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    Clinical Trial Results:
    The AIM-HN and SEQ-HN Study: A 2 Cohort, Non-comparative, Pivotal Study Evaluating the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations (AIM-HN) and the Impact of HRAS Mutations on Response to First Line Systemic Therapies for HNSCC (SEQ-HN)

    Summary
    EudraCT number
    		 2018-001437-40
    Trial protocol
    		 ES   DE   GB   NO   BE   AT   NL   GR   DK   IT  
    Global end of trial date
    02 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 May 2024
    First version publication date
    04 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KO-TIP-007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03719690
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kura Oncology, Inc.
    Sponsor organisation address
    12730 High Bluff Drive, Suite 400, San Diego, United States, CA 92130
    Public contact
    Clinical Operations, Kura Oncology, Inc., KO-TIP-007@kuraoncology.com
    Scientific contact
    Clinical Operations, Kura Oncology, Inc., KO-TIP-007@kuraoncology.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
    02 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to determine the objective response rate (ORR) of tipifarnib in participants with Head and Neck Squamous Cell Carcinoma (HNSCC) with Harvey rat sarcoma virus gene homolog (HRAS) mutations with a variant allele frequency (VAF) ≥20% (High VAF population), as assessed by Independent Review Facility (IRF).
    Protection of trial subjects
    This study was conducted in accordance with the Note for Guidance on Good Clinical Practice International Council for Harmonisation, Harmonised Tripartite Guideline E6 (R1)/Integrated Addendum E6 (R2); United States Food and Drug Administration Code of Federal Regulations (Title 21 Parts 50, 56, 312), requirements for the conduct of clinical studies as provided in the European Union Directive 2011/20/EC; the general guidelines indicated in the Declaration of Helsinki; and all applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 131
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Spain: 56
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Thailand: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    Taiwan: 16
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Australia: 3
    Worldwide total number of subjects
    296
    EEA total number of subjects
    105
    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)
    175
    From 65 to 84 years
    118
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 296 participants were enrolled (59 participants in AIM-HN and 237 participants in SEQ-HN) in 14 countries between March 2019 and May 2023.

    Pre-assignment
    Screening details
    		 This study consisted of 2 non-comparative sub-studies: (1) an interventional open-label, single-arm, pivotal study evaluating the efficacy of tipifarnib in mHRAS HNSCC (AIM-HN) and (2) an observational study to evaluate the impact of HRAS mutations on response to first line systemic therapies for HNSCC (SEQ-HN).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tipifarnib Treatment Cohort: AIM-HN
    Arm description
    		 Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, twice a day (bid) on Days 1-7 and 15-21 of 28-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tipifarnib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet for oral administration.

    Arm title
    		 Observational Cohort: SEQ-HN
    Arm description
    		 Participants with HNSCC in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consented to provide first line outcome data and additional follow-up.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Tipifarnib Treatment Cohort: AIM-HN Observational Cohort: SEQ-HN
    Started
    59
    237
    Safety Analysis Set (SAS)
    59
    0
    Modified Intent-to-Treat Analysis Set
    59
    0
    Completed
    0
    0
    Not completed
    59
    237
         Consent withdrawn by subject
    5
    10
         Death
    40
    149
         Miscellaneous
    12
    56
         Lost to follow-up
    2
    18
         Unwilling or unable to comply with requirements
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tipifarnib Treatment Cohort: AIM-HN
    Reporting group description
    		 Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, twice a day (bid) on Days 1-7 and 15-21 of 28-day cycles.

    Reporting group title
    Observational Cohort: SEQ-HN
    Reporting group description
    		 Participants with HNSCC in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consented to provide first line outcome data and additional follow-up.

    Reporting group values
    		 Tipifarnib Treatment Cohort: AIM-HN Observational Cohort: SEQ-HN Total
    Number of subjects
    		 59 237 296
    Age categorical
    Units: Subjects
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 31 144 175
        >=65 years
    		 28 93 121
    Gender categorical
    Units: Subjects
        Female
    		 15 59 74
        Male
    		 44 178 222
    Race
    Units: Subjects
        White
    		 33 180 213
        Black or African American
    		 1 10 11
        Asian
    		 23 37 60
        American Indian or Alaska Native
    		 0 2 2
        Other
    		 2 7 9
        Missing
    		 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 8 8
        Not Hispanic or Latino
    		 55 217 272
        Not Reported
    		 3 9 12
        Unknown
    		 1 3 4
    Variant Allele Frequency (VAF) Status
    Genetic testing was done for tumor tissue to confirm mutant (variant) allele frequency at Baseline. Data collection and analysis of VAF status for participants in the Observational SEQ-HN Cohort was not pre-specified.
    Units: Subjects
        Participants with low VAF (< 20%)
    		 9 0 9
        Participants with high VAF (>= 20%)
    		 50 0 50
        Not Applicable
    		 0 237 237

