 3 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC100) followed by 3 cycles of Docetaxel: FEC100 (cycles 1 to 3) ddministrated every 3 weeks (5-FU: 500 mg/m2, 30 minutes IV infusion; Epirubicin: 100 mg/m2, 10 minutes IV infusion, Cyclophosphamide: 500 mg/m2, 30 minutes IV infusion Docetaxel (cycles 4 to 6) administered every 3 weeks, beginning 3 weeks after the last administration of FEC100 (Docetaxel : 100 mg/m2, 60 minutes IV infusion)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2, 30 minutes intravenous infusion at weeks 1, 4, and 7

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m2, 10 minutes intravenous infusion at weeks 1, 4, and 7

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2, 30 minutes intravenous infusion at weeks 1, 4, and 7

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m2, 60 minutes intravenous infusion at weeks 10, 13, and 16

    Number of subjects in period 1 [1]
    		Palbociclib + letrozole FEC100-Docetaxel
    Started
    53
    53
    Completed
    42
    42
    Not completed
    11
    11
         Consent withdrawn by subject
    -
    1
         Disease progression
    5
    8
         Death
    6
    1
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 186 patients were enrolled in this study were screened to determine their breast cancer subtype using the genomic PAM50 test. 106 out of the 186 screened patients were eligible to randomization. The baseline period correspond to these 106 randomized patients.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Palbociclib + letrozole
    Reporting group description
    		 Patients received palbociclib (125 mg oral) once daily on a discontinuous 3/4 weeks schedule (i.e 21 days of palbociclib followed by 7 days off) up to the day prior to surgery plus letrozole (2.5 mg, oral) daily up to the day prior to surgery.

    Reporting group title
    FEC100-Docetaxel
    Reporting group description
    		 Patients received the standard chemotherapy consisting of 3 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC100) followed by 3 cycles of Docetaxel: FEC100 (cycles 1 to 3) ddministrated every 3 weeks (5-FU: 500 mg/m2, 30 minutes IV infusion; Epirubicin: 100 mg/m2, 10 minutes IV infusion, Cyclophosphamide: 500 mg/m2, 30 minutes IV infusion Docetaxel (cycles 4 to 6) administered every 3 weeks, beginning 3 weeks after the last administration of FEC100 (Docetaxel : 100 mg/m2, 60 minutes IV infusion)

    Reporting group values
    		 Palbociclib + letrozole FEC100-Docetaxel Total
    Number of subjects
    		 53 53 106
    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)
    		 26 30 56
        From 65-84 years
    		 27 23 50
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 65 (49 to 78) 63 (48 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 53 53 106
        Male
    		 0 0 0
    Body mass index
    Units: Subjects
        <18
    		 2 1 3
        18-24
    		 16 17 33
        25-30
    		 19 21 40
        >30
    		 15 13 28
        Missing
    		 1 1 2
    Eastern Cooperative Oncology Group
    Units: Subjects
        ECOG 0
    		 44 47 91
        ECOG 1
    		 9 6 15
    Molecular subtype
    Molecular subtype defined by the PAM 50 test
    Units: Subjects
        Luminal A
    		 6 6 12
        Luminal B
    		 47 47 94
    Risk of recurrence
    The risk of recurrence status was defined using the PAM50 test
    Units: Subjects
        Intermediate
    		 7 9 16
        High
    		 46 44 90
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients were included in the intent-to-treat population, whether or not any study medication was administered after randomization, and regardless of the eligibility status. As far as statistical inferences were concerned, patients were analyzed in the treatment group and in the stratum to which they were assigned by the randomization.

    Subject analysis sets values
    		 ITT population
    Number of subjects
    106
    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)
    56
        From 65-84 years
    50
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    63 (48 to 80)
    Gender categorical
    Units: Subjects
        Female
    106
        Male
    0
    Body mass index
    Units: Subjects
        <18
    3
        18-24
    33
        25-30
    40
        >30
    28
        Missing
    2
    Eastern Cooperative Oncology Group
    Units: Subjects
        ECOG 0
    91
        ECOG 1
    15
    Molecular subtype
    Molecular subtype defined by the PAM 50 test
    Units: Subjects
        Luminal A
    12
        Luminal B
    94
    Risk of recurrence
    The risk of recurrence status was defined using the PAM50 test
    Units: Subjects
        Intermediate
    16
        High
    90

    End points

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    End points reporting groups
    Reporting group title
    Palbociclib + letrozole
    Reporting group description
    		 Patients received palbociclib (125 mg oral) once daily on a discontinuous 3/4 weeks schedule (i.e 21 days of palbociclib followed by 7 days off) up to the day prior to surgery plus letrozole (2.5 mg, oral) daily up to the day prior to surgery.

