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
- Conditions
- C43.9C79.5Malignant melanoma of skin, unspecifiedSecondary malignant neoplasm of bone and bone marrow
- Registration Number
- DRKS00016064
- Lead Sponsor
- Alcedis GmbH
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Complete
- Sex
- All
- Target Recruitment
- 17
•Provision of tumor tissue from metastatic site of disease for biomarker analysis and confirmation of diagnosis by central laboratory. Tissue must be obtained before PD-1 inhibitor therapy (either baseline FFPE sample or archival tissue (ideally obtained after preceding medical tumor therapies).
•Inoperable metastatic stage IV melanoma arising from a primary cutaneous site or metastatic from an unknown primary site or melanoma of mucosal or uveal origin.
•Planned therapy with PD-1 blocking antibody (nivolumab or nivolumab + ipilimumab or 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 0-2
•Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to registration:
oWBC = 2000/µL
oNeutrophils = 1000/µL
oPlatelets = 100 x103/µL
oHemoglobin = 9.0 g/dL
oSerum creatinine = 2.0 x ULN OR
oCreatinine clearance (CrCl) = 35mL/min (using the Cockcroft-Gault formula)
oAST/ALT = 3 x ULN, in case of liver metastases = 5 x ULN
oTotal Bilirubin = 2.0 x ULN (except subjects with Gilbert Syndrome, who may have total bilirubin up to 5 x ULN)
oSerum calcium or albumin-adjusted serum calcium within normal limits
•Prior radiotherapy must have been completed 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
•Prior therapy with CTLA-4-inhibitor or PD-1-inhibitor or denosumab for distant metastatic disease. Treatments in the adjuvant setting are allowed in case treatment was discontinued at least 4 weeks before inclusion in this study.
•No other concurrent medical treatments for metastatic disease such as targeted therapies or chemotherapies are allowed. Treatments in the adjuvant setting are allowed in case treatment was discontinued at least 4 weeks before inclusion in this study.
•Active CNS metastases requiring local therapy or steroid therapy
•Use of any investigational or non-registered product (drug or vaccine) 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.
•Relevant immune deficiencies or relevant autoimmune disease, as assessed by the investigator.
•Other malignancies within the past three years which need 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 intravenous antibiotics or bleeding disorders.
•Hypersensitivity to the active substances of study treatment 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.
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 1) Dynamic changes of the numbers of central memory, effector memory and/or effector T-cells in circulating blood (based on expression of CD45RA, CD45RO, CCR7, CD62L, and TCF-1 )<br>2) Dynamic changes of the numbers of cytokine and chemokine present in circulating blood.<br>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 expectation is that the numbers are increasing with increasing duration of therapy.<br>
- Secondary Outcome Measures
Name Time Method • Safety<br>Occurrence of adverse events as assessed by NCI CTC-AE criteria version 5.0<br>• Efficacy<br>1) Overall response rate at 12 and 24 weeks as determined by RECIST 1.1 criteria<br>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<br><br>