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    Clinical Trial Results:
    A PHASE II TRIAL OF PF-04856884 (CVX-060), A SELECTIVE ANGIOPOIETIN-2 (ANG-2) INHIBITOR IN COMBINATION WITH AG-013736 (AXITINIB) IN PATIENTS WITH PREVIOUSLY TREATED METASTATIC RENAL CELL CARCINOMA

    Summary
    EudraCT number
    		 2011-002190-33
    Trial protocol
    		 ES   IT   CZ   DE   GB   AT   FI  
    Global end of trial date
    27 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Apr 2016
    First version publication date
    08 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B1131004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01441414
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, , United States, NY 10017
    Public contact
    Clinical Trials.gov Call Center, Pfizer Inc., 001 800 7181021, ClinicalTrials.govCallCenter@pfizer.com
    Scientific contact
    Clinical Trials.gov Call Center, Pfizer Inc., 001 800 7181021, ClinicalTrials.govCallCenter@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Mar 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part I: To confirm that the combination of PF-04856884 and AG-013736 is safe and tolerable at the doses to be used in Part II of the study. Part II: To document clinical activity of the combination of PF-04856884 and AG-013736 or AG-013736 alone as measured by PFS in adult patients with previously treated Metastatic Renal Cell Cancer (mRCC).
    Protection of trial subjects
    Palliative and supportive care for disease related symptoms was available per local standard of care for all patients on this study. Low dose oral steroids (defined as <5 mg per day prednisone or equivalent), short course of oral steroids (defined as <5 consecutive days of therapy) or topical or inhaled steroids at any dose may have been taken during the study. No other chemotherapy, hormonal therapy, radiotherapy, or experimental anticancer medications were permitted while the patient was on study; patients on luteinizing hormone releasing hormone (LHRH) analogs may have been maintained on treatment. Any disease progression requiring other forms of specific anticancer therapy were cause for discontinuation from study drug.
    Background therapy
    		 • Part I: Have received 1 3 prior systemic regimens for treatment of mRCC. • Part II: Evidence of disease progression following 1 prior regimen administered as 1st line therapy for mRCC. The prior regimen must have contained one of the following: • VEGFR 2 TKI such as (but not limited to) pazopanib, sunitinib, tivozanib, or sorafenib; • Other anti VEGF compounds, such as bevacizumab. As of 06 November 2012, based upon the safety findings from Part I of the study, Pfizer decided not to open patient enrolment onto Part II of the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    United States: 17
    Worldwide total number of subjects
    18
    EEA total number of subjects
    1
    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)
    10
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multicenter, open-label study consisted of a safety lead in stage (Part I) followed by a randomized Phase 2 stage (Part II). A total of 18 participants were screened and assigned to treatment in Part I, with 3 participants completing Part I of the study. At the completion of Part I, all 18 participants had discontinued combined treatment.

    Pre-assignment
    Screening details
    		 During Part I, 3 to 4 participants were initially treated with the study drug combination in 28-day cycles. If no participants experienced Cycle 1 dose limiting toxicities (DLTs), another 6 to 9 participants were treated at this dose level. Part II of the study was to be initiated if Cycle 1 DLTs were observed in <33% in at least 12 participants.

    Pre-assignment period milestones
    Number of subjects started
    		 18
    Number of subjects completed
    		 18

    Period 1
    Period 1 title
    PF-04856884 + AG-013736 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 PF-04856884 + AG-013736
    Arm description
    		 Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice a day. Following the decision of 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week).
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF 04856884 and AG 013736
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion, Tablet
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Study treatment began within 3 days of registering the patient for Part I. PF 04856884: During Cycle 1, this was given as a 60 minute infusion. After the first cycle, the infusion duration was reduced to 30 minutes for all subsequent cycles. AG 013736: This was taken orally with or without food. Twice daily doses were approximately 12 hours apart and at approximately the same times each day. For patients enrolled in Part I, the morning dose coincided with the timing of the start of the infusion at all visits with post dose sampling. Patients in Part I received PF 04856884 15 mg/kg/week and AG 013736 5 mg BID. Following the decision of 06 November 2012, any patient remaining in Part I continued to receive PF 04856884 at a reduced dose of 10 mg/kg/week in combination with AG 013736 (5 mg BID) or AG 013736 alone (5 mg BID).

    Number of subjects in period 1
    		PF-04856884 + AG-013736
    Started
    18
    Completed
    3
    Not completed
    15
         Participant died
    9
         Study terminated by sponsor
    2
         Other reasons
    3
         Participant refused further follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-04856884 + AG-013736
    Reporting group description
    		 Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice a day. Following the decision of 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week).

