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    Clinical Trial Results:
    A multicenter, multinational, randomized, double-blind, pharmacokinetic and pharmacodynamic (PK/PD) dose-finding study of oral netupitant administered concomitantly with oral palonosetron in pediatric cancer patients for the prevention of nausea and vomiting associated with emetogenic chemotherapy.

    Summary
    EudraCT number
    		 2020-003730-20
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2020
    First version publication date
    26 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NEPA-15-31
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03204279
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Helsinn Healthcare SA
    Sponsor organisation address
    Via di Pian Scairolo , Lugano, Switzerland, 6912
    Public contact
    Paolo Villasanta, Helsinn Healthcare SA, paolo.villasanta@helsinn.com
    Scientific contact
    Paolo Villasanta, Helsinn Healthcare SA, paolo.villasanta@helsinn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001198-PIP03-17
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    PK/PD correlation between netupitant exposure and antiemetic efficacy after a single oral netupitant administration, concomitantly with oral palonosetron in pediatric cancer patients receiving chemotherapy
    Protection of trial subjects
    The study was conducted in full compliance with the principles outlined in the Declaration of Helsinki the International Council on Harmonisation (ICH) guidelines [2], as well as all local laws, regulations, and applicable guidelines of the countries in which the study was conducted. The appropriateness of the clinical trial protocol as well as the risks and benefits to study participants were approved by relevant IRBs/IECs. The study meets the ethical requirement in accordance with Article 8(1b) of Directive 2001/83/EC
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    Ukraine: 34
    Worldwide total number of subjects
    67
    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)
    23
    Children (2-11 years)
    28
    Adolescents (12-17 years)
    16
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 12 study sites were active for patient recruitment in Russia (3 sites), Serbia (2 sites), Ukraine (3 sites), and the United States (US) (4 sites). One site in the US screened a patient but he was not enrolled (screen failure). the study period was 22 months from 14 Sept 2017 to 16 Jul 2019

    Pre-assignment
    Screening details
    		 Randomization was used to avoid bias in assigning treatment to patients and to increase the likelihood that known and unknown patient attributes were evenly balanced across treatment groups. Randomization/treatment assignment of eligible patients was done using IWRS integrated with an Electronic Data Capture (EDC) system.

    Period 1
    Period 1 title
    overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Netupitant 1.33 mg/kg plus Palonosetron
    Arm description
    		 single oral dose of Netupitant 1.33 mg/kg up to a maximum of 100 mg (for patients < 3 months of age the netupitant dose will be 0.8 mg/kg) administered with single oral dose of 20 µg/Kg palonosetron up to a maximum of 1.5 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    netupitant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Netupitant 1.33mg/kg up to 100mg

    Arm title
    		 Netupitant 4 mg/kg Plus Palonosetron
    Arm description
    		 Single oral dose of Netupitant 4mg/kg up to a maximum of 300 mg (for patients<3 months of age the netupitant will be 2.4 mg/kg) administered with single oral dose of 20µg/kg palonosetron up to a maximum of 1.5 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    netupitant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    netupitant 4 mg/kg oral suspension up to a maximum of 300 mg

    Number of subjects in period 1
    		Netupitant 1.33 mg/kg plus Palonosetron Netupitant 4 mg/kg Plus Palonosetron
    Started
    34
    33
    Completed
    34
    32
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Netupitant 1.33 mg/kg plus Palonosetron
    Reporting group description
    		 single oral dose of Netupitant 1.33 mg/kg up to a maximum of 100 mg (for patients < 3 months of age the netupitant dose will be 0.8 mg/kg) administered with single oral dose of 20 µg/Kg palonosetron up to a maximum of 1.5 mg

    Reporting group title
    Netupitant 4 mg/kg Plus Palonosetron
    Reporting group description
    		 Single oral dose of Netupitant 4mg/kg up to a maximum of 300 mg (for patients<3 months of age the netupitant will be 2.4 mg/kg) administered with single oral dose of 20µg/kg palonosetron up to a maximum of 1.5 mg

