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    Clinical Trial Results:
    Prospective Randomized Phase-III-Trial of Paclitaxel plus Topotecan versus Topotecan plus Cisplatin in Recurrent or Persistent Cervical Carcinoma

    Summary
    EudraCT number
    		 2006-000349-20
    Trial protocol
    		 DE   AT   BE  
    Global end of trial date
    02 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2022
    First version publication date
    29 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IFG-01-0106
    Additional study identifiers
    ISRCTN number
    		 ISRCTN77165120
    US NCT number
    		 NCT01405235
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut für Frauengesundheit GmbH
    Sponsor organisation address
    Universitätsstraße 21-23, Erlangen, Germany, 91054
    Public contact
    Clinical Trial Information, Institut für Frauengesundheit GmbH, studien@ifg-erlangen.de
    Scientific contact
    Clinical Trial Information, Institut für Frauengesundheit GmbH, studien@ifg-erlangen.de
    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 Feb 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Comparison of overall survival
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the applicable guidelines of the International Conference on Harmonization Good Clinical Practice (GCP) concerning informed consent and the protection of rights of human patients and other relevant international guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 The studies GOG 169 and 179 demonstrated that a combination of paclitaxel and cisplatin was superior to a cisplatin monotherapy with respect to therapeutic response and progression-free survival, as was a combination of topotecan and cisplatin with respect to therapeutic response, progression-free survival, and total survival. To achieve further improvement in total survival and to answer questions regarding the value of using a platinum-free combination, we conducted this trial to compare the efficacy of a platinum-free combination of paclitaxel and topotecan to a combination of cisplatin and topotecan.
    Actual start date of recruitment
    22 Jan 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 15 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 34
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Germany: 127
    Worldwide total number of subjects
    173
    EEA total number of subjects
    173
    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)
    155
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The clinical trial was conducted in 52 trials sites of the organ-specific uterine malignoma group and the organ-specific ovarian group of the AGO and other clinics with sufficient experience in conducting clinical studies. Recruitment started from January 2007 and was suspended on 31.12.2012.

    Pre-assignment
    Screening details
    		 A total of 189 patients were assessed fpr eligibility. 11 Patients declined study participation and 5 subjects were identified as screening failures. Therefore, 173 patients were assessed.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Paclitaxel/Topotecan
    Arm description
    		 Paclitaxel 70 mg/m2/d i.v. was administered over one hour and topotecan 1.75 mg/m2/d i.v. over 30 min. on days 1, 8, and 15; this cycle was repeated every four weeks for six cycles or until there was evidence of disease progression, or until unacceptable adverse effects prohibited further therapy. Maximum body surface area used for dose calculations was 2.0 m2. Treatment continued until completion of a maximum of six cycles. The therapy discontinued prior to the completion of six cycles if there was evidence of disease progression, or if unacceptable adverse effects prohibited further therapy. Patients with continued response or stable disease could continue to participate in the study for an additional three cycles beyond the original six cycles with consent of the Study Director.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Solution for infusion , Intravenous use
    Dosage and administration details
    Paclitaxel 70 mg/m2/d i.v. was administered over one hour on days 1, 8, and 15; this cycle was repeated every four weeks for six cycles or until there was evidence of disease progression, or until unacceptable adverse effects prohibited further therapy. Maximum body surface area used for dose calculations was 2.0 m2.

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Hycamtin
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use, Solution for infusion
    Dosage and administration details
    Topotecan administered 1.75 mg/m2/d i.v. over 30 min. on Days 1, 8, and 15; this cycle will be repeated every 4 weeks for 6 cycles or until there is evidence of disease progression, or until unacceptable adverse effects prohibit further therapy. Maximum body surface area used for dose calculations will be 2.0 m2.

