Trial document




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  DRKS00016064

Trial Description

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Title

Evaluation of immunological effects of the RANKL-inhibitor Denosumab when administered concurrently with PD1-blocking antibodies (Nivolumab, Pembrolizumab) in patients with metastatic malignant melanoma with bone involvement

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Trial Acronym

Bonemet

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Evaluation of immunological effects of the RANKL-inhibitor Denosumab when administered concurrently with PD-1-blocking antibodies (Nivolumab, Pembrolizumab) in patients with metastatic malignant melanoma with bone involvement.

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Brief Summary in Scientific Language

Evaluation of immunological effects of the RANKL-inhibitor Denosumab when administered concurrently with PD1-blocking antibodies (Nivolumab, Pembrolizumab) in patients with metastatic malignant melanoma with bone involvement.

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Organizational Data

  •   DRKS00016064
  •   2018/12/13
  •   [---]*
  •   yes
  •   Approved
  •   8062_AMG_M_2018, Ethikkommission der Medizinischen Hochschule Hannover
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Secondary IDs

  •   2016-001925-15 
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Health Condition or Problem studied

  •   C43.9 -  Malignant neoplasm: Malignant melanoma of skin, unspecified
  •   C79.5 -  Secondary malignant neoplasm of bone and bone marrow
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Interventions/Observational Groups

  •   PD-1 blocking antibody Nivolumab (every 2 weeks) or pembrolizumab (every 3 weeks) in combination with the RANKL inhibitor denosumab (every 4 weeks)
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Basic research/physiological study
  •   Single (group)
  •   IV
  •   No
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Primary Outcome

1) Number of activated T-cells in the peripheral blood (positive if number of CD45RA+, CD45RO-, CCR7-, CD62L-, PD-1- increases >50% compared to baseline)
2) Induction of interferon gamma in plasma (positive if interferon gamma becomes detectable or increases >50% compared to baseline)
Variables will be determined at baseline and after 4, 12 and 24 weeks of therapy. The profile over time as well as the time point with the highest difference to baseline will be assessed. The hypothesis is that the numbers are increasing with increasing duration of therapy.

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Secondary Outcome

• Safety
Occurrence of adverse events as assessed by NCI CTC-AE criteria version 5.0
• Efficacy
1) Overall response rate at 12 and 24 weeks as determined by RECIST 1.1 criteria
2) Response rate of bone metastases after 12 and 24 weeks of treatment (size and number) as determined by RECIST 1.1 and bone scans
• Quality of life
QoL as assessed by the EORTC QLQ-C 30 questionnaire

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2019/04/16
  •   20
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

Patients may be included in the study only if they meet all the following criteria:
• Confirmation of the histopathological diagnosis of melanoma in the central laboratory (preferentially from a metastatic lesion, however, the primary tumor is also acceptable)
• Inoperable metastatic stage IV melanoma arising from a primary cutaneous site or metastatic from an unknown primary site.
• Planned therapy with PD-1 blocking antibody (nivolumab, pembrolizumab) and denosumab as standard of care.
• Measurable disease according to RECIST1.1 and at least one documented bone metastasis.
• Age 18 years or above.
• Written, informed consent.
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
• Minimum life expectancy of 6 months
• ECOG performance status of 0-1
• Tumor tissue from metastatic site of disease must be provided for biomarker analyses. Tissue must be obtained before PD1-inhibitor therapy.
• Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to registration:
o WBC ≥ 2000/μL
o Neutrophils ≥ 1500/μL
o Platelets ≥ 100 x103/μL
o Hemoglobin ≥ 9.0 g/dL
o Serum creatinine ≤ 1.5xUL
o Creatinine clearance (CrCl) ≥ 40mL/min (using the Cockcroft-Gault formula)
o AST/ALT ≤ 3 x ULN
o Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who may have total bilirubin < 3.0 mg/dL)
o Serum calcium or albumin-adjusted serum calcium within normal limits
• Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration
• Negative pregnancy test for female subjects within the week before treatment start and effective contraception for both male and female subjects if the risk of conception exists

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Exclusion Criteria

Patients will be excluded from the study for any of the following reasons:
• History of primary uveal or mucosal melanoma.
• Prior therapy with CTLA4-inhibitor or PD-1-inhibitor or denosumab for metastatic disease. Medical treatments in the adjuvant setting (such as interferons or checkpoint inhibitors) are allowed in case treatment was discontinued at least 6 weeks before inclusion in this study.
• No other concurrent medical treatments for metastatic disease such as targeted therapies or chemotherapies are allowed. Medical treatments in the adjuvant setting (such as interferons or checkpoint inhibitors) are allowed in case treatment was discontinued at least 6 weeks before inclusion in this study.
• Active CNS metastases. CNS-metastases stable for a minimum of 4 weeks are allowed.
• Use of any investigational or non-registered product (drug or vaccine) other than the study treatment within the past 30 days before study start and during study
• Psychiatric or addictive disorders of the patient that may compromise his/her ability to give informed consent or to comply with the trial procedures.
• Significant dental/oral disease, including prior history or current evidence of osteonecrosis/osteomyelitis of the jaw, or the following: Active dental or jaw condition which requires oral surgery. Non-healed dental/oral surgery. Planned invasive dental procedures for the course of the study.
• Immune deficiencies or significant autoimmune disease.
• Any immunosuppressive therapy given within the past 30 days.
• Other malignancies within the past three years which needs treatment except basal or squamous skin carcinomas or carcinoma in situ of the cervix
• Serious cardiac, gastrointestinal, hepatic or pulmonary disease
• Patients with serious intercurrent illness, requiring hospitalization.
• Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders.
• The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (e.g., HBV, HCV).or has another confirmed or suspected immunosuppressive or immunodeficient condition.
• Hypersensitivity to the active substances of study treatment (denosumab, pembrolizumab or nivolumab) or to any of the excipients (calcium, vitamin D)
• Hereditary fructose intolerance
• Women of childbearing potential: Refusal or inability to use highly effective means of contraception
• For female patients: the patient is pregnant or lactating or planning to become pregnant within 5 months after the end of the treatment.

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Addresses

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    • Medizinische Hcchschule Hannover
    • Mr.  Prof. Dr. med.   Ralf  Gutzmer 
    • Car Neuberg Str. 1
    • 30625  Hannover
    • Germany
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    • Skin Cancer Center HannoverDepartment of Dermatology and AllergyHannover Medical School
    • Mr.  Prof. Dr. med.  Ralf  Gutzmer 
    • Carl Neuberg Str.1
    • 30625  Hannover
    • Germany
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    • Alcedis GmbH
    • Ms.  Julia  Honig 
    • Wincester Straße 3
    • 35394  Gießen
    • Germany
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Sources of Monetary or Material Support

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    • AMGEN GmbH
    • Ms.  Beate  Mengoni 
    • Riesstraße 24
    • 80992  München
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.