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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
27/03/2019
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
ANZMTG 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 4.03.
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 4.03.
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 4.03.
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 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 naive. (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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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
a. History of allergy to study drug components.
b. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The first ten patients enrolled in the study will be allocated to Arm A. After enrolment of the first 10 patients is complete and has passed the interim safety evaluation, then allocation to either Arm A or B will be performed by random computerised allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation to either Arm A or B will be performed by random computerised allocation and stratified by participating site. Allocation will be concealed and randomisation conducted via a secure web-based interactive randomisation system.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Ten patients from Arm A will initially be recruited and provided they pass the safety evaluation, then recruitment for Arm B will open in parallel. Patients will be randomised to either arm with 21:41 allocation ratio.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,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 postcode(s) [1] 26127 0
2298 - Waratah
Recruitment postcode(s) [2] 26063 0
2640 - Albury
Recruitment postcode(s) [3] 15969 0
3000 - Melbourne
Recruitment postcode(s) [4] 24145 0
3084 - Heidelberg
Recruitment postcode(s) [5] 23213 0
3128 - Box Hill
Recruitment postcode(s) [6] 26062 0
3550 - Bendigo
Recruitment postcode(s) [7] 23212 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 296434 0
Hospital
Name [1] 296434 0
Peter MacCallum Cancer Centre
Address [1] 296434 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC
3000
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
Australia and New Zealand Melanoma Trials Group
Address [1] 279894 0
ANZMTG
The University of Sydney, The Poche Centre
40 Rocklands Road
North Sydney NSW 2060
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.anzmtg.org/trialdetails.aspx?trialno=25
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74750 0
Dr 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
shahneen.sandhu@petermac.org
Contact person for public queries
Name 74751 0
Miss Katrina Diamante
Address 74751 0
ANZMTG
The University of Sydney, The Poche Centre
40 Rocklands Road
North Sydney NSW 2060
Country 74751 0
Australia
Phone 74751 0
+ 61 2 9911 7386
Fax 74751 0
+ 61 2 9954 9435
Email 74751 0
Katrina.Diamante@melanoma.org.au
Contact person for scientific queries
Name 74752 0
Miss Katrina Diamante
Address 74752 0
ANZMTG
The University of Sydney, The Poche Centre
40 Rocklands Road
North Sydney NSW 2060
Country 74752 0
Australia
Phone 74752 0
+ 61 2 9911 7386
Fax 74752 0
+ 61 2 9954 9435
Email 74752 0
Katrina.Diamante@melanoma.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Statistical analysis plan
Clinical study report
Summary results
No Results