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    Clinical Trial Results:
    Phase II, randomized, open-label study of the IGF-1R inhibitor AXL1717 compared to docetaxel in patients with previously treated, locally advanced, or metastatic squamous cell carcinoma or adenocarcinoma of the lung

    Summary
    EudraCT number
    		 2011-002007-15
    Trial protocol
    		 HU  
    Global end of trial date
    11 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 May 2016
    First version publication date
    04 May 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AXL-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01561456
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Axelar AB
    Sponsor organisation address
    Karolinska Institutet Science Park, Fogdevreten 2, Solna, Sweden, 171 65
    Public contact
    Ulrika Wennberg, Axelar AB, +48 70 722 6332, ulrika.wennberg@axelar.se
    Scientific contact
    Ulrika Wennberg, Axelar AB, +48 70 722 6332, ulrika.wennberg@axelar.se
    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
    23 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the rate of progression-free survival (PFS) at 12 weeks between patients treated with AXL1717 (AXL) and patients treated with docetaxel (DCT) in the total study population and in the squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes of non-small cell lung cancer (NSCLC).
    Protection of trial subjects
    Good Clinical Practice; informed consent required; maximum 4 treatment cycles in primary treatment period; extension treatment offered to patients with stable disease or better, only if initiated by investigator; disease progression monitored regularly according to RECIST through death or end of study. Following 12 deaths early in the study, enrollment was suspended while the cases were reviewed. Recommended changes to the protocol were implemented as Amendment 2. The opinion of the Data Safety Monitoring Committee (DSMC) was that steroids should be avoided in neutropenic patients because steroids may stimulate the growth of microorganisms by causing immunosuppression, may mask fever and symptoms of infection, and do not stimulate host defense against microorganisms. Prophylactic antibiotics should be used in all Grade 4 neutropenic patients, irrespective of the presence of fever or other symptoms. Guidelines with respect to prophylactic antibiotic treatment of neutropenic patients were provided to all centers. Guidelines from ASCO were also issued with respect to use of hematologic growth factors for treating neutropenia in patients in the AXL group. Neutropenic patients should be followed daily. The DSMC recommended direct contact between the patient and the study center for all future cases involving events of fever and/or neutropenia.
    Background therapy
    		 None.
    Evidence for comparator
    		 Docetaxel is standard therapy for advanced NSCLC.
    Actual start date of recruitment
    15 Dec 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 14 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belarus: 2
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Ukraine: 50
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Poland: 5
    Worldwide total number of subjects
    99
    EEA total number of subjects
    19
    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)
    85
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The first patient randomized on 27Dec2011. The last patient randomized on 29Apr2013. The recruitment put on hold on 19Jul2012 (until Protocol Amendment approved in each country) -due to additional safety actions in order to decrease the numbers of neutropenia development. During the study the patients were observed at multifunctional hospitals.

    Pre-assignment
    Screening details
    		 138 screened; 37 screen failures due to: hematology (7), non-measurable disease (RECIST) (6), randomization on hold (5), CNS malignancy (4), ECOG status >2 (2), mixed histology of NSCLC (2), infection/other major disease (2), coexisting medical condition (1), history of cancer in 5 years (1), lack of suitability for participation (1), other (6).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AXL1717
    Arm description
    		 Test Arm; The Per Protocol set consisted of 101 randomized patients, 2 of whom were not treated (patient 101-008 withdrew consent; patient 305-007 was mistakenly randomized despite the presence of an exclusion criterion), and therefore the full analysis set (FAS) (also used for safety) consisted of 99 treated patients (58 AXL, 41 DCT).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Picropodophyllin
    Investigational medicinal product code
    AXL1717(H2O)
    Other name
    AXL1717, BVT.51004, BVT.51004G
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg or 400 mg BID (twice daily)

    Arm title
    		 Docetaxel
    Arm description
    		 Active comparator
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard 75 mg/m2 in 100 mL of normal saline solution with IV infusion over 60 minutes

    Number of subjects in period 1
    		AXL1717 Docetaxel
    Started
    58
    41
    Completed
    19
    24
    Not completed
    39
    17
         Consent withdrawn by subject
    5
    1
         On treatment as of data cut off
    1
    -
         Death
    10
    1
         Other
    2
    -
         AE (any)
    4
    1
         Progressive disease
    17
    13
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AXL1717
    Reporting group description
    		 Test Arm; The Per Protocol set consisted of 101 randomized patients, 2 of whom were not treated (patient 101-008 withdrew consent; patient 305-007 was mistakenly randomized despite the presence of an exclusion criterion), and therefore the full analysis set (FAS) (also used for safety) consisted of 99 treated patients (58 AXL, 41 DCT).

