Trial document




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  DRKS00017175

Trial Description

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Title

Non invasive visualization of biologic and topographic changes in (sub-)cutaneous melanoma metastases induced by antitumoral treatment

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

The approval of new therapy approaches has significantly contributed to the success of melanoma treatment in advanced stage. Those therapy approaches reverse the immunosuppressive effect- the suppression of the natural protection system - induced by the melanoma and shall fight the current melanoma cells and restrain a further cell spread. The selection of therapy for the treatment of melanoma will not be modified by the participation in this study and will be judged by non-participating medical doctors. Currently, there are no visualization techniques for estimating treatment respond without additional application of contrast agents. Still, especially metastases located in and beneath the skin can easily be approached to evaluate biological and anatomical changes induced by melanoma treatment. Hence, this study shall contribute to the understanding whether those therapy –induced changes can non-invasively be depicted by means of multispectral optoacoustic tomography (MSOT) without additional contrast agents. The technique of optoacoustic tomography combines common ultrasound with a laser. The laser will neither induce pain nor injuries. By means of MSOT therapy- induced anatomical and biological changes can be visualized relying on endogeneous chromophores (e.g. melanin in metastases, hemoglobin in red blood cells). With this technique, a therapy respond shall be evaluated non-invasively. All melanoma patients of age with at least one (sub-)cutaneous metastasis can participate in this study. The study will be performed in the Department of Dermatology, University Hospital Essen. Appointment for visualization by mens of MSOT will be adapted to regular follow-up appointments in the Department of Dermatology. Each visualization will take about 15 minutes. During examination, a laser protection glasses must be worn. The visualizations will repetitively be perfomed during melanoma treatment with a minimum time interval of 4 weeks and a maximum time interval of 12 weeks between each visualization. The patient can orally reject single visualizations and will not be excluded from the study as long as those time intervals will not be exceeded. As soon as the melanoma treatment will be terminated a visualization will be performed on that very day of termination and once again during the following 6 months. Based on the results of this study, respond to melanoma therapy shall non-invasively be estimated without additional application of contrast agents in future. The visualization of therapy-induced changes can contribute to the decision of further therapy.

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Brief Summary in Scientific Language

The approval of targeted and immunmodulating therapy has significantly contributed to the success of melanoma treatment in advanced stage. Although regression of melanoma metastases can be judged macroscopically and interaction of melanoma cells and immune cells are known, anatomical and biological changes, e.g. oxygen status changes in necrosis and vascular pattern changes have not been fully elucidated. Dynamic visualization of those changes can help to evaluate therapy respond . The correlation of enhanced angiogenesis of primary tumor and an enhanced incidence of distant metastases and a reduced overall survival could already be depicted in different studies. Those analyses mainly rely on postsurgical examination of primary tumor that mainly enable a two-dimensional section of the whole tumor. The evaluation of interaction between malignoma tissue and vascular structure cane merely be extrapolated. The current non-invasive intravital techniques for visualization of malignoma tusse scarcely have a sufficient resolution for depiction of vessels. The depiction of vessels by means of ultrasound is limited to several millimeters. MRI and CT have resolution of 100 to 500 µm. Still, those techniques often request additional application of contrast agents and vessels can be depicted indirectly. Ionising radiation might harm health of patients after repetitive use. The use of multispectral optoacoustic tomography (MSOT) poses a promising alternative. In contrast to other techniques based on the use of light, whose penetration depth is limited due to dispersion of light, the multispectral optoacoustic tomography relies on the photoacoustic effect. The photoacoustic effect has been described by Alexander Graham in 1880. A target structure will be stimulated by repetitive exposure of light energy. The laser light hit the endogeneous fluorescent chromophores (e.g. melanin and hemoglobin). The expansion of chromophores induces a ultrasound signal that can be captured by a detector. The repetitive exposure to light leads to expansion and contraction(“vibration”). The vibration can be perceived as sound but will not be realized by the patient due to high frequency of repetition. The acoustic wave pattern can be converted into a three-dimoensional picture. Hence, fluorescent chromophores will be used for visualization. The multispectral optoacoustic tomography can help to visualize cutaneous and subcutaneous structures to a depth of 5 cm. The MSOT Acuity (iThera Medical GmbH; Munich) is a combination of a laser unit and a hand-held detector. The use of the MSOT resembles the use of a ultrasound. A specific probe (“3D-probe”) is used that enables the three-dimensional reconstruction of the tompgraphy. Currently, there are no approved thechniques that can non-invasively depict both vessels and endogeneous chromophores (e.g. melanin as a surrogate marker for metastases) in such high resolution without additional application of radioactive or fluorescent dyes. As both the oxygenated and the non-oxygenated emit a unique optoacoustic signal, those two signals can be differentiated and simultaneously depicted. This is crucial to depict intratumoral ischemia as a possible consequence of antitumoral treatment. MSOT identifies the microvasculature and tissue oxygenation by detecting the absorbtion of hemoglobin in different wave lengths. The clinical utility of MSOT has already been shown in breast cancer, ovarian cancer and melanoma. The detection of increased vessel density by visualization of oxygenated hemoglobin contributes to the differentiation of malignant tumor and healthy tissue. In general both detection of malignant tumor by characterization of vascular changes and dynamic processes (e.g. different oxygenation in the tumor microenvironment) can be visualized.
In summary, there is no approved technique beside the MSOT that non-invasively depicts dynamic changes in cutaneous metastases (e.g. changes of vascular intratumoral patterns) and documents respond during antitumoral therapy.

