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    Clinical Trial Results:
    An Open-Label Multicenter Phase 2 Window of Opportunity Study Evaluating Ganetespib in Women with Breast Cancer

    Summary
    EudraCT number
    		 2012-000558-71
    Trial protocol
    		 GB   BE   ES  
    Global end of trial date
    31 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2016
    First version publication date
    08 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    9090-11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01677455
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Synta Pharmaceuticals Corp.
    Sponsor organisation address
    45 Hartwell Avenue, Lexington, MA, United States, 02421
    Public contact
    VP Clinical Research, Synta Pharmaceuticals Corp., 001 781- 541-7261,
    Scientific contact
    VP Clinical Research, Synta Pharmaceuticals Corp., 001 781- 541-7261,
    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
    16 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Determine the objective response rate of ganetespib monotherapy in patients with these subtypes of breast cancer: human epidermal growth factor receptor 2 (HER2+), triple negative breast cancer (TNBC), and estrogen receptor/progesterone receptor (ER/PR)-positive disease.
    Protection of trial subjects
    Prior to the start of any protocol-specific evaluations or screening procedures, the Investigator (or designated staff) explained the nature of the study and its risks and benefits to the patient (or the patient’s legal representative). Each patient received an informed consent document with patient information. Patients were given ample time to read the information and the opportunity to ask questions. Informed consent was obtained from each patient prior to performing any protocol-specific evaluations. One copy of the signed informed consent document was given to the patient, and another was retained by the Investigator. The study design mitigated potential risk to patients treated with an investigational agent in the first line setting by implementing multiple decision points based on clinical and objective evaluations in totality. The Investigator assessment of these evaluations, rather than independent review, determined treatment continuation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 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: 5
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Peru: 4
    Worldwide total number of subjects
    51
    EEA total number of subjects
    22
    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)
    42
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A Simon’s optimal 2-stage design was planned for each single-agent ganetespib cohort. Up to 15 evaluable patients were enrolled in the first stage, and if at least 1 patient achieved an objective response (OR, defined as CR + PR), enrollment in the cohort was to proceed to Stage 2 for a total of approximately 35 patients per cohort.

    Pre-assignment
    Screening details
    		 A total of 68 patients were screened for possible inclusion in the study. Of these, 51 patients were enrolled at 22 study centers.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Monotherapy: HER2-positive breast cancer
    Arm description
    		 Cohort A includes the subpopulation of breast cancer patients with human epidermal growth factor receptor 2 (HER2). Patients were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest. Three 4-week cycles were planned.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ganetespib
    Investigational medicinal product code
    Other name
    STA-9090
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganetespib administered at a dose of 150 mg/m2 by 1-hour infusion.

    Arm title
    		 Monotherapy: TNBC
    Arm description
    		 Cohort B includes the subpopulation of breast cancer patients with triple negative breast cancer (TNBC). Patients were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest. Three 4-week cycles were planned.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ganetespib
    Investigational medicinal product code
    Other name
    STA-9090
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganetespib administered at a dose of 150 mg/m2 by 1-hour infusion.

    Arm title
    		 Monotherapy: ER/PR+
    Arm description
    		 Cohort D includes the subpopulation of breast cancer patients with estrogen receptor/progesterone receptor positive (ER/PR+). Patients were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest. Three 4-week cycles were planned.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ganetespib
    Investigational medicinal product code
    Other name
    STA-9090
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganetespib administered at a dose of 150 mg/m2 by 1-hour infusion.

    Arm title
    		 Combination Therapy
    Arm description
    		 Patients with disease progression while on Monotherapy (i.e. treated only with ganetespib) had the option of entering combination therapy (Cohort C) in which patients were treated with intravenous ganetespib 150 mg/m^2 in a weekly 1-hour infusion for 3 out of 4 weeks, ie, Days 1, 8, and 15 every 28 days. After an hour rest, patients were then given paclitaxel administered at a dose of 80 mg/m^2 by a 1-hour infusion on the same treatment days. Combination therapy continued until disease progression, unacceptable toxicity, or withdrawal from the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ganetespib
    Investigational medicinal product code
    Other name
    STA-9090
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganetespib administered at a dose of 150 mg/m2 by 1-hour infusion.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    taxol
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel administered at a dose of 80 mg/m^2 by a 1-hour infusion weekly for 3 out of 4 weeks, eg, Days 1, 8, and 15 every 28 days (the most commonly used paclitaxel schedule).