    Reporting group values
    		 Netupitant 1.33 mg/kg plus Palonosetron Netupitant 4 mg/kg Plus Palonosetron Total
    Number of subjects
    		 34 33 67
    Age categorical
    Units: Subjects
        patients 1 months to 3 months of age
    		 1 0 1
        patients 3 month to 6 months of age
    		 3 2 5
        patients 6 months to 1 year of age
    		 4 5 9
        patients 1 year to 2 years
    		 3 5 8
        patients 2 years to 5 years
    		 6 6 12
        patients 5 years to 12 years
    		 8 8 16
        patients 12 years to 18 years
    		 9 7 16
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 6.6 ( 6.29 ) 5.6 ( 5.46 ) -
    Gender categorical
    Units: Subjects
        Female
    		 13 14 27
        Male
    		 21 19 40
    age
    Units: Subjects
        patients 1 month to 3 months
    		 1 0 1
        patients 3 month to 6 months of age
    		 3 2 5
        patients 6 months to 1 year of age
    		 4 5 9
        patients 2 years to 5 years
    		 6 6 12
        patients 5 years to 12 years
    		 8 8 16
        patients 12 years to 18 years
    		 9 7 16
        patients 1 to 2 years
    		 3 5 8

    End points

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    End points reporting groups
    Reporting group title
    Netupitant 1.33 mg/kg plus Palonosetron
    Reporting group description
    		 single oral dose of Netupitant 1.33 mg/kg up to a maximum of 100 mg (for patients < 3 months of age the netupitant dose will be 0.8 mg/kg) administered with single oral dose of 20 µg/Kg palonosetron up to a maximum of 1.5 mg

    Reporting group title
    Netupitant 4 mg/kg Plus Palonosetron
    Reporting group description
    		 Single oral dose of Netupitant 4mg/kg up to a maximum of 300 mg (for patients<3 months of age the netupitant will be 2.4 mg/kg) administered with single oral dose of 20µg/kg palonosetron up to a maximum of 1.5 mg

    Primary: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant

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    End point title
    		 Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant [1]
    End point description
    Mean values of area under the plasma Concentration versus time curve from time zero to infinity (AUC0-inf) of netupitant after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles. AUC estimates are obtained by non-compartmental analysis of population modelpredicted individual plasma concentration-time profiles.
    End point type
    Primary
    End point timeframe
    within 168 hours after netupitant administration. A sampling windows approach will be used by collecting a single blood sample from each patient in one of these time windows: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h and from 120 to 168 h
    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: individual pk parameters were calculated for each arms and descriptive statistics are presented
    End point values
    		 Netupitant 1.33 mg/kg plus Palonosetron Netupitant 4 mg/kg Plus Palonosetron
    Number of subjects analysed
    34
    30
    Units: AUC
    geometric mean (geometric coefficient of variation)
        patients 6 months to 1 year of age
    7637 ( 113 )
    8617 ( 45.2 )
        patients 1 month to 3 months of age
    4460 ( 0 )
    0 ( 0 )
        patients 3 months to 6 months
    3849 ( 91.3 )
    17340 ( 36.4 )
        patients 1 year to 2 years
    2276 ( 29.8 )
    9886 ( 59.6 )
        patients 2 years to 5 years
    3135 ( 44.0 )
    14404 ( 131 )
        patients 5 years to 12 years
    2676 ( 29.8 )
    10154 ( 70.7 )
        patients 12 years to 18 years
    3107 ( 54.9 )
    12266 ( 26.9 )
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) of Netupitant

