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    Clinical Trial Results:
    A dose-finding phase Ib study followed by an open-label, randomized phase II study of BEZ235 plus paclitaxel in patients with HER2 negative, inoperable locally advanced or metastatic breast cancer Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2011-002400-32
    Trial protocol
    		 FR   ES  
    Global end of trial date
    19 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2018
    First version publication date
    07 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBEZ235B2101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01495247
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Novartis Pharmaceuticals AG, Novartis Pharmaceuticals AG, 41 613241111 ,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 ,
    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
    19 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This was a Phase Ib/II study and each phase had a prmary objective: Phase Ib: To determine the MTD and/or RP2D of oral twice daily (bid) BEZ235 in combinationwith weekly (qw) paclitaxel in patients with in HER2 negative metastatic or inoperable, locally advanced breast cancer. Phase II: To estimate the treatment effect of BEZ235/ paclitaxel combination therapy versus paclitaxel alone in HER2-patients with first line metastatic or inoperable locally advanced breast cancer.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. The MTD was defined as the highest dose of BEZ235 and paclitaxel not causing pre-defined, medically unacceptable, dose-limiting toxicity in more than 35% of patients treated during the first cycle of treatment. The starting BEZ235 dose and paclitaxel dose in the current study met the overdose control requirements. It was recommended that patients use drugs that do not cause QT prolongation. Some anti-emetics were prohibited due to interaction with CYP3A. Patients were instructed to treat diarrhea at its earliest occurrence. Appropriate anti-emetic treatment was recommended, including prophylaxis. Proactive approach to managing skin reactions was encouraged. Patients were informed about the possibility of developing mouth ulcers/ oral mucositis and educated about good oral hygiene. Patients were also instructed about potential effect on glucuse homeostasis and this was monitored.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    France: 10
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    16
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Fifteen to 30 patients were planned for Phase Ib; 18 patients were enrolled and analyzed. Based on DLT, the study did not meet the Phase Ib primary objective to establish MTD/RP2D of BEZ235 with paclitaxel and was terminated. The Phase II part of the study was not conducted.

    Period 1
    Period 1 title
    Phase 1b-Treatment and Evaluation Phases (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BEZ235 100 mg bid + P80
    Arm description
    		 As 200 mg bid did not meet overdose criteria, patients in this arm were treated with BEZ235 100 mg bid plus paclitaxel. BEZ235 was administered orally as a continuous daily dose of 100 mg bid and a fiixed dose of paclitaxel (80 mg/m2 qw per 28 day cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BEZ235
    Investigational medicinal product code
    BEZ235
    Other name
    Pharmaceutical forms
    Oral suspension in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    BEZ235 was administered orally on a continuous bid dosing schedule. Patients were dosed on a flat scale of mg/day and the dose of the drug was not adjusted to body weight or body surface area.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered at a weekly dose of 80 mg/m2 as a one-hour IV infusion after standard premedication. In each 28 day cycle, one week without paclitaxel administration was permitted if judged clinically appropriate by the Investigator.

    Arm title
    		 BEZ235 200 mg bid + P80
    Arm description
    		 This was the first cohort treated. Patients were treated with BEZ235 200 mg bid plus paclitaxel. BEZ235 was administered orally as a continuous daily dose of 200 mg bid and a fiixed dose of paclitaxel (80 mg/m2 qw per 28 day cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BEZ235
    Investigational medicinal product code
    BEZ235
    Other name
    Pharmaceutical forms
    Oral suspension in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    BEZ235 was administered orally on a continuous bid dosing schedule. Patients were dosed on a flat scale of mg/day and the dose of the drug was not adjusted to body weight or body surface area.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered at a weekly dose of 80 mg/m2 as a one-hour IV infusion after standard premedication. In each 28 day cycle, one week without paclitaxel administration was permitted if judged clinically appropriate by the Investigator.

    Number of subjects in period 1
    		BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80
    Started
    5
    13
    Completed
    0
    0
    Not completed
    5
    13
         Physician decision
    -
    1
         Adverse event
    2
    3
         Progressive disease
    3
    8
         Subject/guardian decision
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BEZ235 100 mg bid + P80
    Reporting group description
    		 As 200 mg bid did not meet overdose criteria, patients in this arm were treated with BEZ235 100 mg bid plus paclitaxel. BEZ235 was administered orally as a continuous daily dose of 100 mg bid and a fiixed dose of paclitaxel (80 mg/m2 qw per 28 day cycle).

