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Trial registered on ANZCTR


Registration number
ACTRN12617000772347
Ethics application status
Approved
Date submitted
12/05/2017
Date registered
26/05/2017
Date last updated
7/04/2024
Date data sharing statement initially provided
12/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase Ib/II Trial of Ipilimumab-Nivolumab-Denosumab and Nivolumab-Denosumab in Patients with Unresectable Stage III and IV Melanoma
Scientific title
A Phase Ib/II Trial of Ipilimumab-Nivolumab-Denosumab and Nivolumab-Denosumab in Patients with Unresectable Stage III and IV Melanoma
Secondary ID [1] 291930 0
01.15
Universal Trial Number (UTN)
Nil
Trial acronym
CHARLI (CHeckpoint And RANK-L Inhibition)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma 303261 0
Condition category
Condition code
Cancer 302683 302683 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm A: Nivolumab 3 mg/kg IV (intravenous) given D1 every 2 weeks for 4 doses and denosumab 120 mg SC (subcutaneous) D1, D8, D15, D29. Thereafter, nivolumab 480 mg IV and denosumab 120 mg SC every 4 weeks for a total of 24 months inclusive of the initial phase with/without ipilimumab.

Arm B: Ipilimumab at 3 mg/kg combined with nivolumab at 1 mg/kg IV given D1 every 3 weeks for 4 doses with denosumab 120 mg SC given D1, D8, D15, D29, D57. Followed by nivolumab 480 mg IV and denosumab 120 mg SC every 4 weeks for a total of 24 months inclusive of the initial phase with/without ipilimumab..

One tablet of "600mg Caltrate with 500IU Vitamin D tablets" will be co-administered once a day orally commencing on day 1 of treatment and ceasing 30 days after the final denosumab treatment or as clinically indicated.
Intervention code [1] 298052 0
Treatment: Drugs
Comparator / control treatment
Arm A and Arm B are running independently of each other to look at the additive value of denosumab as an immunomodulatory agent.
Control group
Active

Outcomes
Primary outcome [1] 302090 0
The median progression-free survival (PFS) amongst patients treated with combination ipilimumab-nivolumab-denosumab and amongst patients treated with nivolumab-denosumab.
Timepoint [1] 302090 0
PFS is defined from time of enrolment to disease progression as measured according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) or death. 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.
Primary outcome [2] 302091 0
The rate of grade 3 and 4 selected immune related-adverse events (irAEs) of interest. Safety parameters will be continuously assessed throughout the study prior to each cycle of treatment. Adverse events will be graded and summarised according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
Timepoint [2] 302091 0
At Baseline, every 2 weeks for the first phase, then every every 4 weeks during the nivolumab 480mg-denosumab 120mg phase until 100 days post final dose of nivolumab.
Secondary outcome [1] 334705 0
Rate of grade 3 and 4 immune related-adverse events. Safety parameters will be continuously assessed throughout the study prior to each cycle of treatment. Adverse events will be graded and summarised according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
Timepoint [1] 334705 0
At Baseline, every 2 weeks for the first phase, then every every 4 weeks during the nivolumab 480mg-denosumab 120mg phase until 100 days post final dose of nivolumab.
Secondary outcome [2] 334706 0
Best overall response according to RECIST 1.1.
Timepoint [2] 334706 0
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.
Secondary outcome [3] 334707 0
Progression Free Survival (PFS) defined as the time of enrolment to the first date of documented progression as determined by the investigator (radiographic progression by RECIST 1.1 or unequivocal clinical progression)
Timepoint [3] 334707 0
Assessed at 6 and 12 months post enrolment
Secondary outcome [4] 334708 0
Overall survival (OS) defined from the time of enrolment to the time of death.
Timepoint [4] 334708 0
Median OS and OS at 12 and 24 months post enrolment.
Secondary outcome [5] 334709 0
Toxicity profiles of the of the checkpoint–denosumab combinations. Safety parameters will be continuously assessed throughout the study prior to each cycle of treatment. Adverse events will be graded and summarised according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Timepoint [5] 334709 0
At Baseline, every 2 weeks for the first phase, then every every 4 weeks during the nivolumab 480mg-denosumab 120mg phase until 100 days post final dose of nivolumab.
Secondary outcome [6] 334710 0
Occurrence of treatment discontinuation due to toxicity. Safety parameters will be continuously assessed throughout the study prior to each cycle of treatment. Adverse events will be graded and summarised according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Timepoint [6] 334710 0
Assessed at the end of study treatment
Secondary outcome [7] 334713 0
Exploratory composite objective: to assess the local tumour and systemic immunological responses to both combination treatment regimens
Timepoint [7] 334713 0
Bloods for immunological profiling will be collected at Baseline, Weeks 2, 3, 7, 13, at time of radiological confirmation and at disease progression or end of study.
Secondary outcome [8] 334714 0
Exploratory objective: to evaluate early FDG-PET response as a predictor of clinical benefit using RECIST 1.1
Timepoint [8] 334714 0
PET scans will be undertaken at Baseline, Week 9, Week 25, at progression and in the event of complete response by RECIST 1.1
Secondary outcome [9] 335054 0
Exploratory objective: to evaluate longitudinal cellular and molecular changes in archival tumour tissue, fresh tumour biopsies and circulating biomarkers to define mechanisms of activity and resistance.
Timepoint [9] 335054 0
Patients in the biopsy cohort will undergo serial biopsies at Baseline, Weeks 2-4 and at disease progression. All patients will have serial blood sampling at Weeks 5, 9, 17, 25, 49 then 12 weekly, at time of radiological confirmation of response and at disease progression.
Secondary outcome [10] 343223 0
Exploratory objective: to correlate the makeup and changes in the microbiome with treatment response.
Timepoint [10] 343223 0
Patients will have the option of consenting to collection of saliva (baseline only) and stool samples at baseline, week 17, in the event of a partial or complete response, and at disease progression.