    End points

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    End points reporting groups
    Reporting group title
    Tipifarnib Treatment Cohort: AIM-HN
    Reporting group description
    		 Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, twice a day (bid) on Days 1-7 and 15-21 of 28-day cycles.

    Reporting group title
    Observational Cohort: SEQ-HN
    Reporting group description
    		 Participants with HNSCC in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consented to provide first line outcome data and additional follow-up.

    Primary: Objective Response Rate (ORR) in High Variable Allele Frequency (VAF) Population, as Assessed by Independent Review Facility (IRF)

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    End point title
    		 Objective Response Rate (ORR) in High Variable Allele Frequency (VAF) Population, as Assessed by Independent Review Facility (IRF) [1] [2]
    End point description
    ORR was defined as the percentage of participants who experienced a best overall response (BOR) of complete response (CR; disappearance of all target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by IRF. 95% confidence interval (CI) was calculated by the exact binomial (Clopper-Pearson) method. Modified Intent-to-Treat (mITT) Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF only. Data collection and analysis of ORR for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Primary
    End point timeframe
    Up to approximately 28 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analyses were pre-specified for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    50 [3]
    Units: percentage of participants
        number (confidence interval 95%)
    20.0 (10.03 to 33.72)
    Notes
    [3] - High VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: ORR in All VAF Population, as Assessed by IRF

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    End point title
    		 ORR in All VAF Population, as Assessed by IRF [4]
    End point description
    ORR was defined as the percentage of participants who experienced a BOR of CR or PR and was assessed using RECIST v1.1 by IRF. 95% CI was calculated by the exact binomial (Clopper-Pearson) method. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants. Data collection and analysis of ORR for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    59 [5]
    Units: percentage of participants
        number (confidence interval 95%)
    18.6 (9.69 to 30.91)
    Notes
    [5] - All VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in High VAF Population, as Assessed by IRF

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    End point title
    		 Duration of Response (DoR) in High VAF Population, as Assessed by IRF [6]
    End point description
    DoR was defined as the time from the date of first response (CR or PR [whichever occurred first]) to the date of progression of disease or death of any cause, whichever occurred first, in participants with a confirmed CR or PR and was assessed using RECIST v1.1 by IRF. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation. Values of "99999" indicate the upper CI was not reached due to lack of events. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF and available data only. Data collection and analysis of DoR for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    10 [7]
    Units: months
        median (confidence interval 95%)
    6.51 (3.877 to 99999)
    Notes
    [7] - High VAF Population (mITT Analysis Set) with CR or PR
    No statistical analyses for this end point

    Secondary: DoR in All VAF Population, as Assessed by IRF

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    End point title
    		 DoR in All VAF Population, as Assessed by IRF [8]
    End point description
    DoR was defined as the time from the date of first response (CR or PR [whichever occurred first]) to the date of progression of disease or death of any cause, whichever occurred first, in participants with a confirmed CR or PR and was assessed using RECIST v1.1 by IRF. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation. Values of "99999" indicate the upper CI was not reached due to lack of events. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants with available data. Data collection and analysis of DoR for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    11 [9]
    Units: months
        median (confidence interval 95%)
    6.51 (3.877 to 99999)
    Notes
    [9] - All VAF Population (mITT Analysis Set) with CR or PR
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in High VAF Population, as Assessed by IRF

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    End point title
    		 Progression Free Survival (PFS) in High VAF Population, as Assessed by IRF [10]
    End point description
    PFS was defined as months from the first dose of the study drug to the first documented progressive disease (PD, appearance of one or more new lesions or at least a 20% increase in the sum of the diameters of target lesions) or death, whichever came first and was assessed using RECIST v1.1 by IRF. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF and available data only. Data collection and analysis of PFS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    50 [11]
    Units: months
        median (confidence interval 95%)
    2.60 (1.873 to 4.402)
    Notes
    [11] - High VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: PFS in All VAF Population, as Assessed by IRF