    Reporting group title
    BEZ235 200 mg bid + P80
    Reporting group description
    		 This was the first cohort treated. Patients were treated with BEZ235 200 mg bid plus paclitaxel. BEZ235 was administered orally as a continuous daily dose of 200 mg bid and a fiixed dose of paclitaxel (80 mg/m2 qw per 28 day cycle).

    Reporting group values
    		 BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80 Total
    Number of subjects
    		 5 13 18
    Age categorical
    Included full analysis set.
    Units: Subjects
        <65 years
    		 5 11 16
        ≥ 65 years
    		 0 2 2
    Age continuous
    Included full analysis set.
    Units: years
        arithmetic mean (standard deviation)
    		 43 ( 8.03 ) 53.1 ( 11.77 ) -
    Gender categorical
    The study only included patients that were female ≥ 18 years of age on the day of consenting to the study. Included full analysis set.
    Units: Subjects
        Female
    		 5 13 18
    Race
    Included full analysis set.
    Units: Subjects
        Caucasian
    		 5 13 18
    ECOG performance status
    ECOG=Eastern Cooperative Oncology Group. Included full analysis set.
    Units: Subjects
        ECOG 0
    		 1 3 4
        ECOG 1
    		 4 10 14

    End points

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    End points reporting groups
    Reporting group title
    BEZ235 100 mg bid + P80
    Reporting group description
    		 As 200 mg bid did not meet overdose criteria, patients in this arm were treated with BEZ235 100 mg bid plus paclitaxel. BEZ235 was administered orally as a continuous daily dose of 100 mg bid and a fiixed dose of paclitaxel (80 mg/m2 qw per 28 day cycle).

    Reporting group title
    BEZ235 200 mg bid + P80
    Reporting group description
    		 This was the first cohort treated. Patients were treated with BEZ235 200 mg bid plus paclitaxel. BEZ235 was administered orally as a continuous daily dose of 200 mg bid and a fiixed dose of paclitaxel (80 mg/m2 qw per 28 day cycle).

    Primary: Summary of posterior distribution of DLT rates at end of study

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    End point title
    		 Summary of posterior distribution of DLT rates at end of study [1]
    End point description
    Based on the observed DLTs, the tested dose level (BEZ235 200 mg bid) did not meet the overdose control criterion as per the BLRM with a posterior probability of excessive toxicityof 39.3% (interval of interest [0.35, 1]). As the BLRM did not allow further enrollment at the BEZ235 200 mg bid + P80 dose level, five additional patients were enrolled and given reduced dose of BEZ235 100 mg bid in combination with weekly paclitaxel (80 mg/kg). This was performed on the dose-determining set.
    End point type
    Primary
    End point timeframe
    First 28 days of treatment (first dose up to and including Cycle 1, Day 28)
    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: An adaptive 5-parameter Bayesian logistic regression model guided by the escalation with overdose control principle guided the dose-escalation and determined the MTD/RP2D. The BLRM was fitted on the Cycle 1 DLT data accumulated throughout the dose-escalation phase to model the dose-toxicity relationship of paclitaxel and BEZ235. Therefore, only summary statistics as presented were provided for this endpoint.
    End point values
    		 BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80
    Number of subjects analysed
    1 [2]
    5 [3]
    Units: Probability
    number (not applicable)
        Probability Pr(DLT) in interval 0.35-1
    0.084
    0.137
    Notes
    [2] - Posterior probability that that Pr(DLT) is in interval. Dose determining set.
    [3] - Posterior probability that that Pr(DLT) is in interval. Dose determining set.
    No statistical analyses for this end point

    Primary: Dose limiting toxicities during the first 28 days of treatment by primary system organ class, preferred term

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    End point title
    		 Dose limiting toxicities during the first 28 days of treatment by primary system organ class, preferred term [4]
    End point description
    A DLT is defined as any treatment-related toxicities occurring up to and including Cycle 1 Day 28, and which are unrelated to disease, disease progression, intercurrent illness, and concomitant medications.
    End point type
    Primary
    End point timeframe
    first 28 days of treatment
    Notes
    [4] - 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: Only summary statistics as presented were provided for this primary endpoint.
    End point values
    		 BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80
    Number of subjects analysed
    1 [5]
    5 [6]
    Units: Patients
        Blood and lymphatic system-neutropenia
    1
    2
        Gastrointestinal disorders-stomatitis
    0
    3
        Gastrointestinal disorders-nausea
    0
    2
        Gastrointestinal disorders-vomiting
    0
    1
    Notes
    [5] - Dose-determining set
    [6] - Dose-determining set
    No statistical analyses for this end point