    Number of subjects in period 1
    		Monotherapy: HER2-positive breast cancer Monotherapy: TNBC Monotherapy: ER/PR+ Combination Therapy
    Started
    12
    38
    1
    6
    Completed
    0
    1
    0
    0
    Not completed
    12
    37
    1
    6
         Clinical progression
    1
    3
    -
    1
         Rollover to Combination Therapy
    1
    5
    -
    -
         Adverse event, serious fatal
    -
    1
    -
    -
         Consent withdrawn by subject
    3
    2
    -
    -
         Adverse event, non-fatal
    1
    1
    -
    -
         Progressive disease
    5
    24
    1
    5
         Sponsor decision
    1
    -
    -
    -
         Protocol deviation
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Group combines Cohorts A+B+D and includes all patients who were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest.

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 51 51
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 42 42
        From 65-84 years
    		 9 9
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.5 ± 10.56 -
    Gender categorical
    Units: Subjects
        Female
    		 51 51
        Male
    		 0 0
    Eastern Cooperative Oncology Group Performance Status
    Units: Subjects
        0=fully active
    		 30 30
        1=restrictive but ambulatory
    		 21 21
        2=ambulatory, unable to work
    		 0 0
        3=limited self-care
    		 0 0
        4=completely disabled
    		 0 0
    Breast Cancer Stage
    Stage I: tumor <=2.0 cm, lymph nodes clear, no metastasis Stage IIa: tumor <=2.0 cm, regional lymph node Stage IIb: tumor >2.0<5.0 cm, regional lymph nodes Stage IIIa: tumor >5.0 cm, regional lymph nodes Stage IIIb: tumor extending to chest wall or skin Stage IIIc: tumor with extensive lymph node involvement Stage IV: distant metastasis Not recorded
    Units: Subjects
        Stage I
    		 0 0
        Stage IIa
    		 0 0
        Stage IIb
    		 0 0
        Stage IIIa
    		 0 0
        Stage IIIb
    		 1 1
        Stage IIIc
    		 1 1
        Stage IV
    		 16 16
        Not recorded
    		 33 33
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 70.27 ± 15.1 -
    Body Surface Area (BSA)
    Units: m^2
        arithmetic mean (standard deviation)
    		 1.743 ± 0.1749 -

    End points

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    End points reporting groups
    Reporting group title
    Monotherapy: HER2-positive breast cancer
    Reporting group description
    		 Cohort A includes the subpopulation of breast cancer patients with human epidermal growth factor receptor 2 (HER2). Patients were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest. Three 4-week cycles were planned.

    Reporting group title
    Monotherapy: TNBC
    Reporting group description
    		 Cohort B includes the subpopulation of breast cancer patients with triple negative breast cancer (TNBC). Patients were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest. Three 4-week cycles were planned.

    Reporting group title
    Monotherapy: ER/PR+
    Reporting group description
    		 Cohort D includes the subpopulation of breast cancer patients with estrogen receptor/progesterone receptor positive (ER/PR+). Patients were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest. Three 4-week cycles were planned.

    Reporting group title
    Combination Therapy
    Reporting group description
    		 Patients with disease progression while on Monotherapy (i.e. treated only with ganetespib) had the option of entering combination therapy (Cohort C) in which patients were treated with intravenous ganetespib 150 mg/m^2 in a weekly 1-hour infusion for 3 out of 4 weeks, ie, Days 1, 8, and 15 every 28 days. After an hour rest, patients were then given paclitaxel administered at a dose of 80 mg/m^2 by a 1-hour infusion on the same treatment days. Combination therapy continued until disease progression, unacceptable toxicity, or withdrawal from the study.

