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Evaluation of Denosumab in Combination With Immune Checkpoint Inhibitors in Patients With Unresectable or Metastatic Melanoma (CHARLI)

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ClinicalTrials.gov Identifier: NCT03161756
Recruitment Status : Recruiting
First Posted : May 22, 2017
Last Update Posted : January 6, 2020
Sponsor:
Collaborators:
Peter MacCallum Cancer Centre, Australia
Amgen
Bristol-Myers Squibb
Information provided by (Responsible Party):
Melanoma and Skin Cancer Trials Limited

Brief Summary:

The purpose of this project is to test the addition of a new treatment called denosumab to standard immunotherapies for patients with metastatic melanoma. Denosumab has been used for many years to help treat cancers such as prostate cancer and breast cancer, but it is not currently used in melanoma. We hope the addition of denosumab to current melanoma therapies will make these treatments work better without adding to the side effects.

Who is it for? You may be eligible to join this study if you are aged 18 years or over and have been diagnosed with metastatic melanoma (melanoma that has spread).

Study details: Nivolumab and ipilimumab are approved treatments for advanced melanoma in Australia and overseas. Patients with metastatic melanoma, who are not enrolled in a study, are commonly prescribed nivolumab alone or the combination of nivolumab and ipilimumab as standard care. However, there is limited information on the effectiveness and safety of these treatments in combination with denosumab. Recent melanoma research in animal models has shown that denosumab can make immunotherapies such as ipilimumab and nivolumab work better. Because denosumab has been used in patients with breast and prostate cancer for a long time and is safe, we now want to test the benefits and safety of adding denosumab to immunotherapies in this study.


Condition or disease Intervention/treatment Phase
Melanoma Stage Iv Melanoma Stage Iii Melanoma Drug: Denosumab Drug: Nivolumab Drug: Ipilimumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Trial of Ipilimumab-Nivolumab-Denosumab and Nivolumab-Denosumab in Patients With Unresectable Stage III and IV Melanoma
Actual Study Start Date : December 7, 2017
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Arm A
Patients in Arm A will receive nivolumab 3 mg/kg intravenously (IV) every 2 weeks for 4 doses and denosumab 120 mg subcutaneously (SC) given D1, D8, D15, D29 (induction phase). Thereafter, nivolumab 480 mg IV and denosumab 120 mg SC every 4 weeks for a total of 24 months (maintenance phase).
Drug: Denosumab
Denosumab is a fully human monoclonal immunoglobulin type 2 (IgG2) antibody that binds with high affinity and specificity to RANK ligand (RANKL) and neutralises the activity of human RANKL, similar to the action of endogenous osteoprotegerin (OPG). Denosumab binding prevents the activation of RANK and inhibits the formation, activation, and survival of osteoclasts. As a consequence, bone resorption and cancer-induced bone destruction are reduced.
Other Name: AMG162

Drug: Nivolumab
Nivolumab is a human monoclonal antibody that targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in vitro.
Other Names:
  • Opdivo
  • BMS-936558
  • MDX1106

Experimental: Arm B
Patients in Arm B will receive ipilimumab at 3 mg/kg combined with nivolumab at 1 mg/kg IV every 3 weeks for 4 doses with denosumab 120 mg SC given D1, D8, D15, D29, D57 (induction phase). This will be followed by nivolumab 480 mg IV and denosumab 120 mg SC ever 4 weeks for a total of 24 months (maintenance phase).
Drug: Denosumab
Denosumab is a fully human monoclonal immunoglobulin type 2 (IgG2) antibody that binds with high affinity and specificity to RANK ligand (RANKL) and neutralises the activity of human RANKL, similar to the action of endogenous osteoprotegerin (OPG). Denosumab binding prevents the activation of RANK and inhibits the formation, activation, and survival of osteoclasts. As a consequence, bone resorption and cancer-induced bone destruction are reduced.
Other Name: AMG162

Drug: Nivolumab
Nivolumab is a human monoclonal antibody that targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in vitro.
Other Names:
  • Opdivo
  • BMS-936558
  • MDX1106