    Reporting group values
    		 PF-04856884 + AG-013736 Total
    Number of subjects
    		 18 18
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        < 18
    		 0 0
        18-44
    		 2 2
        45-64
    		 8 8
        65 years and over
    		 8 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.2 ( 10.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 14 14

    End points

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    End points reporting groups
    Reporting group title
    PF-04856884 + AG-013736
    Reporting group description
    		 Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice a day. Following the decision of 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week).

    Subject analysis set title
    All-causality CTCAE Grade 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incidence and severity of all-causality CTCAE Grade 3 TEAEs are presented. Participants with multiple occurrences of an AE within a category were counted once within the category.

    Subject analysis set title
    All-causality CTCAE Grade 4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incidence and severity of all-causality CTCAE Grade 4 TEAEs are presented. Participants with multiple occurrences of an AE within a category were counted once within the category.

    Subject analysis set title
    All-causality CTCAE Grade 5
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incidence and severity of all-causality CTCAE Grade 5 TEAEs are presented. Participants with multiple occurrences of an AE within a category were counted once within the category.

    Subject analysis set title
    Treatment-related CTCAE Grade 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incidence and severity of treatment-related CTCAE Grade 3 TEAEs are presented. Participants with multiple occurrences of an AE within a category were counted once within the category.

    Subject analysis set title
    Treatment-related CTCAE Grade 4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incidence and severity of treatment-related CTCAE Grade 4 TEAEs are presented. Participants with multiple occurrences of an AE within a category were counted once within the category.

    Subject analysis set title
    Treatment related CTCAE Grade 5
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incidence and severity of all-causality CTCAE Grade 5 TEAEs are presented. Participants with multiple occurrences of an AE within a category were counted once within the category.

    Subject analysis set title
    All-causality CTCAE Grade 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of participants who had serious TEAEs (all-causality) of CTCAE Grade 2 TEAEs are presented

    Primary: Number of Participants With non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the participants)

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    End point title
    		 Number of Participants With non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the participants) [1]
    End point description
    Incidence and severity of all treatment-emergent AEs (TEAEs) of both all-causality and treatment-related are presented by preferred term (PT) categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades reported in ≥2 participants (for any PT). Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). Where a TEAE-PT is already included under all-causality TEAEs, the treatment-related TEAE-PTs are presented as "0"; and where less than 2 participants experienced treatment-related TEAE, the data is presented as "0" in the following table.
    End point type
    Primary
    End point timeframe
    4 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not required by the statistical analysis plan (SAP) for this endpoint.
    End point values
    		 All-causality CTCAE Grade 3 All-causality CTCAE Grade 4 All-causality CTCAE Grade 5 Treatment-related CTCAE Grade 3 Treatment-related CTCAE Grade 4 Treatment related CTCAE Grade 5
    Number of subjects analysed
    18
    18
    18
    18
    18
    18
    Units: participants
        Anaemia
    0
    0
    0
    0
    0
    0
        Leukocytosis
    2
    0
    0
    0
    0
    0
        Pericardial effusion
    0
    1
    0
    0
    1
    0
        Hyperthyroidism
    0
    0
    0
    0
    0
    0
        Hypothyroidism
    0
    0
    0
    0
    0
    0
        Vision blurred
    0
    0
    0
    0
    0
    0
        Abdominal pain
    1
    0
    0
    0
    0
    0
        Constipation
    0
    0
    0
    0
    0
    0
        Diarrhoea
    0
    0
    0
    0
    0
    0
        Dry mouth
    0
    0
    0
    0
    0
    0
        Gastritis
    0
    0
    0
    0
    0
    0
        Nausea
    1
    0
    0
    1
    0
    0
        Oral pain
    0
    0
    0
    0
    0
    0
        Stomatitis
    0
    0
    0
    0
    0
    0
        Toothache
    0
    0
    0
    0
    0
    0
        Vomiting
    1
    0
    0
    1
    0
    0
        Asthenia
    1
    0
    0
    1
    0
    0
        Fatigue
    5
    0
    0
    4
    0
    0
        Oedema peripheral
    0
    0
    0
    0
    0
    0
        Pneumonia
    1
    0
    0
    0
    0
    0
        Upper respiratory tract infection
    0
    0
    0
    0
    0
    0
        Urinary tract infection
    1
    0
    0
    0
    0
    0
        Blood creatinine increased
    0
    0
    0
    0
    0
    0
        Weight decreased
    2
    0
    0
    1
    0
    0
        Decreased appetite
    1
    0
    0
    1
    0
    0
        Dehydration
    0
    0
    0
    0
    0
    0
        Hypercalcaemia
    0
    0
    0
    0
    0
    0
        Hypokalaemia
    1
    0
    0
    0
    0
    0
        Hyponatraemia
    1
    0
    0
    0
    0
    0
        Hypovolaemia
    0
    0
    0
    0
    0
    0
        Arthralgia
    1
    0
    0
    0
    0
    0
        Back pain
    1
    0
    0
    0
    0
    0
        Muscle spasms
    0
    0
    0
    0
    0
    0
        Muscular weakness
    0
    0
    0
    0
    0
    0
        Myalgia
    0
    0
    0
    0
    0
    0
        Cerebrovascular accident
    1
    1
    0
    1
    1
    0
        Dizziness
    0
    0
    0
    0
    0
    0
        Headache
    1
    0
    0
    1
    0
    0
        Migraine
    1
    0
    0
    1
    0
    0
        Neuropathy peripheral
    1
    0
    0
    0
    0
    0
        Depression
    1
    0
    0
    0
    0
    0
        Insomnia
    1
    0
    0
    1
    0
    0
        Proteinuria
    0
    0
    0
    0
    0
    0
        Cough
    0
    0
    0
    0
    0
    0
        Dysphonia
    0
    0
    0
    0
    0
    0
        Dyspnoea
    1
    0
    0
    0
    0
    0
        Hypoxia
    1
    0
    0
    0
    0
    0
        Pleural effusion
    1
    0
    0
    0
    0
    0
        Pulmonary embolism
    1
    1
    0
    1
    1
    0
        Night sweats
    0
    0
    0
    0
    0
    0
        Palmar-plantar erythrodysaesthesia
    0
    0
    0
    0
    0
    0
        Hot flush
    0
    0
    0
    0
    0
    0
        Hypertension
    5
    0
    0
    4
    0
    0
        Hypotension
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Serious Adverse Events (SAEs) in Part I (Reported in ≥2 participants)