    Reporting group title
    FEC100-Docetaxel
    Reporting group description
    		 Patients received the standard chemotherapy consisting of 3 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC100) followed by 3 cycles of Docetaxel: FEC100 (cycles 1 to 3) ddministrated every 3 weeks (5-FU: 500 mg/m2, 30 minutes IV infusion; Epirubicin: 100 mg/m2, 10 minutes IV infusion, Cyclophosphamide: 500 mg/m2, 30 minutes IV infusion Docetaxel (cycles 4 to 6) administered every 3 weeks, beginning 3 weeks after the last administration of FEC100 (Docetaxel : 100 mg/m2, 60 minutes IV infusion)

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients were included in the intent-to-treat population, whether or not any study medication was administered after randomization, and regardless of the eligibility status. As far as statistical inferences were concerned, patients were analyzed in the treatment group and in the stratum to which they were assigned by the randomization.

    Primary: Residual cancer burden

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    End point title
    		 Residual cancer burden [1]
    End point description
    End point type
    Primary
    End point timeframe
    The main objective of this trial was to evaluate the ability of each treatment strategy to provide residual cancer burden (RCB) 0-I after the completion of neoadjuvant therapy (19 weeks from 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: The primary endpoint was residual cancer burden in breast and axillary lymph nodes after neoadjuvant treatment. The decision rule was that if fewer than 20% RCB 0-I were seen, the palbociclib + letrozole regimen would be regarded as insufficiently active.
    End point values
    		 Palbociclib + letrozole FEC100-Docetaxel ITT population
    Number of subjects analysed
    53
    53
    106
    Units: percent
        number (not applicable)
    7.7
    15.7
    11.7
    No statistical analyses for this end point

    Secondary: Best clinical response

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    End point title
    		 Best clinical response
    End point description
    "Not applicable" refers to 3 patients who did not undergo surgery (1 in the palbociclib + letrozole arm, 2 in the FEC100-Docetaxel arm) and 1 patient with missing data in the FEC100-Docetaxel arm.
    End point type
    Secondary
    End point timeframe
    At surgery, after 8 weeks of treatment
    End point values
    		 Palbociclib + letrozole FEC100-Docetaxel
    Number of subjects analysed
    53
    53
    Units: percent
    number (not applicable)
        Complete response
    16
    15
        Partial response
    22
    23
        Stable disease
    13
    12
        Not applicable
    1
    3
    No statistical analyses for this end point

    Secondary: Rate of breast cancer surgery

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    End point title
    		 Rate of breast cancer surgery
    End point description
    Rates of breast conservation therapy in both arms, with regard to the initially planned surgery.
    End point type
    Secondary
    End point timeframe
    At surgery (Week 8)
    End point values
    		 Palbociclib + letrozole FEC100-Docetaxel
    Number of subjects analysed
    52 [2]
    51 [3]
    Units: percent
        number (confidence interval 95%)
    69.2 (56.6 to 81.9)
    68.6 (55.9 to 81.4)
    Notes
    [2] - 1 patient did not undergo surgery
    [3] - 2 patients did not undergo surgery
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival was defined as the time from the date of randomization to the date of tumor progression, relapse (local, regional, or distant), or death from any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Palbociclib + letrozole FEC100-Docetaxel
    Number of subjects analysed
    53
    53
    Units: percent
        number (confidence interval 95%)
    86.7 (78 to 96.4)
    92 (84.7 to 99.8)
    Statistical analysis title
    		 PFS analysis
    Comparison groups
    Palbociclib + letrozole v FEC100-Docetaxel
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
    Dispersion value
    0.979