    Arm title
    		 Cisplatin/Topotecan
    Arm description
    		 Topotecan 0.75 mg/m2/d was administered over 30 min. on days 1, 2, and 3 and cisplatin 50 mg/m2 i.v. on day 1; this cycle repeated every three weeks for a maximum of six cycles or until there was evidence of disease progression, or until unacceptable adverse effects prohibited further therapy. Maximum body surface area used for dose calculations was 2.0 m2. Treatment continued until completion of a maximum of six cycles. The therapy discontinued prior to the completion of six cycles if there was evidence of disease progression, or if unacceptable adverse effects prohibited further therapy. Patients with continued response or stable disease could continue to participate in the study for an additional three cycles beyond the original six cycles with consent of the Study Director.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Hycamtin
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use, Solution for infusion
    Dosage and administration details
    Topotecan administered 1.75 mg/m2/d i.v. over 30 min. on Days 1, 8, and 15; this cycle will be repeated every 4 weeks for 6 cycles or until there is evidence of disease progression, or until unacceptable adverse effects prohibit further therapy. Maximum body surface area used for dose calculations will be 2.0 m2.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use, Solution for infusion
    Dosage and administration details
    Cisplatin 50 mg/m2 i.v. was administered on day 1; this cycle repeated every three weeks for a maximum of six cycles or until there was evidence of disease progression, or until unacceptable adverse effects prohibited further therapy. Maximum body surface area used for dose calculations was 2.0 m2.

    Number of subjects in period 1
    		Paclitaxel/Topotecan Cisplatin/Topotecan
    Started
    88
    85
    Completed
    83
    78
    Not completed
    5
    7
         Did not receive assigned treatment
    5
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paclitaxel/Topotecan
    Reporting group description
    		 Paclitaxel 70 mg/m2/d i.v. was administered over one hour and topotecan 1.75 mg/m2/d i.v. over 30 min. on days 1, 8, and 15; this cycle was repeated every four weeks for six cycles or until there was evidence of disease progression, or until unacceptable adverse effects prohibited further therapy. Maximum body surface area used for dose calculations was 2.0 m2. Treatment continued until completion of a maximum of six cycles. The therapy discontinued prior to the completion of six cycles if there was evidence of disease progression, or if unacceptable adverse effects prohibited further therapy. Patients with continued response or stable disease could continue to participate in the study for an additional three cycles beyond the original six cycles with consent of the Study Director.

    Reporting group title
    Cisplatin/Topotecan
    Reporting group description
    		 Topotecan 0.75 mg/m2/d was administered over 30 min. on days 1, 2, and 3 and cisplatin 50 mg/m2 i.v. on day 1; this cycle repeated every three weeks for a maximum of six cycles or until there was evidence of disease progression, or until unacceptable adverse effects prohibited further therapy. Maximum body surface area used for dose calculations was 2.0 m2. Treatment continued until completion of a maximum of six cycles. The therapy discontinued prior to the completion of six cycles if there was evidence of disease progression, or if unacceptable adverse effects prohibited further therapy. Patients with continued response or stable disease could continue to participate in the study for an additional three cycles beyond the original six cycles with consent of the Study Director.

    Reporting group values
    		 Paclitaxel/Topotecan Cisplatin/Topotecan Total
    Number of subjects
    		 88 85 173
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.4 ( 11.1 ) 49.0 ( 11.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 88 85 173
        Male
    		 0 0 0
    ECOG
    Units: Subjects
        ECOG 0
    		 44 38 82
        ECOG 1
    		 37 39 76
        ECOG 2
    		 7 8 15
    concomitant diseases
    Number of concomitant diseases
    Units: Subjects
        N=0
    		 32 33 65
        N=1
    		 25 24 49
        N=2+
    		 31 28 59
    Disease status
    Units: Subjects
        Disatant metastasis
    		 66 62 128
        Local recurrence
    		 22 23 45
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 26.2 ( 6.5 ) 25.6 ( 6.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Paclitaxel/Topotecan
    Reporting group description
    		 Paclitaxel 70 mg/m2/d i.v. was administered over one hour and topotecan 1.75 mg/m2/d i.v. over 30 min. on days 1, 8, and 15; this cycle was repeated every four weeks for six cycles or until there was evidence of disease progression, or until unacceptable adverse effects prohibited further therapy. Maximum body surface area used for dose calculations was 2.0 m2. Treatment continued until completion of a maximum of six cycles. The therapy discontinued prior to the completion of six cycles if there was evidence of disease progression, or if unacceptable adverse effects prohibited further therapy. Patients with continued response or stable disease could continue to participate in the study for an additional three cycles beyond the original six cycles with consent of the Study Director.