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    End point title
    		 Number of Participants with Serious Adverse Events (SAEs) in Part I (Reported in ≥2 participants) [2]
    End point description
    Incidence and severity of all-causality serious adverse events (SAEs) are presented by PT categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). Participants with treatment-related TEAE are coded as NA if they appear for the same preferred term under all-causality TEAE.
    End point type
    Primary
    End point timeframe
    4 months
    Notes
    [2] - 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: Statistical analysis was not required by the statistical analysis plan (SAP) for this endpoint.
    End point values
    		 All-causality CTCAE Grade 3 All-causality CTCAE Grade 4 All-causality CTCAE Grade 5 All-causality CTCAE Grade 2
    Number of subjects analysed
    18
    18
    18
    18
    Units: participants
        Pneumonia
    1
    0
    0
    1
        Pleural effusion
    1
    0
    0
    1
        Ileus
    0
    0
    0
    1
        Abdominal pain
    1
    0
    0
    0
        Ascites
    0
    0
    0
    1
        Lung infection
    1
    0
    0
    0
        Back pain
    1
    0
    0
    0
        Musculoskeletal chest pain
    1
    0
    0
    0
        Convulsion
    0
    0
    0
    1
        Embolism
    0
    0
    0
    1
        Hyponatraemia
    1
    0
    0
    0
        Dyspnoea
    1
    0
    0
    0
        Hypotension
    1
    0
    0
    0
        Cerebrovascular accident
    1
    1
    0
    0
        Migraine
    1
    0
    0
    0
        Meningioma
    1
    0
    0
    0
        Hypovolaemia
    0
    0
    0
    1
        Pulmonary embolism
    1
    1
    0
    0
        Pericardial effusion
    0
    1
    0
    0
        Gastrointestinal disorder
    0
    0
    1
    0
        Chest discomfort
    1
    0
    0
    0
        Hypertension
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: Progression free survival (PFS) in adult participants with previously treated metastatic Renal Cell Cancer (mRCC) in Part II

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    End point title
    		 Progression free survival (PFS) in adult participants with previously treated metastatic Renal Cell Cancer (mRCC) in Part II [3]
    End point description
    PFS is defined as the time (in days) from date of randomization to first documentation of investigator assessed tumor progression or death, whichever comes first. Progression free survival was to be calculated as (first event date – the date of randomization +1).
    End point type
    Primary
    End point timeframe
    3 years
    Notes
    [3] - 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: Statistical analysis was not required by the statistical analysis plan (SAP) for this endpoint.
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    0 [4]
    Units: days
    Notes
    [4] - PFS in Part II was not assessed due to early termination of the study.
    No statistical analyses for this end point