    Reporting group title
    Docetaxel
    Reporting group description
    		 Active comparator

    Reporting group values
    		 AXL1717 Docetaxel Total
    Number of subjects
    		 58 41 99
    Age categorical
    Patients were similar in age, with median ages of 57 years (range 42 to 81 years) for the AXL group and 59 years (range 44 to 73 years) for the DCT group. The majority of patients were male (69.0% AXL group vs. 75.6% DCT group). All treated patients were Caucasian.
    Units: Subjects
        Adults (18-64 years)
    		 52 33 85
        From 65-84 years
    		 6 8 14
    Age continuous
    Units: years
        median (full range (min-max))
    		 57 (42 to 81) 58 (44 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 18 10 28
        Male
    		 40 31 71
    ECOG performance status
    Eastern Cooperative Oncology Group performance status
    Units: Subjects
        ECOG 0
    		 12 12 24
        ECOG 1
    		 43 28 71
        ECOG 2
    		 3 1 4
    ECG status
    Electrocardiogram status
    Units: Subjects
        ECG abnormal
    		 35 28 63
        ECG normal
    		 23 13 36
    Respiratory status
    Units: Subjects
        Respiratory abnormal
    		 38 29 67
        Respiratory normal
    		 20 12 32
    Time since diagnosis
    Time since diagnosis of NSCLC
    Units: years
        arithmetic mean (standard deviation)
    		 1.1 ( 0.8 ) 1.6 ( 1.87 ) -

    End points

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    End points reporting groups
    Reporting group title
    AXL1717
    Reporting group description
    		 Test Arm; The Per Protocol set consisted of 101 randomized patients, 2 of whom were not treated (patient 101-008 withdrew consent; patient 305-007 was mistakenly randomized despite the presence of an exclusion criterion), and therefore the full analysis set (FAS) (also used for safety) consisted of 99 treated patients (58 AXL, 41 DCT).

    Reporting group title
    Docetaxel
    Reporting group description
    		 Active comparator

    Primary: Rate of PFS - by squamous cell carcinoma (SCC) subtype

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    End point title
    		 Rate of PFS - by squamous cell carcinoma (SCC) subtype
    End point description
    The primary efficacy parameter in this study was the assessment of tumor response as evaluated by RECIST 1.1. The PFS rate was defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. To objective was to compare the rate of PFS at 12 weeks between patients treated with AXL1717 and patients treated with docetaxel in the total study population and in the squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes of NSCLC.
    End point type
    Primary
    End point timeframe
    12 weeks following first dose of study drug
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29
    21
    Units: Percent
    number (confidence interval 95%)
        PFS at 12 weeks
    20.7 (8 to 39.7)
    38.1 (18.1 to 61.6)
    Statistical analysis title
    		 The PFS rate - SCC subtype
    Statistical analysis description
    The PFS rate is defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. The PFS rate and associated 95% confidence interval are presented for each treatment group. Difference in PFS rates between treatment groups are presented along with the exact 95% CI.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.213
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -17.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.6
         upper limit
    		 10.6

    Primary: Rate of PFS - adenocarcinoma (AC) subtype

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    End point title
    		 Rate of PFS - adenocarcinoma (AC) subtype
    End point description
    The primary efficacy parameter in this study was the assessment of tumor response as evaluated by RECIST 1.1. The PFS rate was defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. To objective was to compare the rate of PFS at 12 weeks between patients treated with AXL1717 and patients treated with docetaxel in the total study population and in the squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes of NSCLC.
    End point type
    Primary
    End point timeframe
    12 weeks following first dose of study drug
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29
    21
    Units: Percent
    number (confidence interval 95%)
        PFS at 12 weeks
    31 (15.3 to 50.8)
    40 (19.1 to 63.9)
    Statistical analysis title
    		 The PFS rate - AC subtype
    Statistical analysis description
    The PFS rate is defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. The PFS rate and associated 95% confidence interval are presented for each treatment group. Difference in PFS rates between treatment groups are presented along with the exact 95% CI.
    Comparison groups
    Docetaxel v AXL1717
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.555
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.7
         upper limit
    		 19.2

