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Trial registered on ANZCTR


Registration number
ACTRN12614001315606
Ethics application status
Approved
Date submitted
27/10/2014
Date registered
16/12/2014
Date last updated
24/07/2019
Date data sharing statement initially provided
18/02/2019
Date results information initially provided
18/02/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A phase II study of nivolumab and nivolumab combined with ipilimumab in patients with melanoma brain metastases (ABC - Anti-PD1 Brain Collaboration Study)
Scientific title
A phase II study assessing the intracranial response to nivolumab and nivolumab combined with ipilimumab in patients with melanoma brain metastases
Secondary ID [1] 285273 0
Nil known
Universal Trial Number (UTN)
Nil
Trial acronym
ABC Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma Brain Metastases 292928 0
Melanoma 293629 0
Condition category
Condition code
Cancer 293924 293924 0 0
Malignant melanoma
Cancer 293925 293925 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cohorts 1 and 2: Nivolumab 3mg/kg intravenous infusion every 2 weeks, repeated until either of: disease progression, withdrawn consent, unacceptable toxicity or death. Treatment beyond disease progression may occur if clinical benefit agreed upon by treating clinician and study PI and patient’s performance status is stable.

Cohort 3: Nivolumab 1mg/kg intravenous infusion every 3 weeks x four doses combined with ipilimumab 3mg/kg intravenous infusion every 3 weeks x four doses. After 12 weeks, nivolumab 3mg/kg alone every 2 weeks until disease progression or toxicity, with the possibility of treating beyond progression if clinical benefit decided by treating clinician and patient’s performance status is stable.
Intervention code [1] 290177 0
Treatment: Drugs
Comparator / control treatment
There is no control. This is a phase 2, multi-arm study to explore the activity of Nivolumab vs Nivolumab and Ipilimumab in active brain metastases.
Control group
Active

Outcomes
Primary outcome [1] 293093 0
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), following at least ONE dose of study treatment(s).
Timepoint [1] 293093 0
Patients will be evaluated every 6 weeks to week 24. Thereafter assessments will be made 12 weekly until overall disease progression is documented or death.
Secondary outcome [1] 310322 0
Proportion of patients with an overall complete or partial response in extra cranial metastases as measured using bm RECIST.
Timepoint [1] 310322 0
Patients will be evaluated every 6 weeks to week 24. Thereafter assessments will be made 12 weekly until overall disease progression is documented or death.
Secondary outcome [2] 311009 0
Proportion of patients with an overall complete or partial response as measured using bm RECIST 1.1 criteria.
Timepoint [2] 311009 0
Patients will be evaluated every 6 weeks to week 24. Thereafter assessments will be made 12 weekly until overall disease progression is documented or death.
Secondary outcome [3] 311010 0
Time from the baseline assessment to the date of intracranial
progression as measured using bm RECIST 1.1 criteria.
Timepoint [3] 311010 0
Patients will be evaluated every 6 weeks to week 24. Thereafter assessments will be made 12 weekly until overall disease progression is documented or death.
Secondary outcome [4] 311011 0
Time from the baseline assessment to the date of extracranial
progression as measured using bm RECIST 1.1 criteria.
Timepoint [4] 311011 0
Patients will be evaluated every 6 weeks to week 24. Thereafter assessments will be made 12 weekly until overall disease progression is documented or death.
Secondary outcome [5] 311012 0
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] 311012 0
Patients will be evaluated every 6 weeks to week 24. Thereafter assessments will be made 12 weekly until overall disease progression is documented or death.