    Secondary: Best overall response as per Investigator, by dose level

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    End point title
    		 Best overall response as per Investigator, by dose level
    End point description
    The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment depended on the achievement of both measurement and confirmation criteria. The primary analysis of the best overall response was based on the sequence of investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion responses.
    End point type
    Secondary
    End point timeframe
    from the start of the treatment until disease progression/recurrence
    End point values
    		 BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80
    Number of subjects analysed
    5 [7]
    13 [8]
    Units: Patients
        Partial response (PR)
    1
    2
        Non-CR/Non-PD
    0
    2
        Stable disease (SD)
    4
    2
        Progressive disease (PD)
    0
    4
        Unknown (UNK)
    0
    3
    Notes
    [7] - Full analysis set
    [8] - Full analysis set
    No statistical analyses for this end point

    Secondary: Overall response and clinical benefit rate as per Investigator, by dose level

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    End point title
    		 Overall response and clinical benefit rate as per Investigator, by dose level
    End point description
    The Overall response rate is defined as (ORR:CR+PR). The clinical benefit rate is defined as (CBR: CR+PR+SD+Non-CR/Non- PD >24 weeks). The 95% CI for the frequency distribution of each variable were computed using Clopper-Pearson method if there were sufficient data.
    End point type
    Secondary
    End point timeframe
    For ORR: best overall response during the study. For CBR, best overall response wit a duration of 24 weeks or longer.
    End point values
    		 BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80
    Number of subjects analysed
    5 [9]
    13 [10]
    Units: Percentage
    number (confidence interval 95%)
        Overall response rate(ORR:CR+PR), n=1,2
    20 (0.5 to 71.6)
    15.4 (1.9 to 45.4)
        Clinical benefit rate (CBR), n=3, 3
    60 (14.7 to 94.7)
    23.1 (5 to 53.8)
    Notes
    [9] - Full analysis set.
    [10] - Full analysis set
    No statistical analyses for this end point

    Secondary: Mean plasma concentrations of BEZ235, by dose level

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    End point title
    		 Mean plasma concentrations of BEZ235, by dose level
    End point description
    For BEZ235 pharmacokinetic characteristics (PK) in Phase Ib, the pre-dose PK sample were collected prior to the paclitaxel pre-medication/prior to any study treatment on the PK collection day and post-dose samples were to be taken 4-6 hours after the morning BEZ235. All analyses were based on plasma concentrations. The PK analysis set was used for these analyses. Only PK blood sample with date and time and for which the last prior dose dates and times were adequately recorded were included in the population PK analyses. EMA directed use of 999999 as the EU results system will not accept “not estimable”.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and 8, and Day 1 of Cycles 2, 3, 5, 7, 9, 11, 13, and 15
    End point values
    		 BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80
    Number of subjects analysed
    5 [11]
    13 [12]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (0 hrs) n=5, 11
    0 ( 0 )
    0 ( 0 )
        Cycle 1 Day 1 (4-6 hrs) n=5,12
    30.92 ( 13.325 )
    80.47 ( 55.264 )
        Cycle 1 Day 8 (0 hrs) n=5, 11
    57.68 ( 63.494 )
    509.66 ( 695.589 )
        Cycle 1 Day 8 (4-6 hrs) n=5,11
    111.5 ( 68.765 )
    575.1 ( 627.337 )
        Cycle 2 Day 1 (0 hrs) n=4, 10
    43.65 ( 41.018 )
    285.34 ( 425.588 )
        Cycle 2 Day 1 (4-6 hrs) n=5,10
    74.12 ( 72.792 )
    369.14 ( 357.038 )
        Cycle 3 Day 1 (0 hrs) n=4,7
    4.61 ( 6.279 )
    372.86 ( 407.032 )
        Cycle 3 Day 1 (4-6 hrs) n=4,7
    99.35 ( 138.914 )
    283.77 ( 233.317 )
        Cycle 5 Day 1 (0 hrs) n=4,3
    5.38 ( 3.72 )
    143.23 ( 192.136 )
        Cycle 5 Day 1 (4-6 hrs) n=4,3
    39.7 ( 50.241 )
    236.67 ( 30.072 )
        Cycle 7 Day 1 (0 hrs) n=2,1
    2.04 ( 2.885 )
    0 ( 999999 )
        Cycle 9 Day 1 (0 hrs) n=1,2
    0 ( 999999 )
    559.1 ( 736.664 )
        Cycle 11 Day 1 (0 hrs) n=0,3
    999999 ( 999999 )
    848.05 ( 1148.271 )
        Cycle 13 Day 1 (0 hrs) n=0,1
    999999 ( 999999 )
    17.2 ( 999999 )
        Cycle 15 Day 1 (0 hrs) n=0,1
    999999 ( 999999 )
    20.2 ( 999999 )
    Notes
    [11] - Pharmacokinetic analysis set.
    [12] - Pharmacokinetic analysis set.
    No statistical analyses for this end point