    Primary: Rate of PFS

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    End point title
    		 Rate of PFS
    End point description
    The primary efficacy parameter in this study was the assessment of tumor response as evaluated by RECIST 1.1. The PFS rate was defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. To objective was to compare the rate of PFS at 12 weeks between patients treated with AXL1717 and patients treated with docetaxel in the total study population and in the squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes of NSCLC.
    End point type
    Primary
    End point timeframe
    12 weeks following first dose of study drug
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    58
    41
    Units: Percent
    number (confidence interval 95%)
        PFS at 12 weeks
    25.9 (15.3 to 39)
    39 (24.2 to 55.5)
    Statistical analysis title
    		 The PFS rate at 12 weeks following first drug dose
    Statistical analysis description
    The PFS rate is defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. The PFS rate and associated 95% confidence interval are presented for each treatment group. Difference in PFS rates between treatment groups are presented along with the exact 95% CI.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.191
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -13.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.4
         upper limit
    		 6.8

    Secondary: Survival rates

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    End point title
    		 Survival rates
    End point description
    The survival rate was defined as the percentage of patients in the study who had survived for a period of time from randomization. The 12-week and 1-year survival rates and associated 95% CIs were planned for each treatment group. Differences in survival rates between treatment groups were to be presented along with the exact 95% CIs.
    End point type
    Secondary
    End point timeframe
    12 weeks and 1 year
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    58
    41
    Units: Percent
    number (confidence interval 95%)
        12-week survival rate
    78.6 (65.4 to 87.2)
    87.5 (72.5 to 94.6)
        1-year survival rate
    46.7 (32.7 to 59.6)
    43.6 (26.4 to 59.6)
    No statistical analyses for this end point

    Secondary: Survival rates – SCC subtype

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    End point title
    		 Survival rates – SCC subtype
    End point description
    The survival rate was defined as the percentage of patients in the study who had survived for a period of time from randomization. The 12-week and 1-year survival rates and associated 95% CIs were planned for each treatment group. Differences in survival rates between treatment groups were to be presented along with the exact 95% CIs.
    End point type
    Secondary
    End point timeframe
    12 weeks and 1 year
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29
    21
    Units: Percent
    number (confidence interval 95%)
        12-week survival rate
    77.9 (57.2 to 89.4)
    85 (60.4 to 94.9)
        1-year survival rate
    34.3 (15.4 to 54.4)
    36.9 (12.3 to 62.3)
    No statistical analyses for this end point

    Secondary: Survival rates – AC subtype

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    End point title
    		 Survival rates – AC subtype
    End point description
    The survival rate was defined as the percentage of patients in the study who had survived for a period of time from randomization. The 12-week and 1-year survival rates and associated 95% CIs were planned for each treatment group. Differences in survival rates between treatment groups were to be presented along with the exact 95% CIs.
    End point type
    Secondary
    End point timeframe
    12 weeks and 1 year
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29
    20
    Units: Percent
    number (confidence interval 95%)
        12-week survival rate
    79.3 (59.6 to 90.1)
    90 (65.6 to 97.4)
        1-year survival rate
    55.2 (35.6 to 71)
    45 (23.1 to 64.7)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
    End point type
    Secondary
    End point timeframe
    Through cutoff date of analyses.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    58
    41
    Units: Weeks
    number (confidence interval 95%)
        Kaplan-Meier estimate of median overall survival
    32.7 (21.1 to 69.6)
    40.9 (21.4 to 74.3)
    Attachments
    		 Untitled (Filename: Graphical Representation.pdf)
    Statistical analysis title
    		 Kaplan-Meier estimate of median OS
    Statistical analysis description
    Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
    Comparison groups
    Docetaxel v AXL1717
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.907
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall survival – SCC subtype

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    End point title
    		 Overall survival – SCC subtype
    End point description
    Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
    End point type
    Secondary
    End point timeframe
    Through cutoff date of analyses.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29
    21
    Units: Weeks
    number (confidence interval 95%)
        Kaplan-Meier estimate of median overall survival
    28.4 (16.9 to 57.9)
    40.9 (23 to 65.3)
    Statistical analysis title
    		 Kaplan-Meier estimate of median OS – SCC subtype
    Statistical analysis description
    Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.626
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall survival – AC subtype