A patient will be considered to have completed the study if the patient dies during the study, during the follow-up period or has been in survival follow-up for 5 years
Secondary outcome [6] 311013 0
Time from commencing study treatment to the date of death from any cause. Patient still alive will be censored at the date of the last assessment.
Timepoint [6] 311013 0
Date of commencement of study treatment, and date of death. Patients will be followed up until death.
Secondary outcome [7] 311014 0
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] 311014 0
Assessment of adverse events will be continuous during the treatment phase (every 2 weeks) and up to 100 days following discontinuation of study treatment.
Secondary outcome [8] 311015 0
The mean change from the baseline quality of life scores at the time of clinical response, stable disease and progression in each cohort. The following questionnaires will be used: EORTC QLQ-C30, EORTC QLQ BN20, and EQ-5D.
Timepoint [8] 311015 0
- At baseline
- During study treatment(s)
For at Cohort 1 and 2: at weeks 2, 6, 12, then every 6
weeks during the study treatment / For Cohort 3: at weeks
3, 6, 12, then then every 6 weeks during the study
treatment
- At partial or complete response
- At progression
Secondary outcome [9] 311016 0
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] 311016 0
Patients will be evaluated every 6 weeks to week 24. Thereafter assessments will be made 12 weekly until overall disease progression is documented or death.
Secondary outcome [10] 311017 0
To examine the 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] 311017 0
At baseline and at disease progression, and at baseline, after 2 weeks on study treatment and then every 6 weeks until progression.
Secondary outcome [11] 311018 0
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] 311018 0
At 6 weeks and 12 weeks post study treatment

Eligibility
Key inclusion criteria
Cohort 1 and 3
Inclusion criteria
1. equal or greater than 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 equal or greater than 5mm and equal or less than 40mm measurable per RECIST version 1.1 guidelines.
4. In patients with prior BRAF inhibitor treatment, intracranial disease progression must be demonstrated (RECIST greater than 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 greater than 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.

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 (greater than 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 (greater than 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 (greater than 20% increase in SOD or new measurable brain metastases).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria
1. Any melanoma brain metastasis greater than 40mm and any leptomeningeal disease, whether asymptomatic or not.
2. Ocular melanoma.
3. 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.
4. 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.
5. Current systemic treatment with corticosteroids, except prednisone at nonimmunosuppressive doses of less than or equal to 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 intra-articular steroid injections will be permitted.
6. Any investigational drug or other systemic drug therapy for melanoma within 28 days or 5 half-lives from baseline.
7. Known to be HIV positive, or a positive test for hepatitis B and C.
8. Another malignancy or concurrent malignancy unless disease-free for 3 years.
9. Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient’s safety, consent, or compliance.
10. Pregnant or breastfeeding females.
11. 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.

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)
Initially, this study will recruit patients with melanoma brain metastases who have received no prior local treatment for their intracranial metastatic disease and who are asymptomatic (Cohort 1) and in parallel, patients who have been previously treated for their brain metastases, have symptoms, or have concurrent leptomeningeal disease (Cohort 2) will be enrolled to receive nivolumab monotherapy (3mg/kg).

A third group of patients with brain metastases who have received no prior treatment for their metastatic disease and who are asymptomatic to receive combined nivolumab 1 mg/kg and ipilimumab 3mg/kg (Cohort 3) every 3 weeks for 4 doses, then continuing on nivolumab monotherapy per cohorts 1 and 2.

Recruitment to cohort 3 will commence once the first 6 patients from cohort 1 have received at least 6 doses of study treatment (equivalent to 12 weeks) and have a satisfactory adverse event record. After this safety assessment, patients will continue to be recruited to this cohort. To minimise bias, treatment allocation to cohort 3 and the remainder of cohort 1 will be assigned by unequal randomisation ratio to achieve an overall balance of 30 patients receiving nivolumab 3 mg/kg (including the 6 patients from cohort 1) and 30 patients receiving the combination treatment.

Allocation concealment for Cohort 1 and 3 will be performed through central randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Biased Coin Minimisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Cohorts 1 and 2 receive the same treatment nivolumab monotherapy (3mg/kg).