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Netupitant [2]
    End point description
    End point type
    Primary
    End point timeframe
    A sampling window approach was used by collecting a single blood sample from each patient in one of these time windows: from 2 to 8h, from 24h to 48h, from 72h to 96h and from 120 to 168h
    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: individual pk parameters were calculated for each arms and descriptive statistics are presented
    End point values
    		 Netupitant 1.33 mg/kg plus Palonosetron Netupitant 4 mg/kg Plus Palonosetron
    Number of subjects analysed
    34
    30
    Units: Cmax
    geometric mean (geometric coefficient of variation)
        patient 1 month to 3 months
    60.8 ( 0 )
    0 ( 0 )
        patient 3 months to 6 months
    76.0 ( 27.1 )
    233 ( 4.25 )
        patients to 6 months to 12 months
    133 ( 71.7 )
    255 ( 31.2 )
        patients 1 year to 2 years
    69.5 ( 19.3 )
    275 ( 38.2 )
        patients 2 years to 5 years
    74.0 ( 32.3 )
    266 ( 55.0 )
        patients 5 years to 12 years
    67.9 ( 32.3 )
    213 ( 20.1 )
        patients 12 years to 18 years
    76.8 ( 27.3 )
    274 ( 15.6 )
    No statistical analyses for this end point

    Secondary: percentage of pediatric patients with complete response during the delayed phase

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    End point title
    		 percentage of pediatric patients with complete response during the delayed phase
    End point description
    percentage of pediatric patients with complete response (CR, i.e., no emetic episodes and no rescue medication) during the delayed phase (>24 to 120 h after the start of chemotherapy on day 1) after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles The number and percentage of patients with CR (i.e., no emetic episodes and no rescue medication) during the delayed (>24 to 120 hours), acute (0 to 24 hours), and overall (0 to 120 hours) phases after the start of chemotherapy administration on Day 1, along with the 95% confidence intervals (CIs), are calculated using the Clopper-Pearson (exact) method and are summarized by treatment group, overall, and strata for the FAS.
    End point type
    Secondary
    End point timeframe
    24-120 hours after the start of chemotherapy day 1
    End point values
    		 Netupitant 1.33 mg/kg plus Palonosetron Netupitant 4 mg/kg Plus Palonosetron
    Number of subjects analysed
    34
    31
    Units: percentage
        number (confidence interval 95%)
    70.59 (52.5 to 84.9)
    70.97 (52.0 to 85.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from the first dose of study drug on Visit 2 (day 1, inclusively) until Visit 5 (follow uo, day 14[+3]
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Netupitant 1.33 mg/kg plus Palonosetron
    Reporting group description
    		 -

    Reporting group title
    Netupitant 4 mg/kg Plus Palonosetron
    Reporting group description
    		 -

    Serious adverse events
    		 Netupitant 1.33 mg/kg plus Palonosetron Netupitant 4 mg/kg Plus Palonosetron
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 32 (9.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Neutropenic sepsis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Netupitant 1.33 mg/kg plus Palonosetron Netupitant 4 mg/kg Plus Palonosetron
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 34 (64.71%)
    22 / 32 (68.75%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    White blood cell count decreased
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 34 (26.47%)
    7 / 32 (21.88%)
         occurrences all number
    9
    7
    Febrile neutropenia
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 32 (9.38%)
         occurrences all number
    2
    3
    Leukopenia
         subjects affected / exposed
    8 / 34 (23.53%)
    4 / 32 (12.50%)
         occurrences all number
    8
    4
    Neutropenia
         subjects affected / exposed
    3 / 34 (8.82%)
    6 / 32 (18.75%)
         occurrences all number
    3
    6
    Thrombocytopenia
         subjects affected / exposed
    10 / 34 (29.41%)
    6 / 32 (18.75%)
         occurrences all number
    10
    6
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 34 (2.94%)
    5 / 32 (15.63%)
         occurrences all number
    1
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    Stomatitis
         subjects affected / exposed
    2 / 34 (5.88%)
    5 / 32 (15.63%)
         occurrences all number
    2
    5
    Vomiting
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 32 (9.38%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    hypoglycemia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Feb 2019
    Following a specific recommendation from FDA, for purposes of facilitating enrollment in the study, enrollment of the age cohorts 3 < 6 months and 1 < 3 months and birth < 1 month is allowed in parallel (instead of sequentially), keeping the original treatment dose escalation scheme (i.e., first lowest doses are to be given in parallel in all remaining age cohorts, then highest doses are to be given in parallel in all the remaining age cohorts). This approach was also endorsed by DSMB members.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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