    Reporting group title
    Cisplatin/Topotecan
    Reporting group description
    		 Topotecan 0.75 mg/m2/d was administered over 30 min. on days 1, 2, and 3 and cisplatin 50 mg/m2 i.v. on day 1; this cycle repeated every three weeks for a maximum of six cycles or until there was evidence of disease progression, or until unacceptable adverse effects prohibited further therapy. Maximum body surface area used for dose calculations was 2.0 m2. Treatment continued until completion of a maximum of six cycles. The therapy discontinued prior to the completion of six cycles if there was evidence of disease progression, or if unacceptable adverse effects prohibited further therapy. Patients with continued response or stable disease could continue to participate in the study for an additional three cycles beyond the original six cycles with consent of the Study Director.

    Subject analysis set title
    ITT Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population 1 are all patients included in the interim analysis (n=172) and ITT population 2 (ITT2; n=173) is the total study population

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety evaluation was performed in all randomized patients who were treated with at least one cycle of chemotherapy (n=161 (Safety Population); Arm A (Paclitaxel and Topotecan) 83 patients and Arm B (control group; Topotecan and Cisplatin) 78 patients).

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival is the observed length of life from randomization to death or the date of last contact. In the planned interim analysis, the primary efficacy analysis (primary study aim) was performed with all 172 patients (Intention to treat population, ITT population 1), Arm A including 87 patients, Arm B including 85 patients. The ITT population 1 includes all patients (172) who gave informed consent and who were randomized into one of the treatment arms at the time of the interim analysis.
    End point type
    Primary
    End point timeframe
    Duration of trial
    End point values
    		 Paclitaxel/Topotecan Cisplatin/Topotecan
    Number of subjects analysed
    87 [1]
    85 [2]
    Units: month
        median (confidence interval 95%)
    9.6 (7.2 to 12.4)
    12.0 (9.1 to 16.3)
    Notes
    [1] - Patients included in Arm A
    [2] - Patients included in Arm B
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    Paclitaxel/Topotecan v Cisplatin/Topotecan
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.33
    Method
    		 Logrank
    Confidence interval

    Secondary: 6 month PFS rate

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    End point title
    		 6 month PFS rate
    End point description
    Progression-free survival is the period from study entry until disease progression, death, or date of last contact. In the final analysis at the end of the study, the secondary study aims were analyzed with all 173 patients (ITT population 2), Arm A including 88 patients, Arm B including 85 patients. The ITT population 2 includes all patients (173) who gave informed consent and who were randomized into one of the treatment arms during the whole study.
    End point type
    Secondary
    End point timeframe
    Duration of trial
    End point values
    		 Paclitaxel/Topotecan Cisplatin/Topotecan
    Number of subjects analysed
    88
    85
    Units: percent
        number (confidence interval 95%)
    75.66 (71.73 to 79.59)
    75.86 (72.20 to 79.53)
    No statistical analyses for this end point

    Secondary: 12 month PFS rate

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    End point title
    		 12 month PFS rate
    End point description
    In the final analysis at the end of the study, the secondary study aims were analyzed with all 173 patients (ITT population 2), Arm A including 88 patients, Arm B including 85 patients. The ITT population 2 includes all patients (173) who gave informed consent and who were randomized into one of the treatment arms during the whole study.
    End point type
    Secondary
    End point timeframe
    Duration of trial
    End point values
    		 Paclitaxel/Topotecan Cisplatin/Topotecan
    Number of subjects analysed
    88
    85
    Units: percent
        number (confidence interval 95%)
    14 (8 to 24)
    10 (5 to 19)
    No statistical analyses for this end point

    Secondary: 24 month PFS rate

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    End point title
    		 24 month PFS rate
    End point description
    In the final analysis at the end of the study, the secondary study aims were analyzed with all 173 patients (ITT population 2), Arm A including 88 patients, Arm B including 85 patients. The ITT population 2 includes all patients (173) who gave informed consent and who were randomized into one of the treatment arms during the whole study.
    End point type
    Secondary
    End point timeframe
    Duration of Trial
    End point values
    		 Paclitaxel/Topotecan Cisplatin/Topotecan
    Number of subjects analysed
    88
    85
    Units: percent
        number (confidence interval 95%)
    6 (3 to 15)
    6 (2 to 15)
    No statistical analyses for this end point