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Organizational Data

  •   DRKS00017175
  •   2019/05/16
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  •   yes
  •   Approved
  •   18-8332-BO, Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen
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Secondary IDs

  •   U1111-1231-9005 
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Health Condition or Problem studied

  •   C43.9 -  Malignant neoplasm: Malignant melanoma of skin, unspecified
  •   C79.2 -  Secondary malignant neoplasm of skin
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Interventions/Observational Groups

  •   (Sub-) cutaneous metastases will be visualized in MSOT before, during and after melanoma treatment. MSOT is a technique that resembles ultrasound. The visualization will be performed regularly in adaption to the regular examinations during melanoma therapy in our department of dermatology (between 4-12 weeks).

    Visualization of (sub-)cutaneous metastases will be performed in the following cohorts:

    Before and after treatment with

    1.) Electrochemotherapy
    2.) IL2-injection

    before, during and after treatment with:

    3.) Kinase - targeted therapy (BRAFi, MEK),
    4.) immune checkpoint inhibitors (PD1-therapy,CTLA-4-therapy, LAG3 therapy),
    5.) the combination of targeted therapy and immune checkpoint therapy
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Characteristics

  •   Non-interventional
  •   Observational study
  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Prognosis
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

Quantification in decrease of optical density (induced by reduction of melanin containing cells) before (, during) and after melanoma Treatment. The optical density (OD) will comparatively be quantified in the MSOT.

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Secondary Outcome

Quantification of vessel density in cutaneous metastasis before (, during) and after melanoma treatment. The number and size of vessels will comparatively be quantified in the MSOT.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Planned
  •   2019/05/26
  •   50
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   99   Years
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Additional Inclusion Criteria

- patients with (sub-)cutaneous melanoma metastases

- age ≥18 years

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Exclusion Criteria

- age < 18 years

- pregnancy

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Addresses

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    • Universitätsklinik EssenKlinik für Dermatologie
    • Mr.  Professor Dr. med.  Ingo  Stoffels 
    • Hufelanstraße 55
    • 45147  Essen
    • Germany
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    • Klinik für Dermatologie, Universitätklinik Essen
    • Mr.  Professor Dr. med.  Ingo  Stoffels 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Klinik für Dermatologie, Universitätsklinik Essen
    • Mr.  Dr. med.  Philipp  Jansen 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinik EssenKlinik für Dermatologie
    • Mr.  Professor Dr. med.  Ingo  Stoffels 
    • Hufelanstraße 55
    • 45147  Essen
    • Germany
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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