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    End point title
    		 Overall survival – AC subtype
    End point description
    Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date. Kaplan-Meier estimate of median OS, weeks [95% CI] for AC Subtype: AXL1717 - 57.3 [ 18.0, NA] Docetaxel - 24.8 [15.0, NA]
    End point type
    Secondary
    End point timeframe
    Through cutoff date of analyses.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29 [1]
    20 [2]
    Units: Percent
    number (confidence interval 95%)
        Kaplan-Meier estimate of median overall survival
    57.3 (18 to 9999.9)
    24.8 (15 to 9999.9)
    Notes
    [1] - AC subtype of NSCLC covers 29 subjects from AXL1717 group
    [2] - AC subtype of NSCLC covers 20 subjects from Decetaxel group
    Statistical analysis title
    		 Kaplan-Meier estimate of median OS – AC subtype
    Statistical analysis description
    Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.745
    Method
    		 Logrank
    Confidence interval

    Secondary: Kaplan-Meier estimate of median PFS

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    End point title
    		 Kaplan-Meier estimate of median PFS
    End point description
    Using the same definition as for the primary endpoint, PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Through cutoff date of analyses.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29 [3]
    20 [4]
    Units: Weeks
    number (confidence interval 95%)
        Kaplan-Meier estimate of median PFS
    13 (6.3 to 15.4)
    12.4 (6.1 to 20.3)
    Attachments
    		 Untitled (Filename: Graphical Representation_2.pdf)
    Notes
    [3] - AC subtype of NSCLC covers 29 subjects from AXL1717 group
    [4] - AC subtype of NSCLC covers 20 subjects from Decetaxel group
    Statistical analysis title
    		 Kaplan-Meier estimate of median PFS
    Statistical analysis description
    PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.615
    Method
    		 Logrank
    Confidence interval

    Secondary: Kaplan-Meier estimate of median PFS – SCC subtype

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    End point title
    		 Kaplan-Meier estimate of median PFS – SCC subtype
    End point description
    Using the same definition as for the primary endpoint, PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Through cutoff date of analyses.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29
    21
    Units: Weeks
    number (confidence interval 95%)
        Kaplan-Meier estimate of median PFS
    12.3 (6.1 to 13)
    12.4 (6.3 to 30.6)
    Attachments
    		 Untitled (Filename: Graphical Representation_3.pdf)
    Statistical analysis title
    		 Kaplan-Meier estimate of median PFS – SCC subtype
    Comparison groups
    Docetaxel v AXL1717
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.082
    Method
    		 Logrank
    Confidence interval

    Secondary: Kaplan-Meier estimate of median PFS – AC subtype

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    End point title
    		 Kaplan-Meier estimate of median PFS – AC subtype
    End point description
    Using the same definition as for the primary endpoint, PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Through cutoff date of analyses.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    29
    20
    Units: Percent
    number (confidence interval 95%)
        Kaplan-Meier estimate of median PFS
    13 (6.3 to 15.4)
    12.4 (6.1 to 20.3)
    Attachments
    		 Untitled (Filename: Graphical Representation_4.pdf)
    Statistical analysis title
    		 Kaplan-Meier estimate of median PFS – AC subtype
    Statistical analysis description
    PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.615
    Method
    		 Logrank
    Confidence interval

    Secondary: Tumor response – combined local/central reader

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    End point title
    		 Tumor response – combined local/central reader
    End point description
    A secondary endpoint of the study was to compare the rate of CR, PR, SD, PD, disease control (CR + PR + SD), and objective response (CR + PR) at 12 weeks between the AXL and DCT groups in the total study population and in the SCC and AC subtypes. Results are presented combining the RECIST tumor response assessments of central readers and local readers.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    58
    41
    Units: Subjects
    number (not applicable)
        Complete response
    0
    0
        Partial response
    0
    5
        Stable disease
    15
    10
        No measurable disease
    0
    3
        Non CR / Non PD
    0
    2
        Progressive disease
    12
    8
        No assessment
    31
    13
    Statistical analysis title
    		 Tumor response – Combined Local/Central reader
    Statistical analysis description
    Tumor response after four cycles will be summarized descriptively using response categories based on RECIST criteria: PD, SD, PR, CR, or Not Evaluable (NE). Separate analysis will be performed for Central reader and for Local reader data. The rates for disease control and objective response will be calculated based on the best tumor response during four cycles.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.063
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Tumor response – combined local/central reader

