Clinical Trials /

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

NCT03161756

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of Denosumab in Combination With Immune Checkpoint Inhibitors in Patients With Unresectable or Metastatic Melanoma
  • Official Title: A Phase Ib/II Trial of Ipilimumab-Nivolumab-Denosumab and Nivolumab-Denosumab in Patients With Unresectable Stage III and IV Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 01.15
  • NCT ID: NCT03161756

Conditions

  • Melanoma Stage Iv
  • Melanoma Stage Iii
  • Melanoma

Interventions

DrugSynonymsArms
DenosumabAMG162Arm A
NivolumabOpdivo, BMS-936558, MDX1106Arm A
IpilimumabYervoy, BMS-734016, MDX010Arm B

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalPatients 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).
  • Denosumab
  • Nivolumab
Arm BExperimentalPatients 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).
  • Denosumab
  • Nivolumab
  • Ipilimumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Median Progression-Free Survival
Time Frame:Approximately 5 years
Safety Issue:
Description:Defined as the time from enrolment to date of disease progression as measured using RECIST 1.1 criteria

Secondary Outcome Measures

Measure:Rate of Grade 3 and 4 irAEs
Time Frame:Approximately 2 years
Safety Issue:
Description: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.
Measure:Best Overall Response According to RECIST 1.1
Time Frame:Approximately 3 years
Safety Issue:
Description: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.
Measure:Progression-Free Survival
Time Frame:Approximately 5 years
Safety Issue:
Description: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.
Measure:Overall Survival
Time Frame:Approximately 5 years
Safety Issue:
Description:Defined as the time from enrolment to the time of death. Median overall survival will be assessed at 12 and 24 months post enrolment.
Measure:Toxicity Profiles of the Checkpoint-Denosumab Combinations
Time Frame:Approximately 2 years
Safety Issue:
Description: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.
Measure:Occurrence of Treatment Discontinuation Due to Toxicity
Time Frame:Approximately 2 years
Safety Issue:
Description:Number of patients who withdraw from the study due to intolerable adverse reactions

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Melanoma and Skin Cancer Trials Limited

Last Updated

January 3, 2020