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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03161756




Registration number
NCT03161756
Ethics application status
Date submitted
11/05/2017
Date registered
22/05/2017
Date last updated
7/04/2022

Titles & IDs
Public title
Evaluation of Denosumab in Combination With Immune Checkpoint Inhibitors in Patients With Unresectable or Metastatic 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] 0 0
01.15
Universal Trial Number (UTN)
Trial acronym
CHARLI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma Stage Iv 0 0
Melanoma Stage Iii 0 0
Melanoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Denosumab
Treatment: Drugs - Nivolumab
Treatment: Drugs - Ipilimumab

Experimental: 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).

Experimental: 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).


Treatment: Drugs: Denosumab
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.

Treatment: Drugs: Nivolumab
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-?) release in vitro.

Treatment: Drugs: Ipilimumab
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Median Progression-Free Survival
Timepoint [1] 0 0
Approximately 5 years
Primary outcome [2] 0 0
Occurrence of Grade 3 and 4 Selected Immune-related Adverse Events (irAEs) of interest
Timepoint [2] 0 0
Approximately 2 years
Secondary outcome [1] 0 0
Rate of Grade 3 and 4 irAEs
Timepoint [1] 0 0
Approximately 2 years
Secondary outcome [2] 0 0
Best Overall Response According to RECIST 1.1
Timepoint [2] 0 0
Approximately 3 years
Secondary outcome [3] 0 0
Progression-Free Survival
Timepoint [3] 0 0
Approximately 5 years
Secondary outcome [4] 0 0
Overall Survival
Timepoint [4] 0 0
Approximately 5 years
Secondary outcome [5] 0 0
Toxicity Profiles of the Checkpoint-Denosumab Combinations
Timepoint [5] 0 0
Approximately 2 years
Secondary outcome [6] 0 0
Occurrence of Treatment Discontinuation Due to Toxicity
Timepoint [6] 0 0
Approximately 2 years

Eligibility
Key inclusion criteria
1. Histologically confirmed unresectable or metastatic melanoma as per AJCC 7 staging
system.

2. Age = 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. 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.

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 = 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 2 weeks 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 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):

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 = 3 x ULN

- Total Bilirubin = 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL)

- Serum calcium of albumin-adjusted calcium = 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 with a BRAF and/or MEK inhibitor

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 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.

11. 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.

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 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.

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

1. History of allergy to study drug components.

2. 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)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Unknown status
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/12/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2023
Actual
Sample size
Target
72
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,VIC,WA
Recruitment hospital [1] 0 0
Border Medical Oncology Research Unit - Albury
Recruitment hospital [2] 0 0
Bendigo Health - Bendigo
Recruitment hospital [3] 0 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [4] 0 0
Royal Brisbane and Women's Hospital - Herston
Recruitment hospital [5] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 0 0
Box Hill Hospital - Box Hill
Recruitment hospital [7] 0 0
Austin Health - Heidelberg
Recruitment hospital [8] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [9] 0 0
Alfred Health - Melbourne
Recruitment hospital [10] 0 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 0 0
2640 - Albury
Recruitment postcode(s) [2] 0 0
3550 - Bendigo
Recruitment postcode(s) [3] 0 0
2298 - Waratah
Recruitment postcode(s) [4] 0 0
4029 - Herston
Recruitment postcode(s) [5] 0 0
7000 - Hobart
Recruitment postcode(s) [6] 0 0
3128 - Box Hill
Recruitment postcode(s) [7] 0 0
3084 - Heidelberg
Recruitment postcode(s) [8] 0 0
3000 - Melbourne
Recruitment postcode(s) [9] 0 0
3004 - Melbourne
Recruitment postcode(s) [10] 0 0
6009 - Nedlands

Funding & Sponsors
Primary sponsor type
Other
Name
Melanoma and Skin Cancer Trials Limited
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Peter MacCallum Cancer Centre, Australia
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Amgen
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/Industry
Name [3] 0 0
Bristol-Myers Squibb
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03161756
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
A/Prof Shahneen Sandhu
Address 0 0
Peter MacCallum Cancer Centre, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03161756