Treatment allocation to cohort 3 and the remainder of
cohort 1 will be assigned by unequal randomisation ratio to achieve an overall balance of 30 patients receiving nivolumab 3 mg/kg (including the 6 patients from cohort 1) and 30 patients receiving the combination treatment.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not 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,SA,VIC
Recruitment hospital [1] 3071 0
The Poche Centre, Melanoma Institute Australia - North Sydney
Recruitment hospital [2] 3072 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [3] 3073 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [4] 6635 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 8836 0
2060 - North Sydney
Recruitment postcode(s) [2] 8837 0
3002 - East Melbourne
Recruitment postcode(s) [3] 8838 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 14256 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 290136 0
Charities/Societies/Foundations
Name [1] 290136 0
Melanoma Institute Australia
Address [1] 290136 0
40 Rocklands Road North Sydney NSW 2060
Country [1] 290136 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Melanoma Institute Australia
Address
40 Rocklands Road North Sydney NSW 2060
Country
Australia
Secondary sponsor category [1] 288846 0
Other Collaborative groups
Name [1] 288846 0
Australia and New Zealand Melanoma Trials Group
Address [1] 288846 0
40 Rocklands Road North Sydney NSW 2060
Country [1] 288846 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291842 0
St Vincent's Human Research Ethics Committee
Ethics committee address [1] 291842 0
Level 6, de Lacy Building, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst NSW 2010
Ethics committee country [1] 291842 0
Australia
Date submitted for ethics approval [1] 291842 0
24/04/2014
Approval date [1] 291842 0
23/06/2014
Ethics approval number [1] 291842 0
HREC

Summary
Brief summary
The purpose of this research project is to test the effectiveness of a drug, called nivolumab, and the combination of nivolumab together with ipilimumab for the treatment of melanoma that has spread to the brain (known as brain metastases.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with melanoma with brain metastases.

Study details
Both drugs are approved treatments for advanced melanoma in Australia and overseas, but there is limited information on the effectiveness of the combination of these drugs in treating melanoma that has spread to the brain. This is a Phase 2 study and will look to evaluate the effectiveness of nivolumab and nivolumab combined with ipilimumab in three patient groups: groups 1 and 3 are melanoma patients with brain metastases that have had no prior localised treatments and no neurological symptoms related to brain metastases, while group 2 are melanoma patients with brain metastases who have had a prior failed local therapy or have current neurological symptoms or have leptomeningeal disease. Groups 1 and 2 will receive intravenous infusion of nivolumab 3mg/kg every 2 weeks until disease progression, unacceptable toxicity or death. Group 3 will receive nivolumab 1mg/kg combined with ipilimumab 3mg/kg every 3 weeks for 12 weeks then nivolumab monotherapy (3mg/kg every 2 weeks) thereafter.

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 markers.
Trial website
http://www.melanoma.org.au/
http://anzmtg.org/
Trial related presentations / publications
Presentations and publications will be posted in the Australia and New Zealand Melanoma Trials Group website - http://anzmtg.org/
Public notes

Contacts
Principal investigator
Name 51162 0
Prof Georgina Long
Address 51162 0
Melanoma Institute Australia The Poche Centre 40 Rocklands Road North Sydney NSW 2060 Australia
Country 51162 0
Australia
Phone 51162 0
+61 2 9911 7352
Fax 51162 0
+ 61 2 9954 9435
Email 51162 0
abcstudy@melanoma.org.au
Contact person for public queries
Name 51163 0
Miss Monica Osorio
Address 51163 0
The Poche Centre 40 Rocklands Road North Sydney NSW 2060 Australia
Country 51163 0
Australia
Phone 51163 0
+61 2 9911 7296
Fax 51163 0
+ 61 2 9954 9435
Email 51163 0
abcstudy@melanoma.org.au
Contact person for scientific queries
Name 51164 0
Miss Monica Osorio
Address 51164 0
The Poche Centre 40 Rocklands Road North Sydney NSW 2060 Australia
Country 51164 0
Australia
Phone 51164 0
+61 2 9911 7296
Fax 51164 0
+ 61 2 9954 9435
Email 51164 0
abcstudy@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
not required
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 3414 0
THE LANCET Oncology
ARTICLES| VOLUME 19, ISSUE 5, P672-681, MAY 01, 2018

Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study

Prof Georgina V Long, PhD
Victoria Atkinson, MBBS
Serigne Lo, PhD
Shahneen Sandhu, MBBS
Alexander D Guminski, PhD
Prof Michael P Brown, PhD
et al.
March 27, 2018
Attachments [1] 3414 0
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary