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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

Tracking Information
First Submitted Date  ICMJE May 11, 2017
First Posted Date  ICMJE May 22, 2017
Last Update Posted Date January 6, 2020
Actual Study Start Date  ICMJE December 7, 2017
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 18, 2017)
  • 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
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 18, 2017)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 14, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: May 18, 2017)
  • To assess the local tumour and systemic immunological responses to both combination treatment regimens (exploratory objective) [ Time Frame: Approximately 3 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.
  • 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 3 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.
  • 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.
 
Descriptive Information
Brief Title  ICMJE Evaluation of Denosumab in Combination With Immune Checkpoint Inhibitors in Patients With Unresectable or Metastatic Melanoma
Official Title  ICMJE A Phase Ib/II Trial of Ipilimumab-Nivolumab-Denosumab and Nivolumab-Denosumab in Patients With Unresectable Stage III and IV Melanoma
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Melanoma Stage Iv
  • Melanoma Stage Iii
  • Melanoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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).
    Interventions:
    • Drug: Denosumab
    • Drug: Nivolumab
  • 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).
    Interventions:
    • Drug: Denosumab
    • Drug: Nivolumab
    • Drug: Ipilimumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 18, 2017)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Narelle Williams +61 2 9911 7386 charli@masc.org.au
Listed Location Countries  ICMJE Australia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03161756
Other Study ID Numbers  ICMJE 01.15
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Melanoma and Skin Cancer Trials Limited
Study Sponsor  ICMJE Melanoma and Skin Cancer Trials Limited
Collaborators  ICMJE
  • Peter MacCallum Cancer Centre, Australia
  • Amgen
  • Bristol-Myers Squibb
Investigators  ICMJE
Study Chair: Dr. Shahneen Sandhu Peter MacCallum Cancer Centre, Australia
Study Chair: Prof. Grant McArthur Peter MacCallum Cancer Centre, Australia
PRS Account Melanoma and Skin Cancer Trials Limited
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP