Trial document





This trial has been registered retrospectively.
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  DRKS00015159

Trial Description

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Title

Influence of somatic mutational status of DNA repair genes on the clinical course in men with High risk-prostate cancer - a prospective biomarker study

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

BRCA1 and BRCA2, also known as breast cancer genes, belong to DNA repair genes. Women with a mutation in BRCA1 or BRCA2 have a significant higher risk to develop breast cancer or ovarian cancer during their life compared to general population. Approximately 90% of the BRCA1 or BRCA2 mutation in women are inherited (germline mutation), only about 10% are acquired (somatic mutations). BRCA1 or BRCA2 mutations can increase also the risk to develop other foms of cancer, e.g. prostate cancer.
About 50% of the patients with prostate cancer inherit a BRCA1/2 mutation, the other half have somatic mutations and are only detectable in the tumor tissue. Patients with prostate cancer and a known mutation in BRCA1 or BRCA2 show a more aggressive clinical course, a worse differentiation of the cancer cells and have more frequently metastases at the time of diagnosis compared to patients without such a mutation.
Besides BRCA1/2 there are a lot of other DNA repair genes, which are reported to be occasionally mutated in prostate cancer. These clinical and experimental data suggest that prostate cancer is a non-uniformly disease. In the absence of understanding, approved standardized therapy makes no differences due to the mutational status.
We like to address the following questions by this prospective study:
1. How many patients with high risk prostate cancer have a somatic mutation (non-inherited) in 37 selected DNA repair genes at the time of diagnosis? Which genes are affected?
2. How respond patients with a somatic mutation in DNA repair genes to hormone therapy of the first and second generation, chemotherapy agents, radiotherapy or individual therapies in comparison to non-mutated patients?
3. Does the somatic mutational spectrum change during the course of the therapy?
In order to clarify these questions, we analyse your already existing tumor tissue (biopsie or prostatectomy) for mutations in selected DNA repair genes. At the first appointment and at every worsening of the disease we draw 10ml blood and take a urine sample to investigate if the mutational status change during the course of drug treatment.
These analyses have no impact on your treatment. Your treatment does not have to be done by our medical department. You can be further treated by your local urologist or oncologist. However we like to see you every 3 months at our urooncology ambulance (NCT) for a medical consultation, clinical examination and for taking blood samples including PSA value. Beyond this participating in the study will have no further impact to your way of living.

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Brief Summary in Scientific Language

Background:
Mutations in DNA repair gene like BRCA1 and BRCA2 play an important role in origination and development of prostate cancer. Patients with a germline mutation in BRCA1 or BRCA2 present at a younger age, have a more aggressive clinical course of disease and hence worse survival compared to non-mutated patients. DNA sequenzing analyses were able to show, that patients with metastasized castration resistent prostate cancer (mCRPC) have in about one quarter to one third a mutation in a DNA repair gene. Current practice dose not include analyses of tumor tissues for mutations in DNA repair genes.
In case of metastasized prostate cancer a guideline based therapy will be initiated. Usually the first therapy is the Androgen deprivation therapy (ADT). But if the patient has a so-called "High Volume disease" at time of diagnosis a combination treatment of ADT with the chemotherapy agent docetaxel can be recommended, according to the results of the studies available to date. In case of proven disease progression the therapy will be switched to a second line treatment with hormone therapy of the second generation, e.g. abirateronacetat, enzalutamide. Following this, other drugs can be used or a reexposition can be tried; precise recommendations do not exist.

Aims of the study:
The main goal of the study is to determine a possible influence of DNA repair defects in patients with High risk-prostate cancer on their treatment response. Furthermore we like to address the question, if the mutational profile of DNA repair genes changes during sequential treatment regimes and possibly require mechanisms of resistance by that. This study aims to lay a foundation for a better patient stratification and personalized therapy in metastasized High risk-prostate carcinoma.