    Secondary: Invasive disease-free survival

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    End point title
    		 Invasive disease-free survival
    End point description
    Invasive disease-free survival was defined as the interval between the date of randomization and the date of invasive breast cancer relapse (local, regional, or distant) or the date of invasive contralateral breast cancer or second invasive cancer or death from any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Palbociclib + letrozole FEC100-Docetaxel
    Number of subjects analysed
    53
    53
    Units: percent
        number (confidence interval 95%)
    86.7 (78 to 96.4)
    92 (84.7 to 99.8)
    Statistical analysis title
    		 iDFS analysis
    Comparison groups
    Palbociclib + letrozole v FEC100-Docetaxel
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
    Dispersion value
    0.707

    Secondary: Cnetral RCB 0-I rate

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    End point title
    		 Cnetral RCB 0-I rate
    End point description
    End point type
    Secondary
    End point timeframe
    After the completion of neoadjuvant therapy (19 weeks from randomization)
    End point values
    		 Palbociclib + letrozole FEC100-Docetaxel
    Number of subjects analysed
    53
    53
    Units: percent
        number (confidence interval 95%)
    5.8 (0 to 12.1)
    13.7 (4.1 to 23.2)
    No statistical analyses for this end point

    Post-hoc: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Post-hoc
    End point timeframe
    3 years
    End point values
    		 Palbociclib + letrozole FEC100-Docetaxel
    Number of subjects analysed
    53
    53
    Units: percent
        number (confidence interval 95%)
    90.5 (82.9 to 98.8)
    98.0 (94.1 to 100.0)
    Statistical analysis title
    		 OS analysis
    Comparison groups
    Palbociclib + letrozole v FEC100-Docetaxel
    Number of subjects included in analysis
    106
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
    Dispersion value
    0.047

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall period of the study (up to 3 years after first study intake)
    Adverse event reporting additional description
    For non-serious adverse events, the number of patient affected were the only value available, the number of occurrences were not recorded. Thus, the number of patient affected was entered in both "Subjects affected number" and "Occurrence all number" fields.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Palbociclib + letrozole
    Reporting group description
    		 Patients received palbociclib (125 mg oral) once daily on a discontinuous 3/4 weeks schedule (i.e 21 days of palbociclib followed by 7 days off) up to the day prior to surgery plus letrozole (2.5 mg, oral) daily up to the day prior to surgery.

    Reporting group title
    FEC100-Docetaxel
    Reporting group description
    		 Patients received the standard chemotherapy consisting of 3 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC100) followed by 3 cycles of Docetaxel: FEC100 (cycles 1 to 3) ddministrated every 3 weeks (5-FU: 500 mg/m2, 30 minutes IV infusion; Epirubicin: 100 mg/m2, 10 minutes IV infusion, Cyclophosphamide: 500 mg/m2, 30 minutes IV infusion Docetaxel (cycles 4 to 6) administered every 3 weeks, beginning 3 weeks after the last administration of FEC100 (Docetaxel : 100 mg/m2, 60 minutes IV infusion)