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    End point title
    		 Tumor response – combined local/central reader
    End point description
    A secondary endpoint of the study was to compare the rate of CR, PR, SD, PD, disease control (CR + PR + SD), and objective response (CR + PR) at 12 weeks between the AXL and DCT groups in the total study population and in the SCC and AC subtypes. Results are presented combining the RECIST tumor response assessments of central readers and local readers.
    End point type
    Secondary
    End point timeframe
    12 weeks.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    58
    41
    Units: Percent
    number (confidence interval 95%)
        Objective response rate (CR+PR)
    0 (0 to 0)
    12.2 (4.1 to 26.2)
        Disease control rate (CR+PR+SD)
    25.9 (15.3 to 39)
    36.6 (22.1 to 53.1)
    Statistical analysis title
    		 Tumor response – Combined Local/Central reader
    Statistical analysis description
    Tumor response after four cycles will be summarized descriptively using response categories based on RECIST criteria: PD, SD, PR, CR, or Not Evaluable (NE). Separate analysis will be performed for Central reader and for Local reader data. The rates for disease control and objective response will be calculated based on the best tumor response during four cycles.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.063
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Time to progression

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    End point title
    		 Time to progression
    End point description
    Time to progression was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to progression. A patient who stopped treatment with the study drug and received alternative therapy prior to documentation of disease progression was censored on the date that the alternative therapy started. If a patient had not progressed, TTP was censored on the date of the last tumor assessment.
    End point type
    Secondary
    End point timeframe
    Through cutoff date of analyses.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    58
    41
    Units: Weeks
    number (confidence interval 95%)
        Kaplan-Meier estimate of median PFS
    13 (11.9 to 14.7)
    12.7 (12.1 to 20.1)
    Attachments
    		 Untitled (Filename: Graphical Representation_5.pdf)
    Statistical analysis title
    		 Time to progression
    Statistical analysis description
    Time to progression (TTP) is defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to progression.
    Comparison groups
    AXL1717 v Docetaxel
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.662
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to treatment failure

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    End point title
    		 Time to treatment failure
    End point description
    Time to treatment failure was defined as the time from randomization to the first observation of discontinuation of treatment, PD, or death. A patient who stopped treatment with the study drug and received alternative therapy prior to documentation of disease progression was censored on the date that the alternative therapy started. If a patient had not progressed, TTF was censored on the date of the last tumor assessment.
    End point type
    Secondary
    End point timeframe
    Through cutoff date of analyses.
    End point values
    		 AXL1717 Docetaxel
    Number of subjects analysed
    58
    41
    Units: Percent
    number (confidence interval 95%)
        Kaplan-Meier estimate of median PFS
    10.8 (6.3 to 12.3)
    12.4 (10.4 to 16.3)
    Statistical analysis title
    		 Time to treatment failure
    Statistical analysis description
    TTF is defined as the time from randomization to the first observation of discontinuation of treatment, PD or death.
    Comparison groups
    Docetaxel v AXL1717
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.129
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Signing of informed consent through no later than 30 days after last date of study drug exposure.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15,0
    Reporting groups
    Reporting group title
    AXL1717
    Reporting group description
    		 subjects who received AXL1717

    Reporting group title
    Docetaxel
    Reporting group description
    		 Subjects who received docetaxel

