The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02374242




Registration number
NCT02374242
Ethics application status
Date submitted
9/02/2015
Date registered
27/02/2015
Date last updated
21/05/2020

Titles & IDs
Public title
Anti-PD 1 Brain Collaboration for Patients With Melanoma Brain Metastases
Scientific title
A Phase II Study of Nivolumab and Nivolumab Combined With Ipilimumab in Patients With Melanoma Brain Metastases
Secondary ID [1] 0 0
ACTRN12614001315606
Secondary ID [2] 0 0
CA209-170
Universal Trial Number (UTN)
Trial acronym
ABC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma 0 0
Brain Metastases 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma
Cancer 0 0 0 0
Other cancer types
Cancer 0 0 0 0
Brain

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

Active Comparator: Cohort 1 Nivolumab Monotherapy - Nivolumab 3mg/kg every 2 weeks, until disease progression, withdrawn consent, unacceptable toxicity or death.

Active Comparator: Cohort 2 Nivolumab Monotherapy - Nivolumab 3mg/kg every 2 weeks, until disease progression, withdrawn consent, unacceptable toxicity or death.

Active Comparator: Cohort 3 Nivolumab and Ipilimumab - Nivolumab 1mg/kg every 3 weeks x four doses and ipilimumab 3mg/kg every 3 weeks x four doses. After 12 weeks, nivolumab 3mg/kg alone every 2 weeks until disease progression, withdrawn consent, unacceptable toxicity or death.


Treatment: Drugs: Nivolumab
Nivolumab is a fully human monoclonal antibody directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity.

Treatment: Drugs: Ipilimumab
Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab's effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumour immune responses.

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

Outcomes
Primary outcome [1] 0 0
Intracranial response rate - Proportion of patients with a complete or partial response in intracranial metastases as measured using RECIST 1.1 criteria (modified for brain metastases - bm RECIST), from week 12.
Timepoint [1] 0 0
Approximately 3 years
Secondary outcome [1] 0 0
Extracranial response rate - Proportion of patients with an overall complete or partial response in extra cranial metastases as measured using bm RECIST.
Timepoint [1] 0 0
Approximately 3 years
Secondary outcome [2] 0 0
Overall response rate - Proportion of patients with an overall complete or partial response as measured using bm RECIST 1.1 criteria.
Timepoint [2] 0 0
Approximately 3 years
Secondary outcome [3] 0 0
Progression free survival in intracranial disease - Time from the baseline assessment to the date of intracranial progression as measured using bm RECIST 1.1 criteria.
Timepoint [3] 0 0
Approximately 3 years
Secondary outcome [4] 0 0
Progression free survival in extracranial disease - Time from the baseline assessment to the date of extracranial progression as measured using bm RECIST 1.1 criteria.
Timepoint [4] 0 0
Approximately 3 years
Secondary outcome [5] 0 0
Overall progression free survival - Time from the baseline assessment to the date of local or distant progression as measured using bm RECIST 1.1 criteria. Patients dying from causes other than melanoma or treatment related toxicity will be censored at date of death. Patients alive without progression or with second primary cancers will be censored at date of last assessment.
Timepoint [5] 0 0
Approximately 3 years
Secondary outcome [6] 0 0
Overall survival - Time from commencing study treatment to the date of death from any cause. Patient still alive will be censored at the date of last assessment.
Timepoint [6] 0 0
Up to approximately 5 years
Secondary outcome [7] 0 0
Safety and tolerability of nivolumab and nivolumab + ipilimumab (verse events by type, frequency and severity using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.) - Description of adverse events by type, frequency and severity using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Number of patients who withdraw from the study due to intolerable adverse reactions.
Timepoint [7] 0 0
Approximately 3 years
Secondary outcome [8] 0 0
Patient rated quality of life - The mean change from baseline quality of life scores at the time of clinical response, stable disease and progression in each cohort.
Timepoint [8] 0 0
Approximately 3 years
Secondary outcome [9] 0 0
Clinical response using immune related response criteria (irRC) - Proportion of patients with an intracranial, extracranial and overall complete or partial response, stable disease or progression and progression free survival as measured using immune-related response criteria (irRC) and the proportion of concordant or discordant results compared with bm RECIST.
Timepoint [9] 0 0
Approximately 3 years
Secondary outcome [10] 0 0
Tissue and blood biomarkers of response and progression - PD-L1 status, immune markers and genetics of response and resistance in tumour tissue at baseline and at disease progression. Lymphocyte, T cell subsets, myeloid derived suppressor cells and other biomarkers in blood at baseline, after 2 weeks on study treatment and then every 6 weeks, to examine if any specific subsets are predictive or response or progression.
Timepoint [10] 0 0
Approximately 3 years
Secondary outcome [11] 0 0
FET-PET response in the brain at 6 and 12 weeks on therapy (Proportion of patients with a lower standardised uptake value from baseline in intracranial metastases, following at least ONE dose of study treatment) - Comparison of FET-PET to MRI findings. Proportion of patients with a lower standardised uptake value from baseline in intracranial metastases, following at least ONE dose of study treatment(s).
Timepoint [11] 0 0
Approximately 1 year

Eligibility
Key inclusion criteria
Cohort 1 and 3



1. =18 years of age.

