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

NCT03161756 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: 01.15
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 10

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.

Conditions

Melanoma Stage Iv; Melanoma Stage Iii; Melanoma

Outcome Measures

Primary Outcomes (2)

• Median Progression-Free Survival

  Defined as the time from enrolment to date of disease progression as measured using RECIST 1.1 criteria

  Approximately 5 years

• Occurrence of Grade 3 and 4 Selected Immune-related Adverse Events (irAEs) of interest

  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.

  Approximately 2 years

Secondary Outcomes (6)

• Rate of Grade 3 and 4 irAEs

  Approximately 2 years

• Best Overall Response According to RECIST 1.1

  Approximately 3 years

• Progression-Free Survival

  Approximately 5 years

• Overall Survival

  Approximately 5 years

• Toxicity Profiles of the Checkpoint-Denosumab Combinations

  Approximately 2 years

Other Outcomes (4)

• To assess the local tumour and systemic immunological responses to both combination treatment regimens (exploratory objective)

  Approximately 2 years

• To evaluate early FDG (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose) PET (positron emission tomography) response as a predictor of clinical benefit

  Approximately 2 years

• To evaluate longitudinal cellular and molecular changes in archival tumour tissue, fresh tumour biopsies and circulating biomarkers to define mechanisms of activity and resistance

  Approximately 3 years

Study Arms (2)

Arm A

EXPERIMENTAL

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; Drug: Nivolumab

Arm B

EXPERIMENTAL

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; Drug: Nivolumab; Drug: Ipilimumab

Interventions

Denosumab DRUG

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.

Also known as: AMG162

Arm A; Arm B

Nivolumab DRUG

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.

Also known as: Opdivo, BMS-936558, MDX1106

Arm A; Arm B

Ipilimumab DRUG

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.

Also known as: Yervoy, BMS-734016, MDX010

Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed unresectable or metastatic melanoma as per AJCC 7 staging system.
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Patient willing and able to provide written informed consent.
• 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.
• Willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
• Measurable disease by CT or MRI per RECIST 1.1 criteria.
• Patients with asymptomatic brain metastasis may be considered for enrollment. These patients can have up to 3 lesions that are ≤ 1.5 cm in diameter. The brain metastasis may be naïve to local therapy or have previously received local therapy (surgery, stereotactic radiotherapy/radiosurgery but not whole brain radiotherapy) and are stable. Asymptomatic from brain metastases at study entry implies that these patients are without corticosteroid, antiepileptics, analgesia or any other treatment for the management of neurological symptoms. Patients with completely resolved neurological symptoms are permitted.
• At least 2 weeks since the completion of prior therapy, including surgery or radiotherapy.
• Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to registration
• WBC ≥ 2000/μL
• Neutrophils ≥ 1500/μL
• Platelets ≥ 100 x103/μL
• Haemoglobin \> 9.0 g/dL
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

You may not qualify if:

• Patients are excluded if they have symptomatic, large volume brain metastases and/or any evidence of leptomeningeal disease. Large volume brain metastasis for this study is defined as more than 3 brain metastasis and/or any of the brain metastasis being greater than 1.5 cm in dimension. Note: patients with larger brain metastasis (up to 3 cm) that has been adequately treated with prior surgery or stereotactic radiation are permitted to be enrolled as long as they have adequately recovered from the local therapy.
• Neurological symptoms from brain metastases present at baseline (resolved neurological symptoms, prior to enrolment, are permitted).
• Patients with uveal melanoma are excluded.
• 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 other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
• Prior systemic treatment with a BRAF and/or MEK inhibitor
• Prior treatment with denosumab.
• 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.
• Life expectancy of ≤ 6 months.
• Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.
• Active dental or jaw condition, which requires major oral surgery. Patients who have undergone a tooth extraction in less than 4 weeks should be reviewed carefully to ensure they have healed well.
• 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.
• 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.
• 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
• 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.
• Any investigational drug or other systemic drug therapy for melanoma within 28 days or 5 half-lives from baseline.

Sponsors & Collaborators

• Melanoma and Skin Cancer Trials Limited: lead
• Peter MacCallum Cancer Centre, Australia: collaborator
• Amgen: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (10)

Border Medical Oncology Research Unit

Albury, New South Wales, 2640, Australia

Location

Bendigo Health

Bendigo, New South Wales, 3550, Australia

Location

Calvary Mater Newcastle

Waratah, New South Wales, 2298, Australia

Location

Royal Brisbane and Women's Hospital

Herston, Queensland, 4029, Australia

Location

Royal Hobart Hospital

Hobart, Tasmania, 7000, Australia

Location

Box Hill Hospital

Box Hill, Victoria, 3128, Australia

Location

Austin Health

Heidelberg, Victoria, 3084, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Alfred Health

Melbourne, Victoria, 3004, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

MeSH Terms

Conditions

Melanoma

Interventions

Denosumab; Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• A/Prof Shahneen Sandhu

  Peter MacCallum Cancer Centre, Australia

  STUDY CHAIR

• Prof. Grant McArthur

  Peter MacCallum Cancer Centre, Australia

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Trial design updated from randomised allocation of patients to physician's choice as per version 2.2 of protocol, there will be a pre-specified number of patients with stage IV M1c disease in each arm (approximately 60%).

Study Record Dates

• First Submitted: May 11, 2017
• First Posted: May 22, 2017
• Study Start: December 7, 2017
• Primary Completion: December 31, 2021
• Study Completion: December 1, 2023
• Last Updated: April 7, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (10)