COVID-19 studies are our top priority. For all other trials, there is a 4-week delay in processing a trial submitted to the ANZCTR and additional delays for updates of registered trials. We appreciate your patience.

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/NCT03340129




Registration number
NCT03340129
Ethics application status
Date submitted
28/08/2017
Date registered
13/11/2017
Date last updated
14/09/2020

Titles & IDs
Public title
Anti-PD 1 Brain Collaboration + Radiotherapy Extension (ABC-X Study)
Scientific title
A Phase II, Open Label, Randomised, Controlled Trial of Ipilimumab and Nivolumab With Concurrent Intracranial Stereotactic Radiotherapy Versus Ipilimumab and Nivolumab Alone in Patients With Melanoma Brain Metastases.
Secondary ID [1] 0 0
MIA2019/CT/258
Universal Trial Number (UTN)
Trial acronym
ABC-X
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma Stage Iv 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 - Ipilimumab
Treatment: Drugs - Nivolumab
Treatment: Other - Stereotactic Radiotherapy
Other interventions - Salvage therapy

Active Comparator: Nivolumab + ipilimumab - Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks.
Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression.

Active Comparator: Nivolumab + ipilimumab,concurrent SRS - Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks.
Stereotactic radiotherapy 16 to 22 Gy in 1 fraction or 24 to 30 Gy, hypofractionated for larger lesions. Stereotactic radiotherapy to commence within 7 days of of the baseline / planning MRI brain. Hypofractionated stereotactic radiotherapy should be completed within 14 day of the first fraction.
Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression.


Treatment: Drugs: Ipilimumab
Ipilimumab 3mg per kg every 3 weeks for 4 doses

Treatment: Drugs: Nivolumab
Nivolumab 1mg/kg every 3 weeks for 4 doses, then 480mg every 4 weeks.

Treatment: Other: Stereotactic Radiotherapy
The first dose of immunotherapy Must be given prior to the start of radiotherapy. One fraction at between 16 to 22 Gy or 24 to 30 Gy hypofractionated for larger lesions.

Other interventions: Salvage therapy
Any form of salvage therapy (surgery or radiotherapy) for intracranial disease progression, further disease control at any site, symptom control or treatment of cerebral haemorrhage or cerebral radionecrosis.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Intervention code [3] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Neurological specific cause of death - Proportion of patients dead at one year from randomisation and whose immediate cause of death is neurological.
Timepoint [1] 0 0
One year
Secondary outcome [1] 0 0
Intracranial response rate - The best response in intracranial metastases as measured using brain modified (bm) RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 6 onwards and confirmed a minimum of 4 weeks later.
Timepoint [1] 0 0
Approximately 3 years
Secondary outcome [2] 0 0
Extracranial response rate - The best response in extracranial disease for each patient measured using bm RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards.
Timepoint [2] 0 0
Approximately 5 years
Secondary outcome [3] 0 0
Overall response rate - Proportion of patients with an overall complete or partial response as measured using bm RECIST following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards .
Timepoint [3] 0 0
Approximately 5 years
Secondary outcome [4] 0 0
Overall progression free survival - Time from the start of study treatment to the date of any progression of disease as measured using bm RECIST and based on imaging from week 12 onwards.
Timepoint [4] 0 0
1, 2 and 5 years
Secondary outcome [5] 0 0
Non-Neurological specific cause of death - Proportion of patients dead at one year from randomisation and whose immediate cause of death was due to melanoma but from causes other than brain metastases.
Timepoint [5] 0 0
1 years
Secondary outcome [6] 0 0
Overall survival - Time from commencing study treatment to the date of death from any cause. Patients still alive at the end of the study will be censored at the date of their last assessment.
Timepoint [6] 0 0
1, 2 and 5 years.
Secondary outcome [7] 0 0
Incidence of radionecrosis - Proportion of patients with a diagnosis of radionecrosis occuring within 5 years of the start of the first course of radiotherapy.
Timepoint [7] 0 0
5 years
Secondary outcome [8] 0 0
Requirement for salvage radiotherapy - Proportion of patients requiring salvage radiotherapy in each cohort
Timepoint [8] 0 0
1 year
Secondary outcome [9] 0 0
Requirement for salvage intracranial surgery - Proportion of patients requiring salvage craniotomy in each cohort
Timepoint [9] 0 0
1 year
Secondary outcome [10] 0 0
Change in neurocognitive function scores - The mean change from baseline assessment of neurocognitive function to the time of clinical response, stable disease and progression of disease.
Timepoint [10] 0 0
Approximately 5 years
Secondary outcome [11] 0 0
Description of impaired neurological function and neurological adverse events - Description of the nature of impaired function and types of neurological adverse events.
Timepoint [11] 0 0
Approximately 5 years
Secondary outcome [12] 0 0
Time to neurological deterioration - The time from starting immunotherapy to the time of deterioration of MoCA, CTCAE and FACT-Br.
Timepoint [12] 0 0
Approximately 5 years
Secondary outcome [13] 0 0
Duration of neurological deterioration - The time to resolution (if any) of each functional neurocognitive deficit.
Timepoint [13] 0 0
Approximately 5 years
Secondary outcome [14] 0 0
Patient rated quality of life - Time from starting study treatment to the time of deterioration in quality life scores and the duration of deterioration.
Timepoint [14] 0 0
Approximately 5 years
Secondary outcome [15] 0 0
Functional performance status - Incidence of reduced functional performance by 1, 2 or 3 grades of the Eastern Cooperative Oncology Group (ECOG) performance status scale compared to baseline.
Timepoint [15] 0 0
Approximately 5 years
Secondary outcome [16] 0 0
Adverse events - Description of all adverse events per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Timepoint [16] 0 0
Approximately 5 years
Secondary outcome [17] 0 0
Tissue, blood and gut biomarkers of response, progression and toxicity - Correlation of the baseline PD-L1 status, immune markers, genomics and other biomarkers in tumour tissue and blood and the composition and diversity of the gut microbiome with RECIST response and toxicity. Correlation of gastrointestinal mucosal integrity with bacterial composition in stool samples, RECIST response and immune related adverse events.
Timepoint [17] 0 0
Approximately 5 years