    Secondary: Geometric mean of BEZ235 plasma concentration, by dose level

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    End point title
    		 Geometric mean of BEZ235 plasma concentration, by dose level
    End point description
    For BEZ235 pharmacokinetic characteristics (PK) in Phase Ib, the pre-dose PK sample were collected prior to the paclitaxel pre-medication/prior to any study treatment on the PK collection day and post-dose samples were to be taken 4-6 hours after the morning BEZ235. All analyses were based on plasma concentrations. The PK analysis set was used for these analyses. Only PK blood sample with date and time and for which the last prior dose dates and times were adequately recorded were included in the population PK analyses. EMA directed use of 999999 as the EU results system will not accept “not estimable”.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and 8, and Day 1 of Cycles 2, 3, 5, 7, 9, 11, 13, and 15
    End point values
    		 BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80
    Number of subjects analysed
    5 [13]
    13 [14]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (0 hrs) n=5, 11
    999999 ( 999999 )
    999999 ( 999999 )
        Cycle 1 Day 1 (4-6 hrs) n=5,12
    28.1 ( 56.05 )
    59.09 ( 116.87 )
        Cycle 1 Day 8 (0 hrs) n=5, 11
    37.71 ( 132.52 )
    168.87 ( 933.52 )
        Cycle 1 Day 8 (4-6 hrs) n=5,11
    94.24 ( 73.96 )
    326.68 ( 167.45 )
        Cycle 2 Day 1 (0 hrs) n=4, 10
    49.15 ( 89.67 )
    153.22 ( 337.99 )
        Cycle 2 Day 1 (4-6 hrs) n=5,10
    51.5 ( 117.44 )
    228.3 ( 149.34 )
        Cycle 3 Day 1 (0 hrs) n=4,7
    8.25 ( 75.97 )
    211.73 ( 187.23 )
        Cycle 3 Day 1 (4-6 hrs) n=4,7
    47.2 ( 243.96 )
    221.59 ( 86.04 )
        Cycle 5 Day 1 (0 hrs) n=4,3
    7.1 ( 16.54 )
    63.88 ( 374.49 )
        Cycle 5 Day 1 (4-6 hrs) n=4,3
    24.28 ( 141.06 )
    235.44 ( 12.4 )
        Cycle 7 Day 1 (0 hrs) n=2,1
    4.08 ( 999999 )
    999999 ( 999999 )
        Cycle 9 Day 1 (0 hrs) n=1,2
    999999 ( 999999 )
    203.12 ( 1628.36 )
        Cycle 11 Day 1 (0 hrs) n=0,3
    999999 ( 999999 )
    244.8 ( 3900.16 )
        Cycle 13 Day 1 (0 hrs) n=0,1
    999999 ( 999999 )
    17.2 ( 999999 )
        Cycle 15 Day 1 (0 hrs) n=0,1
    999999 ( 999999 )
    20.2 ( 999999 )
    Notes
    [13] - Pharmacokinetic analysis set
    [14] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Secondary: Coefficient of variation of mean of BEZ235 plasma concentration, by dose level