    Serious adverse events
    		 Palbociclib + letrozole FEC100-Docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 52 (15.38%)
    16 / 52 (30.77%)
         number of deaths (all causes)
    6
    1
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma endometrial
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileocecal valve carcinoma
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low grade lymphoma
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion site extravasation
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Chronic subdural hematoma
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischemic attack
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile aplasia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 52 (1.92%)
    8 / 52 (15.38%)
         occurrences causally related to treatment / all
    1 / 1
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis Oral
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Bilateral pneumonia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Palbociclib + letrozole FEC100-Docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 52 (100.00%)
    52 / 52 (100.00%)
    Vascular disorders
    Hot Flashes
         subjects affected / exposed
    20 / 52 (38.46%)
    1 / 52 (1.92%)
         occurrences all number
    20
    1
    Hypertension
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 52 (3.85%)
         occurrences all number
    3
    2
    Lymphocele
         subjects affected / exposed
    3 / 52 (5.77%)
    5 / 52 (9.62%)
         occurrences all number
    3
    5
    General disorders and administration site conditions
    Decrease appetite
         subjects affected / exposed
    2 / 52 (3.85%)
    17 / 52 (32.69%)
         occurrences all number
    2
    17
    Asthenia
         subjects affected / exposed
    21 / 52 (40.38%)
    33 / 52 (63.46%)
         occurrences all number
    21
    33
    Pain
         subjects affected / exposed
    3 / 52 (5.77%)
    5 / 52 (9.62%)
         occurrences all number
    3
    5
    Fatigue
         subjects affected / exposed
    11 / 52 (21.15%)
    14 / 52 (26.92%)
         occurrences all number
    11
    14
    Fever
         subjects affected / exposed
    1 / 52 (1.92%)
    7 / 52 (13.46%)
         occurrences all number
    1
    7
    Hyperthermia
         subjects affected / exposed
    2 / 52 (3.85%)
    5 / 52 (9.62%)
         occurrences all number
    2
    5
    Illness
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Xerosis
         subjects affected / exposed
    1 / 52 (1.92%)
    6 / 52 (11.54%)
         occurrences all number
    1
    6
    Reproductive system and breast disorders
    Vulvovaginal dryness
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    2 / 52 (3.85%)
    10 / 52 (19.23%)
         occurrences all number
    2
    10
    Epistaxis
         subjects affected / exposed
    3 / 52 (5.77%)
    6 / 52 (11.54%)
         occurrences all number
    3
    6
    Nasopharyngitis
         subjects affected / exposed
    1 / 52 (1.92%)
    5 / 52 (9.62%)
         occurrences all number
    1
    5
    Rhinitis
         subjects affected / exposed
    1 / 52 (1.92%)
    6 / 52 (11.54%)
         occurrences all number
    1
    6
    Cough
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 52 (5.77%)
    6 / 52 (11.54%)
         occurrences all number
    3
    6
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 52 (9.62%)
    14 / 52 (26.92%)
         occurrences all number
    5
    14
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 52 (11.54%)
    12 / 52 (23.08%)
         occurrences all number
    6
    12
    Hyperchloraemia
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Creatinine increased
         subjects affected / exposed
    7 / 52 (13.46%)
    3 / 52 (5.77%)
         occurrences all number
    7
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    9 / 52 (17.31%)
    19 / 52 (36.54%)
         occurrences all number
    9
    19
    Hypercalcaemia
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 52 (13.46%)
    3 / 52 (5.77%)
         occurrences all number
    7
    3
    Weight decreased
         subjects affected / exposed
    1 / 52 (1.92%)
    8 / 52 (15.38%)
         occurrences all number
    1
    8
    Cardiac disorders
    Oedema peripheral
         subjects affected / exposed
    2 / 52 (3.85%)
    10 / 52 (19.23%)
         occurrences all number
    2
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 52 (11.54%)
    10 / 52 (19.23%)
         occurrences all number
    6
    10
    Dysgeusia
         subjects affected / exposed
    1 / 52 (1.92%)
    17 / 52 (32.69%)
         occurrences all number
    1
    17
    Neuropathy peripheral
         subjects affected / exposed
    0 / 52 (0.00%)
    9 / 52 (17.31%)
         occurrences all number
    0
    9
    Paraesthesia
         subjects affected / exposed
    2 / 52 (3.85%)
    8 / 52 (15.38%)
         occurrences all number
    2
    8
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    22 / 52 (42.31%)
    38 / 52 (73.08%)
         occurrences all number
    22
    38
    Leukopenia
         subjects affected / exposed
    38 / 52 (73.08%)
    17 / 52 (32.69%)
         occurrences all number
    38
    17
    Lymphopenia
         subjects affected / exposed
    9 / 52 (17.31%)