    Serious adverse events
    		 AXL1717 Docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 58 (24.14%)
    5 / 41 (12.20%)
         number of deaths (all causes)
    33
    23
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-small cell lung cancer
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 41 (9.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary haemorrhage
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 AXL1717 Docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 58 (70.69%)
    34 / 41 (82.93%)
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    11 / 58 (18.97%)
    19 / 41 (46.34%)
         occurrences all number
    16
    21
    Leukopenia
         subjects affected / exposed
    12 / 58 (20.69%)
    9 / 41 (21.95%)
         occurrences all number
    15
    9
    Anemia
         subjects affected / exposed
    12 / 58 (20.69%)
    12 / 41 (29.27%)
         occurrences all number
    13
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 58 (12.07%)
    9 / 41 (21.95%)
         occurrences all number
    7
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 May 2012
    Protocol Amendment 1 addressed safety concerns. A summary of changes included: Added: -additional biomarker evaluation -clarification of inclusion criteria related to radiation therapy -clarification to the exclusion criteria for men who are capable of fathering a child -that AXL patients could be treated with WBC growth factors while in the study. Per Amendment 1, WBC growth factors could be used in the management of patients in the AXL group, according to ASCO guidelines. Investigators were encouraged to use G-CSF for treatment of nonfebrile Grade 3 neutropenia. Upon development of febrile neutropenia or nonfebrile Grade 4 neutropenia, G-CSF use was required in the AXL group -an additional biopsy procedure and evaluation -Appendix 2 to clarify the procedures for both AXL treatment groups -additional safety testing to evaluate the need for dose delays or adjustments -Appendix 9 to include TNM classification -Appendix 10 for clarification of BSA calculation used for DCT dose calculation -Appendix 11 for clarification of list of the CYP3A4 substrate with narrow therapeutic index and CYP2C9 inhibitors Clarified -parameters for WBC with or without differential counts to evaluate safety related to dose delays or interruptions -AXL dose interruptions/adjustment procedures -DCT dose procedures & dose interruption procedures -protocol procedures for toxicity criteria for patient withdrawal -patient withdrawal procedures -local standard of care among clinical sites -end of study procedures -protocol procedures for exploratory assessments, AEs, clinical laboratory, and biomarker evaluations Included a list of medications that were to be avoided Provided an alternate treatment schedule based on safety Patients receiving DCT were to be premedicated with corticosteroids to account for local standard of care among clinical sites
    07 Oct 2012
    Protocol Amendment 2 addressed safety concerns and implemented clarifications throughout the protocol. Changes included: • Clinical update summarizing recruitment, which was temporarily stopped on 19 July 2012 due to safety concerns, as noted above; dose-limiting events; and fatalities. • Implemented a revised treatment regimen based on safety recommendation from the DSMC. The starting dose of AXL was reduced to 300 mg for the first 28 days; then, depending on ANC levels measured during the first 28 days, subsequent doses could be increased to 400 mg BID, remain at 300 mg BID, or be temporarily interrupted and, when ANC levels recovered to an acceptable level, be resumed at the same dose or 1 dose level lower. • Revised the exclusion criteria based on safety recommendations from the DSMC. SCC patients with involvement of major vessels (diagnosis as confirmed by a radiologist) were excluded. • Updated and provided additional safety data and information. • Clarified storage and handling procedures for AXL. • Implementation of procedural changes based on safety recommendations from the DSMC. • Appendix 7 clarified guidelines for the use of WBC growth factors. • Appendix 12 was added as a safety recommendation from the DSMB to provide standard recommendations and procedures for the management of patients who developed neutropenia while treated with AXL. Appendix 12 included guidelines for use of WBC growth factors in the treatment of patients in the AXL group. After implementation of the amended protocol, 1 patient died due to an SAE of clinically suspected pneumonia with neutropenic sepsis. The DSMC investigated the case in detail and decided to recommend to permanently abandon the 400 mg BID dose for the remainder of the study. The 300 mg BID dose of AXL was thus instituted as the recommended Phase II dose for continuous treatment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Jul 2012
    Following the deaths of 12 patients in the study (9 in the AXL group and 3 in the DCT group), with 7 patients dying within 4 weeks of entry into the study, recruitment into the study was temporarily stopped on 19July2012 to allow the DSMC to review the cases. The DSMC monitoring the trial convened 3 times (26Jul2012, 03Aug2012, 13Aug2012) and recommended changes to the conduct of the study and the Sponsor implemented Protocol Amendment 2 (07Oc2012). At the time recruitment was suspended, 75 patients had been treated (46 AXL & 29 DCT). During the review by the DSMC, 23 patients (14 AXL & 9 DCT) already randomized continued receiving study treatment. 7 fatal cases in AXL group and 3 in DCT group were assessed as related to tumor progression. 2 fatal cases in AXL group were directly attributable to neutropenia or leukopenia, 2 cases were reported as disease progression in the clinical setting of neutropenia or leukopenia, 3 cases were reported as disease progression without any known neutropenia or leukopenia, and 2 patients experienced fatal pulmonary hemorrhage. There were 4 fatal cases connected with neutropenia. Three patients were treated with corticosteroids (dexamethasone) during the neutropenic periods. According to DSMC it was not possible to exclude that the treatment with steroids may have contributed to the outcome in these 3 fatal cases. The 2 fatal events of pulmonary hemorrhage were reported as starting 14 & 28 days after the first dose of AXL, respectively. Both of the patients had central squamous NSCLC tumors with tumor involvement of major blood vessels on CT as assessed by the DSMC. The DSMC determined it was not possible to exclude that possible tumor shrinkage could have contributed to the bleeding. The DSMC therefore recommended that patients with central tumors and/or involvement of major blood vessels should be excluded from enrollment into the study; however, patients already randomized were to continue as planned.
    03 Dec 2012

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Following implementation of Protocol Amendment 2, the Sponsor curtailed enrollment in the study from a planned 140 treated patients to the 99 patients described in this report.
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