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    End point title
    		 PFS in All VAF Population, as Assessed by IRF [12]
    End point description
    PFS was defined as months from the first dose of the study drug to the first documented PD or death, whichever came first and was assessed using RECIST v1.1 by IRF. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants with available data. Data collection and analysis of PFS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to 28 approximately months
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    59 [13]
    Units: months
        median (confidence interval 95%)
    2.23 (1.873 to 3.548)
    Notes
    [13] - All VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: PFS Rate in High VAF Population, as Assessed by IRF

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    End point title
    		 PFS Rate in High VAF Population, as Assessed by IRF [14]
    End point description
    PFS rate was defined as the percentage of participants who had not experienced documented PD or death, whichever came first and was assessed using RECIST v1.1 by IRF at 6 and 9 month timepoints. Percentage of participants was calculated using the Kaplan-Meier method. 95% CI was calculated using normal approximation to the log transformed cumulative hazard rate. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF and available data only. Data collection and analysis of PFS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    6 months and 9 months
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    50 [15]
    Units: percentage of participants
    number (confidence interval 95%)
        6 months
    29 (16.2 to 42.9)
        9 months
    20 (8.9 to 33.6)
    Notes
    [15] - High VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: PFS Rate in All VAF Population, as Assessed by IRF

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    End point title
    		 PFS Rate in All VAF Population, as Assessed by IRF [16]
    End point description
    PFS rate was defined as the percentage of participants who had not experienced documented PD or death, whichever came first and was assessed using RECIST v1.1 by IRF at 6 and 9 month timepoints. Percentage of participants was calculated using the Kaplan-Meier method. 95% CI was calculated using normal approximation to the log transformed cumulative hazard rate. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants with available data. Data collection and analysis of PFS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    6 months and 9 months
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    59 [17]
    Units: percentage of participants
    number (confidence interval 95%)
        6 months
    26 (14.9 to 38.4)
        9 months
    18 (8.9 to 30.8)
    Notes
    [17] - All VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in High VAF Population

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    End point title
    		 Overall Survival (OS) in High VAF Population [18]
    End point description
    OS was defined as months from first dose date until death from any cause. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF. Data collection and analysis of OS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    50 [19]
    Units: months
        median (confidence interval 95%)
    6.97 (4.895 to 11.466)
    Notes
    [19] - High VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: OS in All VAF Population

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    End point title
    		 OS in All VAF Population [20]
    End point description
    OS was defined as months from first dose date until death from any cause. Median was calculated using the Kaplan-Meier method. 95% CI was based on Brookmeyer and Crowley method with log-log transformation. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants. Data collection and analysis of OS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    59 [21]
    Units: months
        median (confidence interval 95%)
    6.21 (4.370 to 9.035)
    Notes
    [21] - All VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: OS Rate at 12 Months in High VAF Population

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    End point title
    		 OS Rate at 12 Months in High VAF Population [22]
    End point description
    OS rate was defined as the percentage of participants who had not experienced or death and was assessed at 12 months. Percentage of participants was calculated using the Kaplan-Meier method. 95% CI was calculated using normal approximation to the log transformed cumulative hazard rate. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF only. Data collection and analysis of OS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    12 months
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    50 [23]
    Units: percentage of participants
        number (confidence interval 95%)
    31 (17.2 to 46.6)
    Notes
    [23] - High VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: OS Rate at 12 Months in All VAF Population

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    End point title
    		 OS Rate at 12 Months in All VAF Population [24]
    End point description
    OS rate was defined as the percentage of participants who had not experienced or death and was assessed at 12 months. Percentage of participants was calculated using the Kaplan-Meier method. 95% CI was calculated using normal approximation to the log transformed cumulative hazard rate. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants. Data collection and analysis of OS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    12 months
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    59 [25]
    Units: percentage of participants
        number (confidence interval 95%)
    30 (17.2 to 43.7)
    Notes
    [25] - All VAF Population (mITT Analysis Set)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) in High VAF Population, as Assessed by IRF