    Secondary: Best overall response

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    End point title
    		 Best overall response
    End point description
    In the final analysis at the end of the study, the secondary study aims were analyzed with all 173 patients (ITT population 2), Arm A including 88 patients, Arm B including 85 patients. The ITT population 2 includes all patients (173) who gave informed consent and who were randomized into one of the treatment arms during the whole study. Measurement of the longest dimension of each lesion size was required for follow-up. Change in the sum of these dimensions afforded some estimate of change in tumor size and, hence, of therapeutic efficacy. All assessments were made using the same techniques as were used for the baseline. These changes in an individual case had to be reported in terms of the best response achieved by that case since entering the study.
    End point type
    Secondary
    End point timeframe
    Duration of trial
    End point values
    		 Paclitaxel/Topotecan Cisplatin/Topotecan
    Number of subjects analysed
    66 [3]
    67 [4]
    Units: number of patients
        complete response
    1
    2
        partial remission
    11
    13
        stable disease
    21
    20
        progression
    29
    26
        symptomatic deterioration
    3
    6
        not evaluable
    1
    0
    Notes
    [3] - Only patients with at least one further tumor assessment since baseline were included.
    [4] - Only patients with at least one further tumor assessment since baseline were included.
    No statistical analyses for this end point

    Secondary: Quality of Life

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    End point title
    		 Quality of Life
    End point description
    Association between treatment arm and cQOL was analyzed using linear mixed models with TOI as target variable. First, a linear mixed model was fitted with patient as random effect and treatment arm (categorical, Arm A vs Arm B), TOI before treatment (continuous), time (categorical; before chemotherapy cycle 2, before chemotherapy cycle 5, 9 months after randomization ) and the interaction between treatment arm and time as fixed effect. Next, a linear mixed model with the same fixed effects but without the interaction term was fitted. Both models were compared using the likelihood ratio test. If the p value was significant, adjusted mean TOI in both treatment arms and the mean difference between treatment arms with corresponding 95% CI were estimated for each time point using the interaction model. Otherwise, respective overall mean TOI values were estimated using the reduced regression model. The models were fitted by maximum likelihood instead of of restricted maximuum likelihoood.
    End point type
    Secondary
    End point timeframe
    before chemotherapy cycle 2, before chemotherapy cycle 5, 9 months after randomization
    End point values
    		 Paclitaxel/Topotecan Cisplatin/Topotecan
    Number of subjects analysed
    34 [5]
    38 [6]
    Units: trial outcome index
        arithmetic mean (confidence interval 95%)
    75.66 (71.73 to 79.59)
    75.86 (72.20 to 79.53)
    Notes
    [5] - Patients with TOI information before chemotherapy and at least one follow‐up TOI assessment.
    [6] - Patients with TOI information before chemotherapy and at least one follow‐up TOI assessment.
    Statistical analysis title
    		 Quality of life
    Comparison groups
    Paclitaxel/Topotecan v Cisplatin/Topotecan
    Number of subjects included in analysis
    72
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Likelzhood ratio test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.67
         upper limit
    		 5.09

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The investigator must report all AEs occurring during the clinical study or within 30 days after administration of the last dose of the study drug, regardless of causality.
    Adverse event reporting additional description
    The safety evaluation was performed in all randomized patients who were treated with at least one cycle of chemotherapy (n=161 (Safety Population); Arm A (Paclitaxel and Topotecan) 83 patients and Arm B (control group; Topotecan and Cisplatin) 78 patients).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Arm A (Paclitaxel and Topotecan)
    Reporting group description
    		 -