2. Written informed consent

3. AJCC Stage IV (any T, any N, M1c) histologically confirmed melanoma or unknown primary
melanoma. Patients must have at least 1 radiological definitive brain metastasis that
is = 5mm and =40mm measurable per RECIST version 1.1 guidelines.

4. In patients with prior BRAF inhibitor treatment, intracranial disease progression must
be demonstrated (RECIST >20% or new measurable brain metastases) compared with nadir
of intracranial response during BRAF inhibitor treatment, and confirmed with a second
MRI brain scan at any time from the beginning of the drug washout period (dabrafenib=5
days, trametinib=14 days).

5. No prior localised treatment for brain metastases (eg. surgery or radiotherapy).

6. Neurologically asymptomatic from brain metastases.

7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2, and life
expectancy > 30 days.

8. Able to undergo MRI with Gadolinium contrast agent.

9. Adequate haematological, hepatic and renal organ function.

10. Women of childbearing potential: negative serum pregnancy test and effective
contraception from 14 days prior to study treatment until 23 weeks after the last
dose.

11. Men with female partner of childbearing potential to use effective contraception from
14 days prior to study treatment until 31 weeks after the last dose.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
12. Any melanoma brain metastasis >40mm.

13. Ocular melanoma.

14. Prior treatment with an anti-PD-1 or anti-PD-L1 , anti-PD-L2, anti-CD137, or
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
co-stimulation or checkpoint pathways.

15. Patients with active, known or suspected autoimmune disease. Patients with 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 are permitted
to enroll.

16. Current systemic treatment with corticosteroids, except prednisone at
nonimmunosuppressive doses of = 10 mg/day (or equivalent). Past treatment for
non-neurological symptoms allowed, if ceased 2 weeks prior to starting study
treatment. Inhaled or intranasal corticosteroids (with minimal systemic absorption)
may be continued if patient on a stable dose. Non-absorbed intraarticular steroid
injections will be permitted.

17. Any investigational drug or other systemic drug therapy for melanoma within 28 days or
5 half-lives from baseline.

18. Known to be HIV positive, or a positive test for hepatitis B and C .

19. Another malignancy or concurrent malignancy unless disease-free for 3 years.

20. Serious or unstable pre-existing medical conditions or other conditions that could
interfere with the patient's safety, consent, or compliance.

21. Pregnant or breastfeeding females.

22. Administration of any form of live vaccination (such as influenza vaccine) within 30
days of starting trial and anticipated use during the trial. Administration of any
other vaccine is cautionary within 30 days of starting the trial and during the trial.

Cohort 2 - per Cohorts 1 & 3, except patients must have at least one of the following:

1. Failed prior local therapy for brain metastases (including surgery, stereotactic
radiotherapy or whole brain radiotherapy) where disease has progressed per RECIST
(>20% increase in SOD or new measurable brain metastases),

and/or;

2. Have current neurological symptoms related to brain metastases. IF they have received
prior local therapy for brain metastases, the disease must have progressed per RECIST
(>20% increase in SOD or new measurable brain metastases),

and/or;

3. Have leptomeningeal disease concurrently with measurable brain metastases. IF they
have had failed prior local therapy for brain metastases, this must have progressed
per RECIST (>20% increase in SOD or new measurable brain metastases).

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)
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 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
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,SA,VIC
Recruitment hospital [1] 0 0
Melanoma Institute Australia - North Sydney
Recruitment hospital [2] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 0 0
Peter MacCallum Cancer Centre - East Melbourne
Recruitment postcode(s) [1] 0 0
2060 - North Sydney
Recruitment postcode(s) [2] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
3002 - East Melbourne

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

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this research project is to test the effectiveness of nivolumab versus
nivolumab together with ipilimumab for the treatment of melanoma brain metastases.

Patients are eligible to join this study if they are aged 18 years or above and have been
diagnosed with melanoma with brain metastases.
Trial website
https://clinicaltrials.gov/show/NCT02374242
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Georgina Long
Address 0 0
Melanoma Institute 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
Other publications