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    End point title
    		 Coefficient of variation of mean of BEZ235 plasma concentration, by dose level
    End point description
    For BEZ235 pharmacokinetic characteristics (PK) in Phase Ib, the pre-dose PK sample were collected prior to the paclitaxel pre-medication/prior to any study treatment on the PK collection day and post-dose samples were to be taken 4-6 hours after the morning BEZ235. All analyses were based on plasma concentrations. The PK analysis set was used for these analyses. Only PK blood sample with date and time and for which the last prior dose dates and times were adequately recorded were included in the population PK analyses. Samples taken from patients who vomited within 4 hours of BEZ235 dosing will be excluded from the analysis
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and 8, and Day 1 of Cycles 2, 3, 5, 7, 9, 11, 13, and 15
    End point values
    		 BEZ235 100 mg bid + P80 BEZ235 200 mg bid + P80
    Number of subjects analysed
    5 [15]
    13 [16]
    Units: CV% of mean (ng/mL)
    number (not applicable)
        Cycle 1 Day 1 (0 hrs) n=5, 11
    999999
    999999
        Cycle 1 Day 1 (4-6 hrs) n=5,12
    43.1
    68.68
        Cycle 1 Day 8 (0 hrs) n=5, 11
    110.08
    136.48
        Cycle 1 Day 8 (4-6 hrs) n=5,11
    61.67
    109.08
        Cycle 2 Day 1 (0 hrs) n=4, 10
    93.97
    149.15
        Cycle 2 Day 1 (4-6 hrs) n=5,10
    98.21
    96.72
        Cycle 3 Day 1 (0 hrs) n=4,7
    136.35
    109.17
        Cycle 3 Day 1 (4-6 hrs) n=4,7
    139.82
    82.22
        Cycle 5 Day 1 (0 hrs) n=4,3
    69.18
    134.14
        Cycle 5 Day 1 (4-6 hrs) n=4,3
    126.55
    12.71
        Cycle 7 Day 1 (0 hrs) n=2,1
    141.42
    999999
        Cycle 9 Day 1 (0 hrs) n=1,2
    999999
    131.76
        Cycle 11 Day 1 (0 hrs) n=0,3
    999999
    135.4
        Cycle 13 Day 1 (0 hrs) n=0,1
    999999
    999999
        Cycle 15 Day 1 (0 hrs) n=0,1
    999999
    999999
    Notes
    [15] - Pharmacokinetic analysis set
    [16] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    BEZ235 100 bid + P80
    Reporting group description
    		 BEZ235 100 bid + P80

    Reporting group title
    BEZ235 200 bid + P80
    Reporting group description
    		 BEZ235 200 bid + P80