    Subject analysis set title
    Ganetespib Monotherapy
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Group combines Cohorts A+B+D and includes all patients who were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest.

    Subject analysis set title
    Ganetespib Combination Therapy
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients with disease progression while in the Monotherapy Period had the option of entering the combination therapy period (Cohort C) in which patients were treated with intravenous ganetespib 150 mg/m^2 in a weekly 1-hour infusion for 3 out of 4 weeks, ie, Days 1, 8, and 15 every 28 days. After an hour rest, patients were then given paclitaxel administered at a dose of 80 mg/m^2 by a 1-hour infusion on the same treatment days. Combination therapy continued until disease progression, unacceptable toxicity, or withdrawal from the study.

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1]
    End point description
    The ORR (defined as the percentage of patients with complete response + the percentage with partial response, according to modified RECIST 1.1 according to the investigator’s assessment) was the primary efficacy endpoint. • Complete Response (CR): Disappearance (or normalization) of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to <10 mm. • Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions compared to the baseline sum. Disease assessments in patients with locally advanced disease could be submitted with ultrasound, MRI, mammogram, or physical examination. Digital photographs to detect skin lesions, if present, were taken at baseline. The same method of assessment used at baseline were used for all subsequent assessments.
    End point type
    Primary
    End point timeframe
    Baseline (within one week of first dose of treatment), Weeks 3, 6, 12 after the first dose and repeated every 6 weeks thereafter until drug is discontinued.
    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: This was a two-stage design where success is determined by achieving a minimum number of required responders.
    End point values
    		 Monotherapy: HER2-positive breast cancer Monotherapy: TNBC Monotherapy: ER/PR+ Combination Therapy
    Number of subjects analysed
    12 [2]
    38 [3]
    1 [4]
    6 [5]
    Units: percentage of participants
        number (confidence interval 95%)
    41.7 (15.2 to 72.3)
    5.3 (0.6 to 17.7)
    0 (0 to 0)
    16.7 (0.4 to 65.1)
    Notes
    [2] - All patients
    [3] - All patients
    [4] - All patients
    [5] - Rollover patients
    No statistical analyses for this end point

    Secondary: Best Overall Response

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    End point title
    		 Best Overall Response
    End point description
    Best overall response was the % of patients who obtained the most positive response per RECIST 1.1 according to the investigator’s assessment. • Complete Response: Disappearance of all target lesions. Any pathological lymph nodes must have had reduction in short axis to <10 mm. • Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions compared to the baseline sum. • Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD • Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions. The sum must also have an absolute increase >=5 mm. • Non-evaluable: inadequate or missing images, including the inability to visualize >25% of target disease. Disease assessments in patients with locally advanced disease used ultrasound, MRI, mammogram, or physical exams. Digital photographs were used to detect skin lesions.
    End point type
    Secondary
    End point timeframe
    Baseline (within one week of first dose of treatment) Weeks 3, 6, 12 after the first dose and repeated every 6 weeks thereafter until drug is discontinued.
    End point values
    		 Monotherapy: HER2-positive breast cancer Monotherapy: TNBC Monotherapy: ER/PR+ Combination Therapy
    Number of subjects analysed
    12 [6]
    38 [7]
    1 [8]
    6 [9]
    Units: percentage of patients
    number (confidence interval 95%)
        Complete Response
    16.7 (2.1 to 48.4)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        Partial Response
    25 (5.5 to 57.2)
    5.3 (0.6 to 17.7)
    0 (0 to 0)
    16.7 (0.4 to 64.11)
        Stable Disease
    41.7 (15.2 to 72.3)
    26.3 (13.4 to 43.1)
    0 (0 to 0)
    16.7 (0.4 to 64.7)
        Progressive Disease
    8.3 (0.2 to 38.5)
    42.1 (26.3 to 59.2)
    100 (2.5 to 100)
    50 (11.8 to 88.2)
        Non-evaluable
    8.3 (8.3 to 8.3)
    26.3 (26.3 to 26.3)
    0 (0 to 0)
    16.7 (16.7 to 16.7)
    Notes
    [6] - All patients
    [7] - All patients
    [8] - All patients
    [9] - Rollover patients
    No statistical analyses for this end point

