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    Clinical Trial Results:
    PHASE II STUDY OF LUTETIUM-177 LABELED CHIMERIC MONOCLONAL ANTIBODY cG250 (177Lu-DOTA-cG250) TREATMENT IN PATIENTS WITH ADVANCED RENAL CANCER

    Summary
    EudraCT number
    2008-004548-35
    Trial protocol
    NL  
    Global end of trial date
    03 Aug 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Aug 2024
    First version publication date
    23 Aug 2024
    Other versions
    Summary report(s)
    Synopsis acc ICH e3 177Lutetium_cG250 in RCC Phase II clinical trial

    Trial information

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    Trial identification
    Sponsor protocol code
    15081982
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02002312
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Radboud University Medical Centre
    Sponsor organisation address
    Geert Groote plein Zuid 10, Nijmegen, Nijmegen, Netherlands, 6525GA
    Public contact
    RadboudUMC, RadboudUMC, +31 243613735, secretariaat.uro@radboudumc.nl
    Scientific contact
    RadboudUMC, RadboudUMC, +31 243613735, secretariaat.uro@radboudumc.nl
    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
    03 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the clinical efficacy of multiple doses of 177Lutetium-girentuximab (177Lu-cG250) at MTD in patients with advanced renal cancer using RECIST criteria.
    Protection of trial subjects
    Patients who fulfilled the selection criteria: Inclusion Criteria: - Patients with proven advanced and progressive renal cell carcinoma of the clear cell type - At least one evaluable lesion less than 5 cm - Performance status: Karnofsky > 70 % - Laboratory values obtained less than 14 days prior to registration: - White blood cells (WBC) > 3.5 x 109/l - Platelet count > 100 x 109/l - Hemoglobin > 6 mmol/l - Total bilirubin < 2 x upper limit of normal (ULN) - ASAT, ALAT < 3 x ULN (< 5 x ULN if liver metastases present) - Serum creatinine < 2 x ULN - Negative pregnancy test for women of child¬bearing potential (urine or serum) - Age over 18 years - Ability to provide written informed consent Exclusion Criteria: - Known metastases to the brain - Untreated hypercalcemia - Metastatic disease limited to the bone - Pre-exposure to murine/chimeric antibody - Chemotherapy, external beam radiation, immunotherapy or angiogenesis inhibitors within 4 weeks prior to study. Limited field external beam radiotherapy to prevent pathological fractures is allowed, when unirradiated, evaluable lesions elsewhere are present. - Cardiac disease with New York Heart Association classification of III or IV - Patients who are pregnant, nursing or of reproductive potential and are not practicing an effective method of contraception - Any unrelated illness, e.g. active infection, inflammation, medical condition or laboratory abnormalities, which in the judgment of the investigator will significantly affect patients’ clinical status - Life expectancy shorter than 6 months. Patients were controlled as follows: - Wk 1: screening and injection 111In-cG250 (day 1) and 2 scans (day 2-4 and 5-7) - Wk 2: injection 177Lu-cG250 and subsequent hospital admission for 1 night only - Wk 3 until 8: Weekly visit UMCN for blood draw and physical exam. - W 3 - 6: during fulminant hematological toxicity increased checks laboratory values - Wk 12: CT-scan and Wk 13: blood draw
    Background therapy
    not applicable
    Evidence for comparator
    not applicable
    Actual start date of recruitment
    01 Aug 2011
    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
    Netherlands: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    6
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    In total, 16 adult patients with metastatic clear cell renal cell carcinoma (ccRCC) were enrolled between August 2011 and April 2014 to participate in this Study if metastasis showed targeting of diagnostic imaging.

    Pre-assignment
    Screening details
    After screening 2 patients were excluded from the study because known ccRCC lesions did not show any targeting at diagnostic imaging postinjection of indium 111 (111In)–girentuximab. 14 patients who showed targeting at scans postinjection of indium 111 (111In)–girentuximab were eligible for treatment with 177Lutetium-girentuximab.

    Period 1
    Period 1 title
    Cycle 1
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    No blinding was chosen in this first pilot study of treatment with 177Lutetium-girentuximab.

    Arms
    Arm title
    Cycle 1
    Arm description
    In Cycle 1, 14 patients started treatment with 177Lutetium-cG250 at a dose level of 2405 MBq/m2.
    Arm type
    Experimental

    Investigational medicinal product name
    cG250
    Investigational medicinal product code
    Other name
    LUTETIUM-177 LABELED CHIMERIC MONOCLONAL ANTIBODY cG250; 177Lu-DOTA-cG250; 177Lutetium-girentuximab
    Pharmaceutical forms
    Solution for injection in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Cycle 1, 14 patients received 177Lutetium cG2502 at a dose of 2405 MBq/m2.

    Number of subjects in period 1
    Cycle 1
    Started
    14
    completed Cycle 1
    14
    Completed
    14
    Period 2
    Period 2 title
    Evaluation results Cycle 1
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Eligible to start in Cycle 2
    Arm description
    To evaluate if patients were eligible for treatment in Cycle 2
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Eligible to start in Cycle 2
    Started
    14
    Evaluation of Cycle 1
    14
    Completed
    6
    Not completed
    8
         Adverse event, non-fatal
    3
         Lack of efficacy
    5
    Period 3
    Period 3 title
    Cycle 2
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    In Cycle 2, 6 patients started treatment with 177Lutetium-cG250 at a dose level of 1805 MBq/m2.

