A Phase Ib/II Trial of Ipilimumab-Nivolumab-Denosumab and Nivolumab-Denosumab in Patients With Unresectable Stage III and IV Melanoma
Overview
- Phase
- Phase 1
- Enrollment
- 72
- Locations
- 10
- Primary Endpoint
- Median Progression-Free Survival
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
- •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
Exclusion Criteria
- •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.
Arms & Interventions
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).
Intervention: Denosumab (Drug)
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).
Intervention: Nivolumab (Drug)
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).
Intervention: Denosumab (Drug)
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).
Intervention: Nivolumab (Drug)
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).
Intervention: Ipilimumab (Drug)
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- 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)
- Occurrence of Treatment Discontinuation Due to Toxicity(Approximately 2 years)