A Phase Ib/II Trial of Ipilimumab-Nivolumab-Denosumab and Nivolumab-Denosumab in Patients with Unresectable Stage III and IV Melanoma
- Conditions
- MelanomaCancer - Malignant melanoma
- Registration Number
- ACTRN12617000772347
- Lead Sponsor
- Peter MacCallum Cancer Centre
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 52
1.Histologically confirmed unresectable or metastatic melanoma as per AJCC 7 staging system.
2.Age greater than or equal to 18 years
3.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4.Patient willing and able to provide written informed consent.
5.No prior systemic therapy for unresectable or metastatic melanoma. Prior adjuvant or neoadjuvant melanoma therapy with a BRAF or MEK inhibitor is permitted if it was completed at least 6 months 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.Patients with asymptomatic brain metastasis may be considered for enrollment. These patients can have up to 3 lesions that are lesser than or equal to 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.
9.At least 1 week since the completion of prior therapy, including surgery or radiotherapy.
10.Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomisation/registration
•WBC greater than or equal to 2000/µL
•Neutrophils greater than or equal to 1500/µL
•Plateletsgreater than or equal to 100 x10^3/µL
•Haemoglobin greater than 9.0 g/dL
•Serum creatinine lesser than or equal to 1.5 x ULN or creatinine clearance (CrCl) greater than or equal to 40 mL/min (if using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85 / 72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine in mg/dL
•AST/ALT lesser than or equal to 3 x ULN
•Total Bilirubin lesser than or equal 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin less than 3.0 mg/dL)
•Serum calcium of albumin-adjusted calcium greater than or equal 2.0 mmol/L
11.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. Appropriate methods of contraception includes:
•Intrauterine device with a documented failure rate of less than 1% per year.
•Vasectomised partner who is sterile prior to the female partner patient’s commencement of study treatment and is the sole sexual partner for that female.
•Double barrier contraception: male condom and occlusive cap (diaphragm or cervical /vault caps).
12.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.
13.Men who are sexually active with a 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 a WOCBP will be instructed
1.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.
2.Neurological symptoms from brain metastases present at baseline (resolved neurological symptoms, prior to enrolment, are permitted).
3.Patients with uveal melanoma are excluded.
4.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.
5.Prior systemic treatment for unresectable or metastatic melanoma.
6.Prior treatment with denosumab.
7.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.
8.Life expectancy of = 6 months.
9.Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.
10.Active dental condition, which requires major oral surgery. Patients who have undergone a tooth extraction in less than 4 weeks should be clinically reviewed to ensure they have healed well.
11.Surgery or radiotherapy within less than 1 week 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.
12.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.
13.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
14.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 5 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.
15.Any investigational drug or other systemic drug therapy for melanoma within 28 days or 5 half-lives from baseline.
16.Pregnant or breastfeeding females.
17.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.
18.Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
19.Allergies and Adverse Drug Reaction
a.History of allergy to study drug comp
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method