Eligibility
Key inclusion criteria
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
• Platelets greater 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 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. Effective contraception includes:
• Documented vasectomy and sterility
• In the partner - intrauterine device with a documented failure rate of less than 1% per year
• Double barrier contraception: male condom and occlusive cap (diaphragm or cervical/vault caps).
14. 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.
15. Patients enrolled on the biopsy cohort must be agreeable to have serial tumour biopsies during the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 components.
b. History of severe hypersensitivity reaction to any monoclonal antibody.
20. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable.
21. For those being registered to Arm B (ipilimumab + nivolumab + denosumab), the use of any vaccines against infectious diseases (e.g. influenza, varicella etc.) within 6 weeks of initiation of study therapy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
From 30th July 2019, allocation to either Arm A or B will be per physician's choice in order to ensure representativeness of the study patients in both arms.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
From 30th July 2019, allocation to either Arm A or B will be per physician's choice in order to ensure representativeness of the study patients in both arms.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/12/2017
Actual
7/02/2018
Date of last participant enrolment
Anticipated
30/06/2019
Actual
14/12/2021
Date of last data collection
Anticipated
30/06/2023
Actual
21/11/2023
Sample size
Target
72
Accrual to date
Final
52
Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,WA,VIC
Recruitment hospital [1] 7991 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 11314 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 11315 0
Box Hill Hospital - Box Hill
Recruitment hospital [4] 11991 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [5] 13455 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [6] 13456 0
Border Medical Oncology - Albury
Recruitment hospital [7] 13508 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [8] 22851 0
Royal Hobart Hospital - Hobart
Recruitment hospital [9] 22852 0
The Alfred - Melbourne
Recruitment hospital [10] 22853 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 15969 0
3000 - Melbourne
Recruitment postcode(s) [2] 23212 0
4029 - Herston
Recruitment postcode(s) [3] 23213 0
3128 - Box Hill
Recruitment postcode(s) [4] 24145 0
3084 - Heidelberg
Recruitment postcode(s) [5] 26062 0
3550 - Bendigo
Recruitment postcode(s) [6] 26063 0
2640 - Albury
Recruitment postcode(s) [7] 26127 0
2298 - Waratah
Recruitment postcode(s) [8] 38150 0
7000 - Hobart
Recruitment postcode(s) [9] 38151 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 296434 0
Hospital
Name [1] 296434 0
Peter MacCallum Cancer Centre
Country [1] 296434 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 295388 0
None
Name [1] 295388 0
Address [1] 295388 0
Country [1] 295388 0
Other collaborator category [1] 279894 0
Other Collaborative groups
Name [1] 279894 0
Melanoma and Skin Cancer Trials, Monash University
Address [1] 279894 0
Melanoma and Skin Cancer Trials, Monash University, 553 St Kilda Road, Melbourne VIC 3004
Country [1] 279894 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297666 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 297666 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC
3000
Ethics committee country [1] 297666 0
Australia
Date submitted for ethics approval [1] 297666 0
29/05/2017
Approval date [1] 297666 0
29/06/2017
Ethics approval number [1] 297666 0
HREC

Summary
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.

Patients in Arm A will receive nivolumab 3 mg/kg IV (intravenous) every 2 weeks for 4 doses and denosumab 120 mg SC (subcutaneous) D1, D8, D15, D29. Thereafter, nivolumab 480 mg IV and denosumab 120 mg SC every 4 weeks for a total of 24 months

Patients in Arm B will recieve 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. This will be followed by nivolumab 480 mg IV and denosumab 120 mg SC ever 4 weeks for a total of 24 months.

Responses to treatment and progression will be regularly monitored until the last patient has been in survival follow-up for 5 years. Tumour and blood samples will also be taken to determine possible predictive biomarkers.
Trial website
https://www.masc.org.au/recruiting-trials/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74750 0
A/Prof Shahneen Sandhu
Address 74750 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC
3000
Country 74750 0
Australia
Phone 74750 0
+61 3 8559 5000
Fax 74750 0
+ 61 3 8559 7379
Email 74750 0
[email protected]
Contact person for public queries
Name 74751 0
Gabrielle Byars
Address 74751 0
Melanoma and Skin Cancer Trials, Monash University, 553 St Kilda Road, Melbourne, VIC 3004
Country 74751 0
Australia
Phone 74751 0
+61399039022
Fax 74751 0
+ 61 2 9954 9435
Email 74751 0
[email protected]
Contact person for scientific queries
Name 74752 0
Gabrielle Byars
Address 74752 0
Melanoma and Skin Cancer Trials, Monash University, 553 St Kilda Road, Melbourne, VIC 3004
Country 74752 0
Australia
Phone 74752 0
+61399039022
Fax 74752 0
Email 74752 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No reason required


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16688Statistical analysis plan    Statistical analysis plan can be provided upon req... [More Details]
16689Clinical study report    Clinical study report can be provided upon request... [More Details]



Results publications and other study-related documents

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