Anti-PD 1 Brain Collaboration + Radiotherapy Extension (ABC-X Study)

NCT03340129 | Recruiting Phase 2 DMC

• 2 other identifiers: MIA2019/CT/258 and CA209-8TJCA209-8TJ
• Study Type: interventional
• Target: 218
• Locations: 2 countries
• Sites: 9

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.

Conditions

Melanoma Stage Iv

Keywords

Immunotherapy; Radiotherapy; Brain metastases; Stereotactic radiotherapy; Stereotactic radiosurgery; Cognitive function; Neurological-specific cause of death

Outcome Measures

Primary Outcomes (1)

• Neurological specific cause of death

  Proportion of patients dead at one year from randomisation and whose immediate cause of death is neurological.

  One year

Secondary Outcomes (17)

• Intracranial response rate

  Up to 10 years

• Extracranial response rate

  Approximately 10 years

• Overall response rate

  Up to 10 years

• Overall progression free survival

  1, 2, 5 and 10 years

• Non-Neurological specific cause of death

  Up to 10 years

Study Arms (2)

Nivolumab + ipilimumab

ACTIVE COMPARATOR

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.

Drug: Ipilimumab; Drug: Nivolumab; Other: Salvage therapy

Nivolumab + ipilimumab,concurrent SRS

ACTIVE COMPARATOR

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.

Drug: Ipilimumab; Drug: Nivolumab; Radiation: Stereotactic Radiotherapy; Other: Salvage therapy

Interventions

Stereotactic Radiotherapy RADIATION

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.

Nivolumab + ipilimumab,concurrent SRS

Salvage therapy OTHER

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.

Nivolumab + ipilimumab; Nivolumab + ipilimumab,concurrent SRS

Nivolumab DRUG

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

Also known as: Opdivo

Nivolumab + ipilimumab; Nivolumab + ipilimumab,concurrent SRS

Ipilimumab DRUG

Ipilimumab 3mg per kg every 3 weeks for 4 doses

Also known as: Yervoy

Nivolumab + ipilimumab; Nivolumab + ipilimumab,concurrent SRS

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female or male patients, ≥18 years of age.
• Signed, written, informed consent.
• 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.
• The BRAF mutation status must be available prior to randomisation.
• 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.
• 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.
• 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
• 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.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
• A life expectancy \> 30 days.
• 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.
• Adequate haematological, hepatic and renal organ function as defined by:
• White cell count ≥ 2.0 × 10x9/L
• Neutrophil count ≥ 1.5 × 10x9/L
• Haemoglobin ≥ 90 g/L

You may not qualify if:

• 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.
• Melanoma brain metastasis greater than 40mm.
• 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.
• History of, or current ocular melanoma (patients with mucosal and acral melanoma are eligible).
• Neurological symptoms from brain metastases present at baseline (resolved neurological symptoms, prior to enrolment, are permitted).
• Prior radiotherapy to the brain (surgery permitted).
• Prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting and completed 6 months before enrolment in this study.
• Patients with active, known or suspected autoimmune disease. Patients with the following are permitted to enrol:
• Vitiligo
• Type I diabetes mellitus
• Residual hypothyroidism due to an autoimmune condition only requiring hormone replacement
• Psoriasis not requiring systemic treatment
• Autoimmune conditions not expected to recur in the absence of an external trigger.
• 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:
• Past treatment for non-neurological symptoms allowed, if this was ceased 7 days prior to randomisation

Sponsors & Collaborators

• Melanoma Institute Australia: lead
• Bristol-Myers Squibb: collaborator

Study Sites (9)

Westmead Hospital

Sydney, New South Wales, 2145, Australia

RECRUITING

Calvary Mater NewcastleHospital

Waratah, New South Wales, 2298, Australia

RECRUITING

Melanoma Institute Australia

Wollstonecraft, New South Wales, 2065, Australia

RECRUITING

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

RECRUITING

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

RECRUITING

Peter MacCallum Cancer Centre

East Melbourne, Victoria, 3002, Australia

RECRUITING

Alfred Hospital

Melbourne, Victoria, 3004, Australia

RECRUITING

Sir Charles Gairdner Hosptial

Perth, Western Australia, 6009, Australia

RECRUITING

Oslo Univesity Hospital Radiumhospitalet

Oslo, Oslo County, 0379, Norway

TERMINATED

Related Publications (1)

• Phillips WJ, Baghai T, Ong M, Lo B, Ibrahim AM, Smith TKT, Song X. A Contemporary Report of Clinical Outcomes in Patients with Melanoma Brain Metastases. Curr Oncol. 2021 Jan 13;28(1):428-439. doi: 10.3390/curroncol28010045.

  PMID: 33450821 DERIVED

Related Links

• Trial Information

MeSH Terms

Conditions

Melanoma; Brain Neoplasms

Interventions

Ipilimumab; Nivolumab; Radiosurgery; Salvage Therapy

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Georgina V Long, MBBS PhD

  Melanoma Institute Australia

  STUDY CHAIR

Central Study Contacts

Georgina V Long, MBBS PhD

CONTACT

+61 2 9911 7200; info@melanoma.org.au

Maria Gonzalez, RN MHSc

CONTACT

+61 2 9911 7200; maria.gonzalez@melanoma.org.au

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open label, randomised trial.

Study Record Dates

• First Submitted: August 28, 2017
• First Posted: November 13, 2017
• Study Start: August 14, 2019
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2029
• Last Updated: February 2, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

AU (8); NO (1)