    Reporting group title
    Arm B (Topotecan and Cisplatin)
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A (Paclitaxel and Topotecan) Arm B (Topotecan and Cisplatin)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 83 (44.58%)
    23 / 78 (29.49%)
         number of deaths (all causes)
    65
    61
         number of deaths resulting from adverse events
    7
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Nephrostomy tube removal
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    8 / 83 (9.64%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal fistula
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 83 (3.61%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    4 / 83 (4.82%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Polyneuropathy in malignant disease
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 83 (10.84%)
    5 / 78 (6.41%)
         occurrences causally related to treatment / all
    8 / 14
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 83 (0.00%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 83 (0.00%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incontinence
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial diarrhoea
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 83 (0.00%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter colitis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (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
    Dehydration
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Arm A (Paclitaxel and Topotecan) Arm B (Topotecan and Cisplatin)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 83 (100.00%)
    77 / 78 (98.72%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 83 (1.20%)
    6 / 78 (7.69%)
         occurrences all number
    1
    9
    Tumour associated fever
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Cancer pain
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Hypertension
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    4
    Lymphoedema
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    2
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Thrombosis
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 78 (2.56%)
         occurrences all number
    1
    7
    Hot flush
         subjects affected / exposed
    2 / 83 (2.41%)
    4 / 78 (5.13%)
         occurrences all number
    2
    15
    Venous thrombosis limb
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Chest discomfort
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 78 (2.56%)
         occurrences all number
    1
    3
    Fatigue
         subjects affected / exposed
    59 / 83 (71.08%)
    59 / 78 (75.64%)
         occurrences all number
    155
    181
    Hernia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Mucosal dryness
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Oedema
         subjects affected / exposed
    34 / 83 (40.96%)
    22 / 78 (28.21%)
         occurrences all number
    86
    50
    Pain
         subjects affected / exposed
    5 / 83 (6.02%)
    8 / 78 (10.26%)
         occurrences all number
    6
    23
    Peripheral swelling
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Infusion site extravasation
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    9 / 83 (10.84%)
    4 / 78 (5.13%)
         occurrences all number
    11
    6
    Social circumstances
    Rash
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Breast disorder female
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Breast pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Pelvic pain
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences all number
    3
    1
    Vaginal discharge
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 78 (2.56%)
         occurrences all number
    1
    3
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 78 (2.56%)
         occurrences all number
    1
    2
    Female genital tract fistula
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Perineal pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Genital lesion
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    3
    0
    Vaginal fistula
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    3
    Vulvovaginal burning sensation
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Vulvovaginal pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 83 (3.61%)
    2 / 78 (2.56%)
         occurrences all number
    4
    3
    Dyspnoea
         subjects affected / exposed
    24 / 83 (28.92%)
    16 / 78 (20.51%)
         occurrences all number
    46
    42
    Epistaxis
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences all number
    2
    2
    Pleural effusion
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Larynx irritation
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences all number
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    25 / 83 (30.12%)
    21 / 78 (26.92%)
         occurrences all number
    61
    37
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 83 (26.51%)
    22 / 78 (28.21%)
         occurrences all number
    36
    38
    Blood bilirubin increased
         subjects affected / exposed
    7 / 83 (8.43%)
    6 / 78 (7.69%)
         occurrences all number
    9
    9
    Blood calcium decreased
         subjects affected / exposed
    21 / 83 (25.30%)
    31 / 78 (39.74%)
         occurrences all number
    37
    48
    Blood calcium increased
         subjects affected / exposed
    7 / 83 (8.43%)
    2 / 78 (2.56%)
         occurrences all number
    10
    48
    Blood creatinine increased
         subjects affected / exposed
    25 / 83 (30.12%)
    24 / 78 (30.77%)
         occurrences all number
    50
    75
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    37 / 83 (44.58%)
    36 / 78 (46.15%)
         occurrences all number
    84
    83
    Blood magnesium decreased
         subjects affected / exposed
    23 / 83 (27.71%)
    35 / 78 (44.87%)
         occurrences all number
    33
    77
    Blood magnesium increased
         subjects affected / exposed