Eligibility
Key inclusion criteria
1. Female or male patients, =18 years of age.

2. Signed, written, informed consent.

3. AJCC Stage IV [any T, any N, M1d (0) or M1D(1)] histologically confirmed cutaneous,
acral or mucosal unresectable melanoma or unknown primary melanoma and at least 1
radiological definitive brain metastasis that is = 5mm and =40mm, measurable per
RECIST version 1.1 guidelines (modified for brain metastases, enabling up to 5 target
lesions in the brain as well as up to 5 extracranial target lesions). There is no
upper limit restriction in the number of brain metastases, provided the remaining
eligibility criteria are met.

4. The BRAF mutation status must be available prior to randomisation.

5. The treating clinician(s) should consider the intracranial disease amenable to
stereotactic radiotherapy over whole brain radiotherapy. Patients for whom there is a
definite and immediate indication for radiotherapy (e.g. rapidly progressing disease
with associated clinical signs and /or symptoms) should not be considered for
enrolment.

6. Brain metastases must be untreated with any modality of radiotherapy or systemic
treatment. Previous surgery for melanoma brain metastases is permitted if it resulted
in gross total resection and no radiotherapeutic cavity boost was required.

7. No prior systemic treatment for brain metastases is permitted unless given in the
neoadjuvant or adjuvant settings for systemic drug the treatment for extracranial
disease only. At the time of neoadjuvant or adjuvant systemic therapy for extracranial
disease, there should be radiological evidence of the absence of brain metastases. The
presenting diagnosis of brain metastases at the time of enrolment in this study must
have occurred a minimum of 6 months after stopping neoadjuvant or adjuvant systemic
therapy (prior anti PD1, anti PD-L1, anti CTLA-4, BRAF / MEK inhibitors or clinical
trial agents) are acceptable in the setting of neoadjuvant or adjuvant treatment

8. Asymptomatic from brain metastases at the time of study enrolment without
corticosteroids, analgesia or any other treatment for the management of neurological
symptoms (with the exception of antiepileptics prescribed for any reason, provided
patient is asymptomatic). Resolved neurological symptoms are permitted if complete
resolution, without any intervention, has been sustained for a minimum of 7 days prior
to randomisation.

9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

10. A life expectancy > 30 days.

11. Able to undergo MRI with Gadolinium contrast agent. CT of the brain is not an
acceptable alternative should patients be unable to safely undergo a contrast MRI.

12. Adequate haematological, hepatic and renal organ function as defined by:

1. White cell count = 2.0 × 10x9/L

2. Neutrophil count = 1.5 × 10x9/L

3. Haemoglobin = 90 g/L

4. Platelet count = 100 x 10x9/L

5. Total bilirubin = 1.5 x ULN

6. Alanine transaminase = 3.0 x ULN

7. Aspartate aminotransferase = 3.0 x ULN

8. Serum creatinine = 1.5 x the upper limit of normal (ULN). If serum creatinine is
> 1.5 x ULN, calculate creatinine clearance using standard Cockcroft-Gault
formula. Creatinine clearance must be 40ml/min to be eligible.

13. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 7 days of the first dose of study treatment and agree to use effective
contraception from 14 days prior to commencing study treatment, throughout the
treatment period and for 23 weeks * after the last dose of study treatment. Effective
contraception includes:

1. Intrauterine device with a documented failure rate of less than 1% per year.

2. 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.

3. Combined (oestrogen and progestogen) hormonal contraception associated with
inhibition of ovulation or progestogen only hormonal contraception associated
with inhibition of ovulation.