    Arms
    Arm title
    Cycle 2
    Arm description
    In Cycle 2, 6 patients started treatment with 177Lutetium-cG250 at a dose level of 1805 MBq/m2.
    Arm type
    Experimental

    Investigational medicinal product name
    cG250
    Investigational medicinal product code
    Other name
    LUTETIUM-177 LABELED CHIMERIC MONOCLONAL ANTIBODY cG250; 177Lu-DOTA-cG250; 177Lutetium-girentuximab
    Pharmaceutical forms
    Solution for injection in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Cycle 2, 14 patients received 177Lutetium cG2502 at a dose of 1805 MBq/m2.

    Number of subjects in period 3
    Cycle 2
    Started
    6
    completed Cycle 2
    6
    Completed
    6
    Period 4
    Period 4 title
    Evaluation results Cycle 2
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Eligible to start in Cycle 3
    Arm description
    To evaluate if patients were eligible for treatment in Cycle 3
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    Eligible to start in Cycle 3
    Started
    6
    Completed
    0
    Not completed
    6
         Adverse event, non-fatal
    5
         Lack of efficacy
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cycle 1
    Reporting group description
    In Cycle 1, 14 patients started treatment with 177Lutetium-cG250 at a dose level of 2405 MBq/m2.

    Reporting group values
    Cycle 1 Total
    Number of subjects
    14 14
    Age categorical
    14 patients were treated according to protocol with a median age of 68 years; range: 56-75 years.
    Units: Subjects
        Adults (18-64 years)
    6 6
        From 65-84 years
    8 8
    Gender categorical
    Gender
    Units: Subjects
        Female
    5 5
        Male
    9 9

    End points

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    End points reporting groups
    Reporting group title
    Cycle 1
    Reporting group description
    In Cycle 1, 14 patients started treatment with 177Lutetium-cG250 at a dose level of 2405 MBq/m2.
    Reporting group title
    Eligible to start in Cycle 2
    Reporting group description
    To evaluate if patients were eligible for treatment in Cycle 2
    Reporting group title
    Cycle 2
    Reporting group description
    In Cycle 2, 6 patients started treatment with 177Lutetium-cG250 at a dose level of 1805 MBq/m2.
    Reporting group title
    Eligible to start in Cycle 3
    Reporting group description
    To evaluate if patients were eligible for treatment in Cycle 3

    Primary: Clinical response 3 months after treatment

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    End point title
    Clinical response 3 months after treatment [1]
    End point description
    End point type
    Primary
    End point timeframe
    Clinical response was evaluated 3 months after treatment by using CT scanning and evaluation according to RECIST v1.1.
    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: A Simon two-stage minimax design was used to calculate the no. of patients needed to reach a desirable response rate (RR) defined as at least Stable Disease (RECIST v1.1). If RR >0.25 after the first cycle of treatment in the first 6 patients after 3 months, 14 patients had to be included. Desirable RR was set at 0.65 with alpha of 0.05 and beta of 0.10. Response was defined as at least SD on RECIST v1.1 evaluation after 3 months. After 6 patients RR was 0.5 so 14 patients were included.
    End point values
    Eligible to start in Cycle 2 Eligible to start in Cycle 3
    Number of subjects analysed
    14
    6
    Units: 14
        PR
    1
    1
        SD
    8
    4
        PD
    5
    1
    No statistical analyses for this end point

    Secondary: Toxicity of treatment 12 weeks after treatment

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    End point title
    Toxicity of treatment 12 weeks after treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Patients were monitored at least once a week for 12 weeks for hematological toxicity (using Common Toxicity Criteria for Adverse Events v.3.0)
    End point values
    Eligible to start in Cycle 2 Eligible to start in Cycle 3
    Number of subjects analysed
    14 [2]
    6 [3]
    Units: 14
        CTC hematological toxicity Grade 0,1 or 2
    1
    1
        CTC hematological toxicity Grade 3 or 4
    13
    5
    Notes
    [2] - 14 patients received Cycle 1
    [3] - 6 patients received Cycle 2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were evaluated the whole study period.
    Adverse event reporting additional description
    Adverse events were evaluated using the Common Toxicity Criteria V3.0
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    v3
    Reporting groups
    Reporting group title
    Per Protocol reporting group
    Reporting group description
    All 14 patients who received treatment according to the protocol were in the intention to treat reporting group for adverse event reporting.

    Serious adverse events
    Per Protocol reporting group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 14 (50.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Investigations
    prolonged hospital stay
    Additional description: Prolonged hospital stay without clear system organ class
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cell carcinoma
    Additional description: One patient died due to progression of Renal cell carcinoma.
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    facialis paresis
    Additional description: One patient developed a one-sided facialis parese. This patient also had a thrombocytopenia and leucopenia. This event was considered unexpected.
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
    Additional description: A total of 2 patients were hospitalised with fever and shivers due to neutropenia. Treated with antibiotics. One patient was hospitalised with severe neutropenia for observation only.
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    thrombocytopenia
    Additional description: One patient was hospitalised for thrombocytopenia and received thrombocytes suppletion. Another patient prolonged hospitalisation for 2 days due to thrombocytopenia.
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Confusional state
    Additional description: One patient was hospitalised in a confusional state, possibly due to cerebral vascular infarction. This event was considered unexpected.
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    Additional description: One patient was hosptitalised due to a pulmonary embolism. This event was considered as unexpected.
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
    Additional description: prolonged hospital stay for observation hypercalcaemia possibly due to progressive disease
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Per Protocol reporting group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    General disorders and administration site conditions
    Fatigue
    Additional description: A total of 13 patients experienced mild (grade 1-2) general adverse events such as fatigue, anorexia, nausea, and diarrhea. Only two patients had grade 3 general adverse events, 1 with fatigue and 1 with anorexia.
         subjects affected / exposed
    14 / 14 (100.00%)
         occurrences all number
    14

    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? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26706103
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