    3 / 83 (3.61%)
    4 / 78 (5.13%)
         occurrences all number
    3
    4
    Blood potassium decreased
         subjects affected / exposed
    20 / 83 (24.10%)
    18 / 78 (23.08%)
         occurrences all number
    28
    27
    Blood potassium increased
         subjects affected / exposed
    17 / 83 (20.48%)
    15 / 78 (19.23%)
         occurrences all number
    20
    26
    Blood sodium decreased
         subjects affected / exposed
    19 / 83 (22.89%)
    23 / 78 (29.49%)
         occurrences all number
    22
    45
    Blood sodium increased
         subjects affected / exposed
    4 / 83 (4.82%)
    5 / 78 (6.41%)
         occurrences all number
    4
    7
    Body temperature increased
         subjects affected / exposed
    4 / 83 (4.82%)
    6 / 78 (7.69%)
         occurrences all number
    4
    9
    Creatinine renal clearance increased
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    51 / 83 (61.45%)
    52 / 78 (66.67%)
         occurrences all number
    133
    169
    Weight decreased
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Blood phosphorus increased
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Transaminases increased
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    General physical condition abnormal
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    36 / 83 (43.37%)
    36 / 78 (46.15%)
         occurrences all number
    87
    92
    Urine analysis abnormal
         subjects affected / exposed
    38 / 83 (45.78%)
    39 / 78 (50.00%)
         occurrences all number
    75
    74
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    6 / 83 (7.23%)
    3 / 78 (3.85%)
         occurrences all number
    9
    4
    Sinus tachycardia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences all number
    2
    2
    Dizzines
         subjects affected / exposed
    3 / 83 (3.61%)
    3 / 78 (3.85%)
         occurrences all number
    4
    6
    Dysaesthesia
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Dysarthria
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    3 / 83 (3.61%)
    5 / 78 (6.41%)
         occurrences all number
    4
    7
    Monoparesis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Neurotoxicity
         subjects affected / exposed
    35 / 83 (42.17%)
    21 / 78 (26.92%)
         occurrences all number
    100
    49
    Polyneuropathy in malignant disease
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    2
    Sciatica
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Radicular syndrome
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    82 / 83 (98.80%)
    76 / 78 (97.44%)
         occurrences all number
    1075
    832
    Febrile neutropenia
         subjects affected / exposed
    3 / 83 (3.61%)
    4 / 78 (5.13%)
         occurrences all number
    3
    4
    Leukopenia
         subjects affected / exposed
    64 / 83 (77.11%)
    74 / 78 (94.87%)
         occurrences all number
    381
    468
    Neutropenia
         subjects affected / exposed
    45 / 83 (54.22%)
    61 / 78 (78.21%)
         occurrences all number
    117
    264
    Pancytopenia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    23 / 83 (27.71%)
    55 / 78 (70.51%)
         occurrences all number
    60
    243
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Ototoxicity
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    2
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Vision blurred
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 83 (1.20%)
    8 / 78 (10.26%)
         occurrences all number
    6
    9
    Abdominal pain lower
         subjects affected / exposed
    7 / 83 (8.43%)
    6 / 78 (7.69%)
         occurrences all number
    8
    11
    Abdominal pain upper
         subjects affected / exposed
    2 / 83 (2.41%)
    5 / 78 (6.41%)
         occurrences all number
    2
    5
    Ascites
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Colitis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    27 / 83 (32.53%)
    33 / 78 (42.31%)
         occurrences all number
    43
    68
    Diarrhoea
         subjects affected / exposed
    30 / 83 (36.14%)
    26 / 78 (33.33%)
         occurrences all number
    51
    49
    Dry mouth
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 78 (2.56%)
         occurrences all number
    1
    2
    Gastric haemorrhage
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 83 (2.41%)
    3 / 78 (3.85%)
         occurrences all number
    3
    4
    Gastrointestinal pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Haematochezia
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Ileus
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    35 / 83 (42.17%)
    52 / 78 (66.67%)
         occurrences all number
    78
    134
    Rectal haemorrhage
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Stomatitis
         subjects affected / exposed
    15 / 83 (18.07%)
    13 / 78 (16.67%)
         occurrences all number
    26
    23
    Vomiting
         subjects affected / exposed
    22 / 83 (26.51%)
    29 / 78 (37.18%)
         occurrences all number
    36
    56
    Subileus
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Dyschezia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Tooth pulp haemorrhage
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Bile duct obstruction
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    58 / 83 (69.88%)
    53 / 78 (67.95%)
         occurrences all number
    69
    196
    Dry skin
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    2
    Neurodermatitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    4
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Swelling face
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Nail pigmentation
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences all number
    4
    2
    Renal and urinary disorders
    Bladder discomfort
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Bladder pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    2