Drug: Ipilimumab
Ipilimumab is a fully human monoclonal immunoglobulin specific for human cytotoxic T-lymphocyte antigen 4 (CTLA-4), which is expressed on a subset of activated T cells. Ipilimumab is a monoclonal antibody(mAb) that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, cluster of differentiation antigen 80 / cluster of differentiation antigen 86 (CD80 / CD86). Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor-infiltrating T-effector cells.
Other Names:
  • Yervoy
  • BMS-734016
  • MDX010




Primary Outcome Measures :
  1. Median Progression-Free Survival [ Time Frame: Approximately 5 years ]
    Defined as the time from enrolment to date of disease progression as measured using RECIST 1.1 criteria

  2. Occurrence of Grade 3 and 4 Selected Immune-related Adverse Events (irAEs) of interest [ Time Frame: Approximately 2 years ]
    Defined as all irAEs except skin-related toxicity not requiring systemic treatment and laboratory abnormalities not requiring intervention or cessation of treatment with the exception of liver dysfunction and grade 3 thrombocytopenia of greater than 7 days; using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.


Secondary Outcome Measures :
  1. Rate of Grade 3 and 4 irAEs [ Time Frame: Approximately 2 years ]
    Description of all adverse events by type, frequency and severity using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  2. Best Overall Response According to RECIST 1.1 [ Time Frame: Approximately 3 years ]
    Disease assessment by CT using RECIST v1.1 will be undertaken at Baseline and every 8 weeks (from Week 9) until Week 49 and then every 12 weeks until disease progression.

  3. Progression-Free Survival [ Time Frame: Approximately 5 years ]
    Defined as the time from enrolment to date of disease progression as measured using RECIST 1.1 criteria. Assessed at 6 and 12 months post enrolment.

  4. Overall Survival [ Time Frame: Approximately 5 years ]
    Defined as the time from enrolment to the time of death. Median overall survival will be assessed at 12 and 24 months post enrolment.

  5. Toxicity Profiles of the Checkpoint-Denosumab Combinations [ Time Frame: Approximately 2 years ]
    Description of all adverse events by type, frequency and severity using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  6. Occurrence of Treatment Discontinuation Due to Toxicity [ Time Frame: Approximately 2 years ]
    Number of patients who withdraw from the study due to intolerable adverse reactions


Other Outcome Measures:
  1. To assess the local tumour and systemic immunological responses to both combination treatment regimens (exploratory objective) [ Time Frame: Approximately 2 years ]
    As an exploratory objective, this will be done to comprehensively characterise lymphocyte populations residing within the tumour bed and peripheral blood prior to, during and following treatment with RANKL and immune checkpoint inhibition.

  2. To evaluate early FDG (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose) PET (positron emission tomography) response as a predictor of clinical benefit [ Time Frame: Approximately 2 years ]
    As an exploratory objective, this will be done to assess the predictive and prognostic significance of early changes in FDG-PET to immune checkpoint inhibitors and denosumab in conjunction with conventional CT imaging.

  3. To evaluate longitudinal cellular and molecular changes in archival tumour tissue, fresh tumour biopsies and circulating biomarkers to define mechanisms of activity and resistance [ Time Frame: Approximately 3 years ]
    As an exploratory objective, these studies will focus on the mechanism of action of the combination, putative determinants of response and resistance and monitoring of tumour kinetics.