    Secondary: Number of Participants with non-serious AEs and SAEs

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    End point title
    		 Number of Participants with non-serious AEs and SAEs
    End point description
    Incidence and severity of all-causality AEs and SAEs to be presented by PT categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week).
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    0 [5]
    Units: participants
    Notes
    [5] - This endpoint was not assessed due to the early termination of the study.
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) in metastatic Renal Cell Cancer (mRCC) patients treated with PF-04856884 in combination with AG-013736 vs. AG-013736 alone

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    End point title
    		 Overall Response Rate (ORR) in metastatic Renal Cell Cancer (mRCC) patients treated with PF-04856884 in combination with AG-013736 vs. AG-013736 alone
    End point description
    ORR is defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST), relative to all randomized participants as defined in the FA Set. Confirmed responses are those that persist on repeat imaging study ≥ 4 weeks after initial documentation of response. Participants who do not have on-study radiographic tumor evaluation or who die, progress, or drop out for any reason prior to reaching a CR or PR will be counted as non-responders (NR) in the assessment of ORR.
    End point type
    Secondary
    End point timeframe
    4 months
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    18
    Units: Percentage of participants
    number (not applicable)
        Complete response (CR)
    0
        Partial response (PR)
    11.1
        ORR (CR + PR)
    11.1
    No statistical analyses for this end point

    Secondary: Duration of Response (DR) in metastatic Renal Cell Cancer (mRCC) patients treated with PF-04856884 in combination with AG-013736 vs. AG-013736 alone

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    End point title
    		 Duration of Response (DR) in metastatic Renal Cell Cancer (mRCC) patients treated with PF-04856884 in combination with AG-013736 vs. AG-013736 alone
    End point description
    DR is defined as the time from the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of tumor progression or to death due to cancer. Duration of tumor response was to be calculated as (the end date for DR − first CR or PR that is subsequently confirmed +1).
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    0 [6]
    Units: weeks
    Notes
    [6] - This endpoint was not assessed due to the early termination of the study.
    No statistical analyses for this end point

    Secondary: Tmax (Time when maximum serum PF-04856884 concentration was reached)

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    End point title
    		 Tmax (Time when maximum serum PF-04856884 concentration was reached)
    End point description
    Pharmacokinetic parameter, Tmax (Time when maximum serum PF-04856884 concentration was reached) was done using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    18
    Units: hour
    arithmetic mean (standard deviation)
        CYCLE1/DAY1
    2 ( 1.645 )
        CYCLE1/DAY22
    3 ( 2.1122 )
    No statistical analyses for this end point

    Secondary: Cmax (observed peak serum PF-04856884 concentration)

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    End point title
    		 Cmax (observed peak serum PF-04856884 concentration)
    End point description
    Pharmacokinetic parameter Cmax (observed peak PF-04856884 serum concentration) was estimated using noncompartmental methods.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    18
    Units: ng/mL
    arithmetic mean (standard deviation)
        CYCLE1/DAY1
    337100 ( 76245 )
        CYCLE1/DAY22
    531400 ( 154780 )
    No statistical analyses for this end point

    Secondary: Cmin (trough PF-04856884 serum concentration)

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    End point title
    		 Cmin (trough PF-04856884 serum concentration)
    End point description
    Pharmacokinetic parameter Cmin (trough PF-04856884 serum concentration) was estimated using noncompartmental methods.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    18
    Units: ng/mL
    arithmetic mean (standard deviation)
        CYCLE1/DAY1
    932.7 ( 3499.1 )
        CYCLE1/DAY22
    168900 ( 84507 )
    No statistical analyses for this end point

    Secondary: Number of Anti-drug antibodies (ADA) Samples Confirmed Positive

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    End point title
    		 Number of Anti-drug antibodies (ADA) Samples Confirmed Positive
    End point description
    Detection of neutralizing anti-PF-04856884 antibodies was based on the ability of anti-PF-04856884 neutralizing antibodies to bind to Tag-PF-04856884.
    End point type
    Secondary
    End point timeframe
    0 and 360 hours post dose and end of study
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    18
    Units: ADA samples
        Number of ADA samples Analyzed
    91
        Number of ADA Samples Confi
    8
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) in adult participants with previously treated metastatic Renal Cell Cancer (mRCC) as measured by an Independent Radiological Assessment