    Serious adverse events
    		 BEZ235 100 bid + P80 BEZ235 200 bid + P80
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 5 (60.00%)
    5 / 13 (38.46%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 13 (23.08%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BEZ235 100 bid + P80 BEZ235 200 bid + P80
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    13 / 13 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    METASTASES TO SKIN
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Vascular disorders
    FLUSHING
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    HAEMATOMA
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    HOT FLUSH
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    LYMPHOEDEMA
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    5 / 5 (100.00%)
    9 / 13 (69.23%)
         occurrences all number
    8
    14
    FATIGUE
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    INDURATION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    LOCALISED OEDEMA
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    PAIN
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    3
    PYREXIA
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 13 (15.38%)
         occurrences all number
    3
    3
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    SEASONAL ALLERGY
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    VAGINAL INFLAMMATION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    DYSPHONIA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    COUGH
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 13 (23.08%)
         occurrences all number
    1
    4
    DYSPNOEA
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    EPISTAXIS
         subjects affected / exposed
    1 / 5 (20.00%)
    7 / 13 (53.85%)
         occurrences all number
    1
    7
    LARYNGEAL DISCOMFORT
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    NASAL CONGESTION
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    RHINITIS ALLERGIC
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    PRODUCTIVE COUGH
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    RHINORRHOEA
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    TRACHEAL PAIN
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Psychiatric disorders
    FOOD AVERSION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    ANXIETY
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    INSOMNIA
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    BLOOD ALKALINE PHOSPHATASE
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    BLOOD PHOSPHORUS INCREASED
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 5 (60.00%)
    1 / 13 (7.69%)
         occurrences all number
    5
    2
    GLYCOSYLATED HAEMOGLOBIN INCREASED
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    TRANSAMINASES INCREASED
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    4
    Cardiac disorders
    PALPITATIONS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    SUPRAVENTRICULAR EXTRASYSTOLES
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    HEADACHE
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    2
    DYSGEUSIA
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    HYPERAESTHESIA
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    HYPOREFLEXIA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    HYPOAESTHESIA
         subjects affected / exposed
    3 / 5 (60.00%)
    0 / 13 (0.00%)
         occurrences all number
    9
    0
    NEUROTOXICITY
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    PARAESTHESIA
         subjects affected / exposed
    1 / 5 (20.00%)
    4 / 13 (30.77%)
         occurrences all number
    1
    7
    PRESYNCOPE
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    TREMOR
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 5 (40.00%)
    5 / 13 (38.46%)
         occurrences all number
    7
    7
    LYMPHOPENIA
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    NEUTROPENIA
         subjects affected / exposed
    3 / 5 (60.00%)
    10 / 13 (76.92%)
         occurrences all number
    18
    21
    Ear and labyrinth disorders
    TINNITUS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    EAR PAIN
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Eye disorders
    EYELID OEDEMA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    MACULAR OEDEMA
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    VISUAL ACUITY REDUCED
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    VITREOUS HAEMORRHAGE
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    CHEILITIS
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 13 (30.77%)
         occurrences all number
    3
    4
    DYSPEPSIA
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    DIARRHOEA
         subjects affected / exposed
    3 / 5 (60.00%)
    10 / 13 (76.92%)
         occurrences all number
    9
    49
    CONSTIPATION
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 13 (30.77%)
         occurrences all number
    2
    5
    GINGIVAL INFLAMMATION
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    7
    GINGIVAL BLEEDING
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    ODYNOPHAGIA
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    2
    NAUSEA
         subjects affected / exposed
    5 / 5 (100.00%)
    11 / 13 (84.62%)
         occurrences all number
    11
    19
    HAEMORRHOIDS
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    REFLUX GASTRITIS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    STOMATITIS
         subjects affected / exposed
    2 / 5 (40.00%)
    10 / 13 (76.92%)
         occurrences all number
    8
    21
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    VOMITING
         subjects affected / exposed
    3 / 5 (60.00%)
    7 / 13 (53.85%)
         occurrences all number
    20
    10
    TONGUE ULCERATION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    CHOLESTASIS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    HEPATOCELLULAR INJURY
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    4
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    DRY SKIN
         subjects affected / exposed
    0 / 5 (0.00%)
    6 / 13 (46.15%)
         occurrences all number
    0
    7
    DERMATITIS CONTACT
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    ECZEMA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    ERYTHEMA
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    ERYTHEMA MULTIFORME
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    NAIL DISORDER
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    NAIL DYSTROPHY
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    ONYCHOLYSIS
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 13 (23.08%)
         occurrences all number
    3
    6
    ONYCHOMADESIS
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    PRURIGO
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    PRURITUS
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 13 (23.08%)
         occurrences all number
    1
    4
    RASH
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 13 (30.77%)
         occurrences all number
    6
    9
    RASH ERYTHEMATOUS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    SKIN HYPOPIGMENTATION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    URINARY TRACT PAIN
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    DYSURIA
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 13 (23.08%)
         occurrences all number
    7
    4
    BACK PAIN
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    JOINT SWELLING
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    MUSCLE SPASMS
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    MYALGIA
         subjects affected / exposed
    3 / 5 (60.00%)
    4 / 13 (30.77%)
         occurrences all number
    7
    5
    NECK PAIN
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    OSTEONECROSIS OF JAW
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    PAIN IN JAW
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Infections and infestations
    ANAL FUNGAL INFECTION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    BRONCHITIS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    CONJUNCTIVITIS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    FOLLICULITIS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    GINGIVITIS
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    HERPES SIMPLEX
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    HORDEOLUM
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    NAIL INFECTION
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    3
    ORAL CANDIDIASIS
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    ORAL HERPES
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    PHARYNGITIS
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    RHINITIS
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    3
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    VULVOVAGINAL MYCOTIC INFECTION
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    4 / 5 (80.00%)
    7 / 13 (53.85%)
         occurrences all number
    5
    8
    DEHYDRATION
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    2
    HYPERPHOSPHATAEMIA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    HYPOALBUMINAEMIA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    5
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Aug 2012
    The main purpose of this amendment was to introduce a new dose strength of BEZ235 (50 mg sachet) and permit exploration of dose levels below 200 mg bid in future cohorts in combination with paclitaxel. Based on the clinical findings in the first 2 cohorts, the Bayesian logistic regression model (BLRM) did not allow continuation at a dose level of BEZ235 (200 mg BID) or any other of the higher planned BEZ235 doses in the original protocol. It did support the clinical recommendation to test lower dose level of BEZ235 (e.g. 100 mg bid). Two additional time points for PMBC collection will be added at trough concentrations during cycles 1 and 2 to study the effects of BEZ235 on PI3K signaling in surrogate tissue. In additional optional pre-post treatment tumor biopsies for patients in phase Ib (orginally planned only phase II) was included in order to gather data on pathway inhibition at lower dose of BEZ235BID in tumor tissue.The clinical experience section was updated based on new information. Updated data on managing stomatitis and pneumonitis was added.

    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.
    The study did not meet the Phase Ib primary objective to establish MTD. Therefore, Novartis terminated the study during Phase Ib and Phase II was not conducted.
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