    25 / 52 (48.08%)
         occurrences all number
    9
    25
    Neutropenia
         subjects affected / exposed
    42 / 52 (80.77%)
    26 / 52 (50.00%)
         occurrences all number
    42
    26
    Thrombocytopenia
         subjects affected / exposed
    15 / 52 (28.85%)
    6 / 52 (11.54%)
         occurrences all number
    15
    6
    Eye disorders
    Increased tear secretion
         subjects affected / exposed
    1 / 52 (1.92%)
    10 / 52 (19.23%)
         occurrences all number
    1
    10
    Conjunctivitis
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Dry eye
         subjects affected / exposed
    1 / 52 (1.92%)
    4 / 52 (7.69%)
         occurrences all number
    1
    4
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    2 / 52 (3.85%)
    6 / 52 (11.54%)
         occurrences all number
    2
    6
    Constipation
         subjects affected / exposed
    5 / 52 (9.62%)
    13 / 52 (25.00%)
         occurrences all number
    5
    13
    Diarrhoea
         subjects affected / exposed
    3 / 52 (5.77%)
    17 / 52 (32.69%)
         occurrences all number
    3
    17
    Abdominal pain
         subjects affected / exposed
    0 / 52 (0.00%)
    4 / 52 (7.69%)
         occurrences all number
    0
    4
    Upper abdominal pain
         subjects affected / exposed
    4 / 52 (7.69%)
    7 / 52 (13.46%)
         occurrences all number
    4
    7
    Stomatitis
         subjects affected / exposed
    6 / 52 (11.54%)
    19 / 52 (36.54%)
         occurrences all number
    6
    19
    Nausea
         subjects affected / exposed
    5 / 52 (9.62%)
    37 / 52 (71.15%)
         occurrences all number
    5
    37
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Aphthous ulcer
         subjects affected / exposed
    7 / 52 (13.46%)
    7 / 52 (13.46%)
         occurrences all number
    7
    7
    Vomiting
         subjects affected / exposed
    1 / 52 (1.92%)
    10 / 52 (19.23%)
         occurrences all number
    1
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 52 (3.85%)
    26 / 52 (50.00%)
         occurrences all number
    2
    26
    Erythema
         subjects affected / exposed
    1 / 52 (1.92%)
    4 / 52 (7.69%)
         occurrences all number
    1
    4
    Pruritus
         subjects affected / exposed
    5 / 52 (9.62%)
    2 / 52 (3.85%)
         occurrences all number
    5
    2
    Dry skin
         subjects affected / exposed
    5 / 52 (9.62%)
    4 / 52 (7.69%)
         occurrences all number
    5
    4
    Acral peeling skin syndrome
         subjects affected / exposed
    0 / 52 (0.00%)
    16 / 52 (30.77%)
         occurrences all number
    0
    16
    Nail disorder
         subjects affected / exposed
    0 / 52 (0.00%)
    13 / 52 (25.00%)
         occurrences all number
    0
    13
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Blood urea increased
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 52 (7.69%)
         occurrences all number
    2
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 52 (17.31%)
    20 / 52 (38.46%)
         occurrences all number
    9
    20
    Muscle spasms
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 52 (5.77%)
         occurrences all number
    3
    3
    Back pain
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Musculoskeletal pain
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Pain in extremity
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Myalgia
         subjects affected / exposed
    3 / 52 (5.77%)
    18 / 52 (34.62%)
         occurrences all number
    3
    18
    Infections and infestations
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 52 (0.00%)
    4 / 52 (7.69%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jan 2015
    - In 2014, preclinical and clinical data demonstrated that the anti-proliferation effect of palbociclib was reversible shortly after the end of treatment. To avoid relapse and disease progression between the end of palbociclib treatment and surgery, the treatment schedule was modified in Arm A to stop the palbociclib treatment 1 day instead of 14 days before surgery. - The primary objective was modified to include only the local evaluation (at the investigator sites) of the RCB. The central RCB evaluation was then evaluated as secondary objective. - The secondary objective disease-free survival was clarified to be evaluate as the invasive disease-free survival.
    15 Dec 2015
    In 2015, the results of the PALOMA-1 and PALOMA-3 studies showed that palbocilib increased hormonal therapy-incuded PFS in the metastatic setting. Based on these results, the investigators decided to include luminal A N- patients in the NEOPAL study to receive a neoadjuvant treatment of palbociclib plus letrozole. These patients were then followed in an open cohort.

    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.
    Recruited patients were mostly luminal B breast cancer with very limited number of luminal A. RCB might not be the most suitable primary Endpoint for the evaluation of neoadjuvant adjuvant therapy. 53 patients were recruited by arm, 60 were planned

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30307466
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    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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