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    End point title
    		 Progression free survival (PFS) in adult participants with previously treated metastatic Renal Cell Cancer (mRCC) as measured by an Independent Radiological Assessment
    End point description
    PFS is defined as the time (in days) from date of randomization to first documentation of investigator assessed tumor progression or death, whichever comes first. PFS was to be calculated as (first event date – the date of randomization +1).
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    0 [7]
    Units: days
    Notes
    [7] - This endpoint of estimating median PFS was not assessed due to early termination of the study.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) at 2 years

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    End point title
    		 Overall Survival (OS) at 2 years
    End point description
    OS is defined as the time from the first dose date to date of death. For participants not expiring, their survival times will be censored at the last date they are known to be alive, or 2 year whichever is earlier. The 2-year OS rate will be estimated from a time-to event analysis of OS.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 PF-04856884 + AG-013736
    Number of subjects analysed
    0 [8]
    Units: months
    Notes
    [8] - This endpoint was not assessed due to the early termination of the study.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the day the first dose of the investigational product was administered up to 1 year.
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    PF 04856884 + AG 013736
    Reporting group description
    		 Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice a day. Following the decision of 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week).

    Serious adverse events
    		 PF 04856884 + AG 013736
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 18 (66.67%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migrane
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Ileus
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 PF 04856884 + AG 013736
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 18 (100.00%)
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hot flush
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Hypertension
         subjects affected / exposed
    9 / 18 (50.00%)
         occurrences all number
    19
    Hypotension
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    6
    Chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Chills
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    11 / 18 (61.11%)
         occurrences all number
    22
    Inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Localised oedema
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Oedema
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    9
    Pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    4
    Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    3
    Seasonal allergy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Scrotal oedema
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 18 (38.89%)
         occurrences all number
    10
    Dysphonia
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    5
    Dyspnoea
         subjects affected / exposed
    6 / 18 (33.33%)
         occurrences all number
    8
    Dyspnoea exertional
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Haemoptysis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    Rhinalgia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Confusional state
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    5
    Flat affect
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    7 / 18 (38.89%)
         occurrences all number
    7
    Restlessness
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Sleep disorder
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Investigations
    Blood creatine increased
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Coagulation time prolonged
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Haptoglobin increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Neutrophil count abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    17
    White blood cell count abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Tooth fracture
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Depressed level of consciousness
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    4
    Dysgeusia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    5
    Hypoaesthesia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Lethargy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Memory impairment
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    4
    Neuropathy peripheral
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    6
    Somnolence
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    7
    Leukocytosis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Thrombocytopenia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Vision blurred
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Vitreous floaters
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Visual impairment
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Abdominal distension
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    7
    Aphthous stomatitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Ascites
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    7
    Constipation
         subjects affected / exposed
    8 / 18 (44.44%)
         occurrences all number
    11
    Diarrhoea
         subjects affected / exposed
    10 / 18 (55.56%)
         occurrences all number
    22
    Dry mouth
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Eructation
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Faecal incontinence
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Glossodynia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    11 / 18 (61.11%)
         occurrences all number
    18
    Oral pain
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Stomatitis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Toothache
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    10 / 18 (55.56%)
         occurrences all number
    24
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hepatic cyst
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nail disorder
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Night sweats
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Onychalgia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin disorder
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    4
    Urinary retention
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Hypothyroidism
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    7
    Groin pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Muscular weakness
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    7
    Musculoskeletal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Neck pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pain in jaw
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Candida infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Cellulitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Peritonitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 18 (66.67%)
         occurrences all number
    26
    Dehydration
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    7
    Hypercalcaemia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    Hypomagnesaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypovolaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Nov 2012
    PF-04856884 in combination with AG-013736 during Part I of the study showed a higher than expected frequency of arterial thrombotic events or venous thrombotic events in the 18 patients with mRCC. These specific events included pulmonary embolism in 2 patients, cerebrovascular accident in 2 patients, gastrointestinal disorder (presumed bowel ischemia) in 1 patient, and chest discomfort in 1 patient. Based on these safety concerns, Pfizer decided not to open patient enrolment onto Part II of the study. On 06 November 2012, based upon the safety findings from Part I of this study (B1131004) and due to strategic considerations, Pfizer decided not to open patient enrolment onto Part II of the study and terminated the study.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Since this application does not allow the character strings in the data fields, some data which is actually reported as "not reported" in the Clinical Study Report as "NOT REPORTED" have been reported as 0 in this disclosure.
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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
    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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