All patients with a diagnosed High risk-prostate cancer, who present in the University hospital of Heidelberg (Urology department or NCT Heidelberg) will be offered a participation in the trial. The diagnosis will be made through a histological examination of a biopsy of the primary tumor or a metastasis. For next generation sequencing (NGS) of 37 DNA repair genes of tumor tissue can be used paraffin embedded biopsies or if present prostatectomies. Furthermore we like to take 10 ml blood and a urine sample for analyses of circulating tumor DNA (ct-DNA) at primary presentation and in case of tumorprogression. Tumor tissue, blood and urine samples, which are not needed immediate will be stored under standardized conditions. Upon request, patients will be informed about their results of gene sequenzing for somatic mutations of the tumor tissues. Depending on the results, patients will be recommended a human genetic counselling at our human genetic department.
All patients will receive a guideline based therapy depending on the stage and severity of the condition. The course of disease and therapy will be documented through a follow-up by the study administration.

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Organizational Data

  •   DRKS00015159
  •   2019/02/25
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  •   yes
  •   Approved
  •   S-051/2017, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

  •   U1111-1229-0829 
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Health Condition or Problem studied

  •   High grade prostate carcinoma
  •   C61 -  Malignant neoplasm of prostate
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Interventions/Observational Groups

  •   Next generation sequencing (NGS) of an extended DNA repair gene panel of paraffin embedded tumor tissue at time of diagnosis (biopsy or prostatectomy).
    At Initial presentation and at every progression of the disease we like to take 10 ml blood and a urine sample for analyses of circulating tumor DNA (ct-DNA).
    Patients receive a guideline based treatment within the study. Follow up at regular intervals will be documented by the study coordination office.
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Characteristics

  •   Non-interventional
  •   Other
  •   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

progression of disease

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Secondary Outcome

overall survival

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2017/05/01
  •   500
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Male
  •   no minimum age
  •   no maximum age
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Additional Inclusion Criteria

• Histological subtype: adenocarcinoma of the prostate without neuroendocrine differentiation
• age at disease onset ≤50 years and/or
• M1 (primary metastasized; every Gleason score, every T, every N, every M) and/or
• Gleason Score 9 or 10 (every T, every M) and/or
• Gleason Score 8 in combination with ≥pT3 or N1 or PSA ≥20 ng/ml and/or
• early tumor recurrence or persistence after local therapy (Prostatectomy or Radiotherapy of the prostate) within ≤12 months and with high PSA doubling time of ≤3 months and/or
• early development of castrations resistance of the prostate cancer under first line treatment with ADT alone or combination of ADT with Docetaxel or Abiraterone
• no contraindication for approved treatments
• ECOG: 0-1
• availability of tumor tissue in good quality for DNA sequencing
• Complete clinical documentation (PSA at diagnosis, histology, Gleason Score, TNM-Score, course of treatment, course of PSA, radiological reports of all scans since the time of diagnosis

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Exclusion Criteria

• pre-existing psychiatric disorder
• other active malignant diseases
• non legally competent or incapacitated patients
• patients, who refuse to undergo systemic treatments

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Addresses

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    • Universitätsklinikum Heidelberg Nationales Centrum für Tumorerkrankungen (NCT) Medizinische Onkologie und Urologische Klinik
    • 69120  Heidelberg
    • Germany
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    • Universitätsklinikum Heidelberg Nationales Centrum für Tumorerkrankungen (NCT) Medizinische Onkologie
    • Ms.  Dr. med.  Cathleen  Nientiedt 
    • Im Neuenheimer Feld 460
    • 69120  Heidelberg
    • Germany
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    • Universitätsklinikum Heidelberg Nationales Centrum für Tumorerkrankungen (NCT) Medizinische Onkologie
    • Ms.  Dr. med.  Cathleen  Nientiedt 
    • Im Neuenheimer Feld 460
    • 69120  Heidelberg
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum Heidelberg Nationales Centrum für Tumorerkrankungen (NCT) Medizinische Onkologie und Urologische Klinik
    • 69120  Heidelberg
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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