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    End point title
    		 Time to Response (TTR) in High VAF Population, as Assessed by IRF [26]
    End point description
    TTR was defined as months from treatment start to first CR or PR (whichever was first recorded) in participants with confirmed CR or PR and was assessed using RECIST v1.1 by IRF. TTR was summarized descriptively by summary statistics. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants with high VAF and available data only. Data collection and analysis of TTR for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    10 [27]
    Units: months
        median (full range (min-max))
    1.9 (1.7 to 3.8)
    Notes
    [27] - High VAF Population (mITT Analysis Set) with confirmed CR or PR by IRF
    No statistical analyses for this end point

    Secondary: TTR in All VAF Population, as Assessed by IRF

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    End point title
    		 TTR in All VAF Population, as Assessed by IRF [28]
    End point description
    TTR was defined as months from treatment start to first CR or PR (whichever was first recorded) in participants with confirmed CR or PR and was assessed using RECIST v1.1 by IRF. TTR was summarized descriptively by summary statistics. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for all VAF participants with available data. Data collection and analysis of TTR for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    11 [29]
    Units: months
        median (full range (min-max))
    1.9 (1.7 to 18.4)
    Notes
    [29] - All VAF Population (mITT Analysis Set) with confirmed CR or PR by IRF
    No statistical analyses for this end point

    Secondary: Number of Participants who Experienced Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants who Experienced Treatment-Emergent Adverse Events (TEAEs) [30]
    End point description
    TEAEs were defined as adverse events (AEs) that started on or after the first dose of the study drug and within 30 days of the last administration of the study drug. Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was used for toxicity grading (Grade 3: severe or disabling; Grade 4: life-threatening; Grade 5: death related to AE). Clinically significant changes in laboratory tests, vital signs, and electrocardiogram results were reported as AEs. Safety Analysis Set (SAS): consisted of all participants in the AIM-HN who received at least one dose of tipifarnib. Analysis was pre-specified for participants in the AIM-HN Cohort only. Data collection and analysis of safety for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    59 [31]
    Units: participants
        Any TEAEs
    58
        Any Grade 3 or Higher TEAEs
    43
    Notes
    [31] - SAS
    No statistical analyses for this end point

    Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module 35 (EORTC QLQ-H&N35) Subscales

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    End point title
    		 Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module 35 (EORTC QLQ-H&N35) Subscales [32]
    End point description
    Change from Baseline score in pain, swallowing, speech problems, and senses problems subscales of EORTC QLQ-H&N35 are summarized individually. Raw scores for each subscale were linear transformations and standardized to range (0 - 100), with higher scores representing worse levels of symptoms. Change from Baseline was calculated as End of Treatment Observed - Baseline with a negative change representing a reduction in symptoms. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants in the AIM-HN Cohort with available data. Data collection and analysis of EORTC QLQ-H&N35 for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Baseline and End of Treatment Visit (up to approximately 28 months)
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    27 [33]
    Units: score on a scale
    median (full range (min-max))
        Pain (n = 27)
    0.0 (-41.7 to 58.3)
        Swallowing (n = 26)
    8.3 (-58.3 to 75.0)
        Senses problems (n = 27)
    0.0 (-50.0 to 66.7)
        Speech problems (n = 26)
    0.0 (-44.4 to 66.7)
    Notes
    [33] - mITT Analysis Set with available data
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EuroQol-Visual Analog Scale (EQ-VAS) Score

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    End point title
    		 Change From Baseline in the EuroQol-Visual Analog Scale (EQ-VAS) Score [34]
    End point description
    The EQ-VAS forms part of the EQ-5D-5L and collects the self-rating health status from 0 (the worst imaginable health) to 100 (the best imaginable health). Change from Baseline was calculated as End of Treatment Observed - Baseline with a negative change representing an increase in symptoms. mITT Analysis Set: consisted of all participants who received at least one dose of tipifarnib. Analysis was pre-specified for participants in the AIM-HN Cohort with available data. Data collection and analysis of EQ-VAS for participants in the Observational SEQ-HN Cohort was not pre-specified.
    End point type
    Secondary
    End point timeframe
    Baseline and End of Treatment Visit (up to approximately 28 months)
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were only pre-specified for the AIM-HN arm.
    End point values
    		 Tipifarnib Treatment Cohort: AIM-HN
    Number of subjects analysed
    26 [35]
    Units: score on a scale
        median (full range (min-max))
    3.5 (-30.0 to 60.0)
    Notes
    [35] - mITT Analysis Set with available data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 28 months
    Adverse event reporting additional description
    SAS: consisted of all participants in the AIM-HN who received at least one dose of tipifarnib. Analysis was pre-specified for participants in the AIM-HN Cohort only. Data collection and analysis of safety for participants in the Observational SEQ-HN Cohort was not pre-specified.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Tipifarnib Treatment Cohort: AIM-HN
    Reporting group description
    		 Participants enrolled as part of AIM-HN received tipifarnib administered with food at a starting dose of 600 mg, orally, bid on Days 1-7 and 15-21 of 28-day cycles.