Women who are not of childbearing potential are defined as any female who has had a
documented hysterectomy, bilateral oophorectomy or bilateral tubal ligation or any
female who is post-menopausal (= one year without menses and >50 years of age in the
absence of hormone replacement therapy).

14. Men with any female partner of childbearing potential must agree to use effective
contraception from 14 days prior to commencing study treatment, throughout the
treatment period and for 31 weeks* after the last dose of study treatment. Effective
contraception includes:

1. Documented vasectomy and sterility

2. In the partner - intrauterine device with a documented failure rate of less than
1% per year

3. In the female partner - Combined (oestrogen and progestogen) hormonal
contraception associated with inhibition of ovulation or progestogen only
hormonal contraception associated with inhibition of ovulation.

- These durations have been calculated using the upper limit of the half-life
for nivolumab (25 days) and are based on the protocol requirement that WOCBP
use contraception for 5 half-lives plus 30 days and men who are sexually
active with WOCBP use contraception for 5 half-lives plus 90 days.
Minimum age
18 Years
Maximum age
120 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

1. Patients whose intracranial disease changes between the diagnostic MRI scan and the
baseline / SRS planning MRI scan and who are no longer suitable for SRS and / or
require a specific alternative treatment outside of this protocol.

2. Melanoma brain metastasis greater than 40mm.

3. Evidence of leptomeningeal disease, with the exception of pathological findings seen
at a previous resection of brain disease, but with no evidence of leptomeningeal
disease elsewhere at the time of resection or at study entry.

4. History of, or current ocular melanoma (patients with mucosal and acral melanoma are
eligible).

5. Neurological symptoms from brain metastases present at baseline (resolved neurological
symptoms, prior to enrolment, are permitted).

6. Prior radiotherapy to the brain (surgery permitted).

7. Prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant
setting and completed 6 months before enrolment in this study.

8. Patients with active, known or suspected autoimmune disease. Patients with the
following are permitted to enrol:

1. Vitiligo

2. Type I diabetes mellitus

3. Residual hypothyroidism due to an autoimmune condition only requiring hormone
replacement

4. Psoriasis not requiring systemic treatment

5. Autoimmune conditions not expected to recur in the absence of an external
trigger.

9. Current systemic treatment with corticosteroids, or within 7 days of randomisation,
with the exception of prednisone at non-immunosuppressive doses of = 10 mg/day (or
equivalent, e.g. e.g. prednisone 10mg = dexamethasone 1.6mg = hydrocortisone 40mg).
Patients with the following circumstances are permitted to enrol:

1. Past treatment for non-neurological symptoms allowed, if this was ceased 7 days
prior to randomisation

2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be
continued if the patient is on a stable dose

3. Non-absorbed intra-articular steroid injections.

During the study, treatment with systemic corticosteroids is permitted during
radiotherapy if the patient experiences radiation related symptoms but this should be
tapered per standard clinical practice as soon as possible and before the next
infusion of study drug is due. This also refers to steroids for drug related signs or
symptoms.

10. Any active infection requiring treatment.

11. A history of interstitial lung disease.

12. Any concurrent malignancy requiring any treatment or a history of another malignancy,
unless the patient has been disease-free for 3 years.

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

14. Pregnant or breastfeeding females.

15. Administration of any form of live vaccine within 30 days of starting the trial and
during the trial. Administration of any other vaccine is cautionary within 30 days of
starting the trial and for the duration of the treatment phase of 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)
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
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,VIC
Recruitment hospital [1] 0 0
Westmead Hospital - Sydney
Recruitment hospital [2] 0 0
Calvary Mater NewcastleHospital - Waratah
Recruitment hospital [3] 0 0
Melanoma Institute Australia - Wollstonecraft
Recruitment hospital [4] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [5] 0 0
Peter MacCallum Cancer Centre - East Melbourne
Recruitment hospital [6] 0 0
Alfred Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
2145 - Sydney
Recruitment postcode(s) [2] 0 0
2298 - Waratah
Recruitment postcode(s) [3] 0 0
2065 - Wollstonecraft
Recruitment postcode(s) [4] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [5] 0 0
3002 - East Melbourne
Recruitment postcode(s) [6] 0 0
3004 - Melbourne

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

Ethics approval
Ethics application status

Summary
Brief summary
This is a phase II, open label, randomised trial of ipilimumab and nivolumab with concurrent
intracranial stereotactic radiotherapy versus ipilimumab and nivolumab alone in patients with
asymptomatic, untreated melanoma brain metastases.
Trial website
https://clinicaltrials.gov/show/NCT03340129
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Georgina V Long, MBBS PhD
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
Georgina V Long, MBBS PhD
Address 0 0
Country 0 0
Phone 0 0
+61 2 9911 7200
Fax 0 0
Email 0 0
info@melanoma.org.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03340129