    Secondary: Metabolic Response Rate

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    End point title
    		 Metabolic Response Rate
    End point description
    Investigators assessed F-18-fluorodeoxyglucose (FDG)-PET for metabolic response and identification of metabolic progressive disease. The European Organization for Research and Treatment of Cancer (EORTC) PET study group general quantitative parameters was used [Young, Eur J Cancer, 1999]. The exception was that Metabolic Progressive Disease (mPD) was defined as the identification of new lesions and/or >25% increase in maximum standard uptake value >=1 target lesion, to more accurately assess responses. FDG-PET Patient-based Response Classification: • Class 1=All lesions showed a metabolic progressive response (mPR) or metabolic complete response (mCR) • Class 2=Mixed response: dominant part of tumor load showed metabolic response - without any progressive lesions • Class 3=Mixed response: dominant part of tumor load showed non-response - without any progressive lesions • Class 4=No lesions showed a response, or presence of =>1 progressive new lesion
    End point type
    Secondary
    End point timeframe
    Baseline (within one week prior to first treatment), Week 3
    End point values
    		 Monotherapy: HER2-positive breast cancer Monotherapy: TNBC Monotherapy: ER/PR+ Combination Therapy
    Number of subjects analysed
    12 [10]
    38 [11]
    1 [12]
    0 [13]
    Units: percentage of patients
    number (not applicable)
        Class 1
    75
    21.1
    0
        Class 2
    16.7
    28.9
    0
        Class 3
    8.3
    2.6
    100
        Class 4
    0
    31.6
    0
        Not applicable
    0
    15.8
    0
    Notes
    [10] - All patients
    [11] - All patients
    [12] - All patients
    [13] - Reporting timeframe is during monotherapy only
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    Clinical benefit rate is an established clinical endpoint in breast cancer trials in the metastatic setting. It provides a more comprehensive assessment of response to treatment. CBR is defined as the percentage of patients with best response, according to modified RECIST 1.1, of CR, PR, or SD. • Complete Response (CR): Disappearance (or normalization) of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in SA to <10 mm. • Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions compared to the baseline sum. • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. For patients with a best response of SD, duration of SD must be for at least 18 weeks.
    End point type
    Secondary
    End point timeframe
    Baseline (within one week of first treatment), Weeks 5, 9, 13 and repeated every 6 weeks thereafter until drug is discontinued.
    End point values
    		 Monotherapy: HER2-positive breast cancer Monotherapy: TNBC Monotherapy: ER/PR+ Combination Therapy
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    Units: percentage of patients
        number (not applicable)
    Notes
    [14] - No data was summarized due to early study termination
    [15] - No data was summarized due to early study termination
    [16] - No data was summarized due to early study termination
    [17] - No data was summarized due to early study termination
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is the interval from the date of Day 1 until objective tumor progression or death from any cause, whichever occurs first. Patients who discontinue from the study for other reasons than disease progression were censored at the time of the last radiological scans. Patients who started an alternative anticancer therapy were treated as censored at that time.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 625 (maximum treatment days)
    End point values
    		 Monotherapy: HER2-positive breast cancer Monotherapy: TNBC Monotherapy: ER/PR+ Combination Therapy
    Number of subjects analysed
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    Units: months
        median (standard error)
    ±
    ±
    ±
    ±
    Notes
    [18] - No data was summarized due to early study termination
    [19] - No data was summarized due to early study termination
    [20] - No data was summarized due to early study termination
    [21] - No data was summarized due to early study termination
    No statistical analyses for this end point

    Secondary: Patients with Treatment-Emergent Adverse Events

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    End point title
    		 Patients with Treatment-Emergent Adverse Events
    End point description
    An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of 1=mild, 2=moderate, 3=severe, 4=life-threatening and 5=death. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 625 (maximum treatment days)
    End point values
    		 Ganetespib Monotherapy Ganetespib Combination Therapy
    Number of subjects analysed
    51
    6
    Units: patients
        =>1 adverse event (AE)
    51
    6
        =>1 AE severity grade 3 or 4
    34
    4
        =>1 serious AE (SAE)
    13
    3
        =>1 AE leading to dose reduction
    14
    0
        =>1 AE leading to dose delay
    24
    4
        =>1 AE leading to study drug discontinuation
    3
    1
        =>1 SAE leading to study drug discontinuation
    1
    1
        =>1 SAE leading to hospitalization
    12
    3
        =>1 AE with outcome of death
    4
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Day 625 (maximum treatment days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Ganetespib Monotherapy
    Reporting group description
    		 Group combines Cohorts A+B+D and includes all patients who were treated with intravenous ganetespib 150 mg/m^2 twice weekly for 3 consecutive weeks followed by a 1-week rest.

    Reporting group title
    Ganetespib Combination Therapy
    Reporting group description
    		 Patients with disease progression while in the Monotherapy Period had the option of entering the combination therapy period (Cohort C) in which patients were treated with intravenous ganetespib 150 mg/m^2 in a weekly 1-hour infusion for 3 out of 4 weeks, ie, Days 1, 8, and 15 every 28 days. After an hour rest, patients were then given paclitaxel administered at a dose of 80 mg/m^2 by a 1-hour infusion on the same treatment days. Combination therapy continued until disease progression, unacceptable toxicity, or withdrawal from the study.

    Serious adverse events
    		 Ganetespib Monotherapy Ganetespib Combination Therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 51 (25.49%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (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
    Asthenia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (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
    2 / 51 (3.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder perforation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (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
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ganetespib Monotherapy Ganetespib Combination Therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 51 (100.00%)
    6 / 6 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 51 (25.49%)
    2 / 6 (33.33%)
         occurrences all number
    18
    2
    Amylase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 6 (16.67%)
         occurrences all number
    8
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 51 (23.53%)
    1 / 6 (16.67%)
         occurrences all number
    18
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 6 (0.00%)
         occurrences all number
    9
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    7
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    Weight decreased
         subjects affected / exposed
    7 / 51 (13.73%)
    1 / 6 (16.67%)
         occurrences all number
    7
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 6 (0.00%)
         occurrences all number
    10
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 51 (21.57%)
    1 / 6 (16.67%)
         occurrences all number
    23
    2
    Neuropathy peripheral
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Paraesthesia
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 6 (33.33%)
         occurrences all number
    5
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 6 (16.67%)
         occurrences all number
    5
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 51 (17.65%)
    1 / 6 (16.67%)
         occurrences all number
    16
    1
    Fatigue
         subjects affected / exposed
    21 / 51 (41.18%)
    2 / 6 (33.33%)
         occurrences all number
    44
    8
    Oedema peripheral
         subjects affected / exposed
    8 / 51 (15.69%)
    0 / 6 (0.00%)
         occurrences all number
    8
    0
    Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 51 (21.57%)
    0 / 6 (0.00%)
         occurrences all number
    14
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Constipation
         subjects affected / exposed
    10 / 51 (19.61%)
    1 / 6 (16.67%)
         occurrences all number
    14
    1
    Diarrhoea
         subjects affected / exposed
    43 / 51 (84.31%)
    3 / 6 (50.00%)
         occurrences all number
    193
    6
    Dry mouth
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Dyspepsia
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Haemorrhoids
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Nausea
         subjects affected / exposed
    30 / 51 (58.82%)
    4 / 6 (66.67%)
         occurrences all number
    66
    10
    Proctalgia
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Rectal haemorrhage
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Vomiting
         subjects affected / exposed
    16 / 51 (31.37%)
    2 / 6 (33.33%)
         occurrences all number
    29
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    Dyspnoea
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 6 (16.67%)
         occurrences all number
    6
    1
    Productive cough
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 6 (33.33%)
         occurrences all number
    3
    3
    Dermatitis acneiform
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Pruritus
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    Rash
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Depression
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Insomnia
         subjects affected / exposed
    17 / 51 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    25
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Back pain
         subjects affected / exposed
    6 / 51 (11.76%)
    0 / 6 (0.00%)
         occurrences all number
    7
    0
    Muscle spasms
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal pain
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Myalgia
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Neck pain
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 6 (16.67%)
         occurrences all number
    5
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 51 (31.37%)
    1 / 6 (16.67%)
         occurrences all number
    24
    1
    Hyperglycaemia
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 6 (16.67%)
         occurrences all number
    6
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2012
    Deleted that patients with OR or SD at the end of the 12-week treatment phase might be offered the opportunity to enroll in a companion study of ganetespib in combination with standard treatment.  Modified the inclusion criteria as follows:  HER2+ patients must have relapsed following prior trastuzumab or other approved anti-HER2 agent in the adjuvant setting, and at least 6 months must have elapsed since the discontinuation of prior adjuvant therapy.  Required a biopsy at study entry for patients with accessible tumors, and patients with inaccessible tumors could substitute an archived tissue with prior Sponsor approval. The original protocol required archived tissue and a fresh biopsy (or recent biopsy, with Sponsor approval) at study entry.  Modified the exclusion criteria as follows:  Clarified that exclusion criteria regarding prior systemic therapy for metastatic breast cancer applied to such therapy received in the first line setting.  All patients with de novo diagnosed HER2+ disease were excluded.  Clarified that patients with "active" coronary artery disease were excluded (rather than "current" coronary artery disease, as worded in the original protocol). Specified that during the extended treatment phase, bone scans would be repeated only if clinically indicated and that CT would be repeated every 12 weeks post Week 12.  Specified that vital signs would be measured prior to each dose of ganetespib, rather than at Week 1 Day 1 and Week 2 Day 8 only.  Added the definition of an evaluable patient, ie, a patient who received at least 1 dose of ganetespib and had a subsequent follow-up scan.
    29 Jan 2013
    Protocol Amendment 2 was prepared and submitted but not implemented; therefore, no patients were enrolled under this amendment.
    06 Mar 2013
    Protocol Amendment 3 was prepared and submitted but not implemented; therefore, no patients were enrolled under this amendment.
    11 Sep 2013
    A total of 11 patients were enrolled under Protocol Amendment 4. The primary changes specified in this amendment were as follows:  Revised the study design to encompass all types of breast cancer; therefore, specific types of breast cancer (HER2+ and TNBC) were removed from the description of the study population and the study title.  Expanded Cohorts A and B and added Cohort D was added based on the results of the formal interim analysis, which showed that ganetespib monotherapy on a twice-weekly schedule was well tolerated with a safety profile similar to the overall experience in the ganetespib program and Cohorts A and B exceeded the protocol specified criteria for proceeding to Stage 2: Cohort A - 2 of the first 4 patients achieved OR and the other 2 patients achieved SD; Cohort B - 2 of the first 10 patients achieved OR and 3 achieved SD.  Enrollment in Cohorts A and B were continued to approximately 35 patients (previously approximately 33 evaluable patients per cohort).  Cohort D, which evaluated ganetespib monotherapy activity in patients with hormone receptor (ER/PR)-positive disease) was added, with a planned enrollment of approximately 35 patients.  Specified that patients with OR or SD in any cohort could continue ganetespib monotherapy beyond the initial 12-week treatment period.  Added treatment with ganetespib once weekly in combination with weekly paclitaxel for patients with disease progression after ganetespib monotherapy (optional for Cohort A, mandatory for Cohorts B and D). The secondary study objectives were expanded as follows:  Added the evaluation of the clinical benefit rate (CBR), duration of response (DOR), and progression free survival (PFS) with ganetespib monotherapy  Added the evaluation of the ORR, CBR, DOR, and PFS with ganetespib in combination with weekly paclitaxel in patients whose disease progressed on ganetespib monotherapy Other....

    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 was terminated early since the objective of determining the level of activity in the patient populations was met. There was no impact on the study data due to early termination.
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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