    Serious adverse events
    		 Tipifarnib Treatment Cohort: AIM-HN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 59 (47.46%)
         number of deaths (all causes)
    41
         number of deaths resulting from adverse events
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Laryngeal stenosis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    9 / 59 (15.25%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 3
    Sepsis
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    Septic shock
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Bacteraemia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tipifarnib Treatment Cohort: AIM-HN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 59 (94.92%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 59 (32.20%)
         occurrences all number
    29
    Asthenia
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    7
    Mucosal inflammation
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    6
    Pyrexia
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 59 (13.56%)
         occurrences all number
    13
    Cough
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    7
    Productive cough
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Haemoptysis
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 59 (13.56%)
         occurrences all number
    8
    Anxiety
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Confusional state
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    10 / 59 (16.95%)
         occurrences all number
    17
    Weight decreased
         subjects affected / exposed
    7 / 59 (11.86%)
         occurrences all number
    9
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    5
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    7
    Dizziness
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    29 / 59 (49.15%)
         occurrences all number
    56
    Neutropenia
         subjects affected / exposed
    20 / 59 (33.90%)
         occurrences all number
    45
    Leukopenia
         subjects affected / exposed
    13 / 59 (22.03%)
         occurrences all number
    26
    Thrombocytopenia
         subjects affected / exposed
    11 / 59 (18.64%)
         occurrences all number
    27
    Lymphopenia
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    16 / 59 (27.12%)
         occurrences all number
    26
    Vomiting
         subjects affected / exposed
    13 / 59 (22.03%)
         occurrences all number
    16
    Constipation
         subjects affected / exposed
    11 / 59 (18.64%)
         occurrences all number
    11
    Diarrhoea
         subjects affected / exposed
    10 / 59 (16.95%)
         occurrences all number
    16
    Dysphagia
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    9
    Abdominal pain
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    7
    Abdominal distension
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    6
    Abdominal pain upper
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Dry mouth
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Musculoskeletal pain
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 59 (20.34%)
         occurrences all number
    18
    Hypokalaemia
         subjects affected / exposed
    9 / 59 (15.25%)
         occurrences all number
    17
    Hypercalcaemia
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    6
    Hyponatraemia
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    9
    Hypophosphataemia
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    5
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Hypocalcaemia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    5
    Hypomagnesaemia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jul 2018
    The protocol was amended for the following reasons: • The starting dose of tipifarnib was reduced. • AIM-HN inclusion criteria 9b was modified. • AIM-HN exclusion criteria 11 was added.
    15 Nov 2018
    The protocol was amended for the following reasons: • AIM-HN inclusion criteria 4 was modified. • AIM-HN inclusion criteria 8 was modified. • AIM-HN inclusion criteria 12 was added. • AIM-HN inclusion criteria 14 was clarified. • AIM-HN exclusion criteria 11 was modified. • SEQ-HN inclusion criteria 3 was further clarified. • SEQ-HN inclusion criteria 5 was clarified. • Provided additional guidance on the management of Grade 2 and 3 renal toxicity. • Adjusted the blood chemistry panel.
    09 Jun 2020
    The protocol was amended for the following reasons: • The primary objective was clarified. • Secondary objectives and endpoints were revised. • Other secondary objectives and endpoints for the SEQ-HN study and mHRAS population were revised. • Exploratory objectives were moved to other secondary objectives. • The total number of participants for enrollment into AIM and SEQ was increased. • Determination of HRAS status was further defined. • Circumstances of ineligibility for prior platinum therapy were revised. • Inclusion criteria number 4 was clarified/revised. • Inclusion criteria number 6 was clarified. • Exclusion criteria were updated to include female subjects who were pregnant or lactating. • Populations for analysis were defined. • Detailed RECIST v1.1 criteria was included. • Sensitivity analyses were revised.

    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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