  4. To correlate the makeup and changes in the microbiome with treatment response. [ Time Frame: Approximately 2 years ]
    As an exploratory objective, this is an optional assessment that will allow the collection of samples which will be used to assess and characterise the microbiome in order to better understand determinants of sensitivity and resistance to the study treatments.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed unresectable or metastatic melanoma as per American Joint Committee on Cancer (AJCC) staging system
  2. Equal or greater than 18 years of age
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  4. Patient willing and able to provide written informed consent.
  5. Treatment naïve (no prior systemic therapy for unresectable or metastatic melanoma). Note that prior adjuvant or neoadjuvant melanoma therapy (except anti-PD1 and/or anti-CTLA-4 therapy) is permitted if it was completed at least 6 weeks prior to allocation, and all related adverse events have either returned to baseline or resolved.
  6. Willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
  7. Measurable disease by CT or MRI per RECIST 1.1 criteria.
  8. At least 2 weeks since the completion of prior therapy, including surgery or radiotherapy.
  9. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomisation/registration
  10. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
  11. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of treatment.
  12. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.
  13. Patients must agree to have archival tumour material collected. This can either be from a resected lymph node, primary melanoma or metastatic site. Where possible the most recently acquired tumour specimen should be provided. If archival tumour tissue is not available, subjects must consent to allow the acquisition of additional tumour tissue prior to trial entry.
  14. Patient enrolled on the biopsy cohort must be agreeable to have serial tumour biopsies during the study.

Exclusion Criteria:

  1. Patients are excluded if they have ever had any brain or leptomeningeal metastases.
  2. Prior exposure to a CTLA-4 inhibitor (e.g. ipilimumab, tremelimumab), PD-1 inhibitor (e.g. nivolumab, pembrolizumab), PD-L1 inhibitor (e.g. MEDI-4736), PD-L2 inhibitor or any or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
  3. Prior systemic treatment with a BRAF and/or MEK inhibitor.
  4. Prior treatment with denosumab.
  5. Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast.
  6. Life expectancy of less than or equal to 6 months.
  7. Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.
  8. Active dental or jaw condition, which requires oral surgery, including tooth extraction.
  9. Non-healed dental/oral surgery.
  10. Surgery, or radiotherapy within less than 2 weeks of Cycle 1 Day 1. Any clinically relevant sequelae from the surgery or radiotherapy must have improved to grade 1 prior to Cycle 1 Day 1.
  11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  12. Patients should be excluded if they have an active, known or suspected autoimmune disease.Subjects are permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  13. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  14. Any investigational drug or other systemic drug therapy for melanoma within 28 days or 5 half-lives from baseline.
  15. Pregnant or breastfeeding females.
  16. Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
  17. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  18. Allergies and Adverse Drug Reaction

    1. History of allergy to study drug components.
    2. History of severe hypersensitivity reaction to any monoclonal antibody.
  19. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable.
  20. Use of any vaccines against infectious diseases (e.g., influenza, varicella, etc.) within 3 weeks (21 days)of initiation of study therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03161756


Contacts
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Contact: Narelle Williams +61 2 9911 7386 charli@masc.org.au

Locations
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Australia, New South Wales
Border Medical Oncology Research Unit Recruiting
Albury, New South Wales, Australia, 2640
Bendigo Health Recruiting
Bendigo, New South Wales, Australia, 3550
Calvary Mater Newcastle Recruiting
Waratah, New South Wales, Australia, 2298
Australia, Queensland
Royal Brisbane and Women's Hospital Recruiting
Herston, Queensland, Australia, 4029
Australia, Tasmania
Royal Hobart Hospital Not yet recruiting
Hobart, Tasmania, Australia, 7000
Australia, Victoria
Box Hill Hospital Recruiting
Box Hill, Victoria, Australia, 3128
Austin Health Recruiting
Heidelberg, Victoria, Australia, 3084
Peter MacCallum Cancer Centre Recruiting
Melbourne, Victoria, Australia, 3000
Sponsors and Collaborators
Melanoma and Skin Cancer Trials Limited
Peter MacCallum Cancer Centre, Australia
Amgen
Bristol-Myers Squibb
Investigators
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Study Chair: Dr. Shahneen Sandhu Peter MacCallum Cancer Centre, Australia
Study Chair: Prof. Grant McArthur Peter MacCallum Cancer Centre, Australia

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Responsible Party: Melanoma and Skin Cancer Trials Limited
ClinicalTrials.gov Identifier: NCT03161756    
Other Study ID Numbers: 01.15
First Posted: May 22, 2017    Key Record Dates
Last Update Posted: January 6, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Denosumab
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Bone Density Conservation Agents
Physiological Effects of Drugs