    Haematuria
         subjects affected / exposed
    4 / 83 (4.82%)
    1 / 78 (1.28%)
         occurrences all number
    6
    1
    Hydronephrosis
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 78 (1.28%)
         occurrences all number
    2
    1
    Incontinence
         subjects affected / exposed
    3 / 83 (3.61%)
    0 / 78 (0.00%)
         occurrences all number
    7
    0
    Nocturia
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Pollakiuria
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Renal disorder
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Renal failure
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Renal pain
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Urine abnormality
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Urogenital fistula
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Urinary tract obstruction
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 78 (2.56%)
         occurrences all number
    1
    2
    Urinary tract pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Stress urinary incontinence
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Urinary tract discomfort
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 83 (18.07%)
    16 / 78 (20.51%)
         occurrences all number
    18
    23
    Back pain
         subjects affected / exposed
    3 / 83 (3.61%)
    2 / 78 (2.56%)
         occurrences all number
    6
    4
    Bone pain
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 78 (2.56%)
         occurrences all number
    8
    2
    Myalgia
         subjects affected / exposed
    15 / 83 (18.07%)
    12 / 78 (15.38%)
         occurrences all number
    24
    22
    Neck pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    5
    0
    Pain in extremity
         subjects affected / exposed
    4 / 83 (4.82%)
    3 / 78 (3.85%)
         occurrences all number
    5
    5
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Spinal pain
         subjects affected / exposed
    5 / 83 (6.02%)
    4 / 78 (5.13%)
         occurrences all number
    7
    8
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    7 / 83 (8.43%)
    5 / 78 (6.41%)
         occurrences all number
    8
    5
    Erysipelas
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    3
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Herpes simplex
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    17 / 83 (20.48%)
    15 / 78 (19.23%)
         occurrences all number
    21
    17
    Influenza
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Pyelonephritis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Rash pustular
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 83 (3.61%)
    2 / 78 (2.56%)
         occurrences all number
    4
    3
    Urethritis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 78 (2.56%)
         occurrences all number
    2
    4
    Vulvitis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Urosepsis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Vascular access site infection
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Weight fluctuation
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Malnutrition
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 78 (2.56%)
         occurrences all number
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2011
    After a 2-year extension of the recruitment period and slow recruitment (172 of 312 planed patients) an amendment of the study protocol (Amendment 1; protocol Version 2) was accepted by the IEC to perform an interim analysis, to check if a continuation of the study could answer the primary objective (difference in overall survival). An adaptive interim analysis (AIA) was performed on February 27th 2012. The AIA allows sample size re-calculation for the second stage of the trial after the interim analysis or, if the case may be, early stopping of the trial after the interim analysis. In the first case, a final p-value is calculated from the p-values of both stages. In the second case, the p-value of the interim analysis is the p-value of the primary objective. The following parameters were selected for the planning of the two phases of the study (first phase up to AIA, second phase after AIA: a global α = 0.05 (two-sided) and the total power of 80%. Let p1 be the p-value for the statistical test of the interim analysis. α0 = 0.5 was the critical lower limit, so that for p1 ≥ α0, the interim analysis would lead to early stopping with the acceptance of the null hypothesis (“no treatment effect”). One would also stop if a treatment difference has been estimated that does not indicate the intended direction. α1 = 0.0233 was critical upper limit, so that for p1 < α1 the interim analysis would stop with the rejection of the null hypothesis. If p1 was between α1 and α0 and the estimated treatment difference indicates the intended direction, a second study phase would be planned. The interim analysis revealed no significant difference in overall survival rates, but a trend toward superiority of the control group (Arm B). From a statistical perspective, continuing recruitment to demonstrate superiority of arm A was not reasonable; therefore, recruitment was terminated after the interim analysis. Patients were allowed to continue trial therapy that had already been started.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    31 Dec 2012
    Recriutment was stopped on 31-Sec-20111 for preparation of an interim analysis. The interim analysis perfomred on 27-Apr-2012 revealed no significant difference in overall survival rates, but a trend toward superiority of the control group (Arm B). From a statistical perspective, continuing recruitment to demonstrate superiority of arm A was not reasonable; therefore, recruitment was terminated after the interim analysis. At the same time, since there were no safety concerns identified from the safety report, patients were allowed to continue effective therapy that had already been started.
    -

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