Anti-PD 1 Brain Collaboration + Radiotherapy Extension: The ABC-X Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Melanoma Institute Australia

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-12-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bristol-Myers Squibb Research and Development Pty Ltd, Australia · Melanoma Institute Australia, Australia

External identifiers

EU CT number

2024-518545-13-00

EudraCT number

2020-005647-24

ClinicalTrials.gov

NCT03340129

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Neurological-specific death rate at 1 year

Secondary objectives 14

1. Intracranial response rate
2. Extracranial response rate
3. Overall response rate
4. Overall progression-free survival
5. Non-neurological death at 1 year
6. Overall survival
7. Incidence of radionecrosis up to 5 years from start of any intracranial radiotherapy
8. Incidence of salvage radiotherapy for intracranial disease in both cohorts
9. Incidence of salvage surgery for intracranial in both cohorts
10. Neurocognitive function – researcher-rated (MoCA) and patient-rated (FACT-cog)
11. Patient-rated quality of life (QLQ C30, QLQ-BN20, EQ-5D and FACT-Br)
12. Functional performance status (ECOG)
13. Overall safety and tolerability of study treatments (CTCAE version 5.0)
14. Tissue, blood, stool and urine biomarkers of response to systemic and local treatment, disease progression and treatment toxicity

Conditions and MedDRA coding

melanoma brain metastases

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. ≥18 years of age
2. Written informed consent
3. AJCC Stage IV (any T, any N, M1d) histologically confirmed cutaneous, acral or mucosal melanoma, or unknown primary melanoma, with metastases to the brain that are considered unresectable. Patients must have a minimum of one radiological definitive brain metastasis that is ≥ 5mm and ≤40mm, measurable per bm RECIST guidelines. There is no upper limit restriction to the number of brain metastases
4. Known BRAF mutation status prior to randomisation
5. The treating clinician(s) should consider all intracranial lesions (target and non-target) amenable to stereotactic radiotherapy over whole brain radiotherapy. This includes brain metastases ≤5mm diameter
6. No prior radiotherapy for brain metastases (previous surgery for melanoma brain metastases is permitted). Prior radiotherapy for extracranial disease is permitted
7. No prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting and for the treatment of extracranial disease only. Radiological confirmation of the absence of brain metastases throughout prior systemic treatment should be documented. The presenting diagnosis of brain metastases must have occurred ≥ 6 months after stopping 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 active neurological symptoms. Resolved neurological symptoms are permitted if complete resolution has been sustained for a minimum of 7 days prior to randomisation. Antiepileptics are permitted regardless of the indication, provided the patient is asymptomatic at the time of randomisation
9. ECOG performance status of 0-2
10. Life expectancy of > 30 days
11. Able to undergo MRI with Gadolinium contrast agent
12. Adequate haematological, hepatic and renal organ function
13. Women of childbearing potential with a negative pregnancy test, effective contraception
14. Men with female partner of childbearing potential use effective contraception and refrain from donating sperm during the study and for 31 weeks from end of treatment

Exclusion criteria 16

1. Patients whose intracranial disease changes between the eligibility MRI scan and the SRS planning MRI rendering the patient unsuitable for randomised treatment on trial, or requires a specific alternative treatment
2. Any melanoma brain metastasis >40mm
3. Evidence of leptomeningeal disease, with the exception of pathological findings seen at previous resection of brain disease, but no evidence of leptomeningeal disease elsewhere at the time of resection or at study entry
4. Ocular (both uveal and conjunctival) melanoma (mucosal and acral melanoma are eligible)
5. Current neurological symptoms from brain metastases or a requirement for corticosteroids, analgesia or other treatment for the management of symptoms
6. Prior radiotherapy to the brain (prior surgery for melanoma brain metastases permitted)
7. Prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting, prior to the development of any brain metastases and completed ≥ 6 months before enrolment in this study
8. Patients with significant active, known or suspected autoimmune disease requiring past or current immunosuppression
9. Current systemic treatment with corticosteroids, or within 7 days of randomisation, except prednisone at non-immunosuppressive doses of ≤ 10 mg/day (or equivalent)
10. Active infection requiring therapy
11. History of interstitial lung disease
12. Any concurrent malignancy (excluding successful resection or curative treatment of in situ disease, superficial bladder cancer or non-melanoma skin cancer) requiring any treatment or a history of another malignancy, unless the patient has been disease-free for 1 year
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 trial. Other vaccine use is cautionary within 30 days of starting trial and during treatment phase of trial
16. Hypersensitivity to study treatment or to any of the excipients listed in the corresponding Investigator's Brochure

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The incidence of neurological-specific death in the whole patient population at 1 year, from start of nivolumab and ipilimumab, where the immediate cause of death is due to brain metastases

Secondary endpoints 17

1. 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 12 onwards and confirmed a minimum of 4 weeks later
2. 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 and confirmed a minimum of 4 weeks later
3. 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 and confirmed a minimum of 4 weeks later
4. a. Time from the start of nivolumab and ipilimumab to the date of any progression of disease as measured using bm RECIST with confirmation of response a minimum of 4 weeks later. b. Patients dying from causes other than melanoma or treatment related toxicity will be censored at the date of death. c. Patients alive without progression will be censored at the date of their last assessment. d. A diagnosis of a second primary melanoma is not considered a progression event.
5. The incidence of non-neurological death in the whole patient population at 1 year from the start of nivolumab and ipilimumab where the immediate cause of death is due to melanoma but from causes other than brain metastases
6. a. Time from the start of nivolumab and ipilimumab to the date of death from any cause. b. Patients still alive at the end of the study will be censored at the date of their last assessment.
7. a. The incidence of radionecrosis, diagnosed by imaging and / or histopathology assessment, occurring within 5 years from the start of the first course of radiotherapy in either treatment arm (i.e. the start of concurrent SRS with immunotherapy and / or the start of any form of salvage radiotherapy). b. The number of repeat radionecrosis events per patient.
8. Incidence of salvage radiotherapy to intracranial brain metastases in each cohort
9. Incidence of craniotomy for intracranial brain metastases in each cohort
10. a. The mean change from baseline assessment [CTCAE neurocognitive adverse events, Montreal Cognitive Assessment [MoCA] and FACT-cog) to the time of best response and progression of disease. b. The duration of each neurocognitive deficit. c. Proportion of patients in each Cohort recording decreased neurocognitive function. d. The proportion of patients requiring an intervention to treat neurocognitive dysfunction.
11. e. The correlation of neurocognitive function with neurological-specific death and overall survival. f. The correlation of patient-perceived cognitive impairment and researcher-rated neurocognitive function.
12. a. The mean change from baseline quality of life scores [ED 5Q, QLQ-C30 + BN20, FACT-Br] to the time of response, stable disease or progression. b. Time from the start of nivolumab and ipilimumab to the time of deterioration of quality life scores and the duration of deterioration.
13. The incidence of reduced functional performance by 1, 2 or 3 grades of the Eastern Cooperative Oncology Group (ECOG) performance status scale compared to baseline following at least ONE dose of nivolumab and ipilimumab
14. a. Number of adverse events by type, frequency, duration, relatedness to any treatment, relatedness to disease progression and severity of the event using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5) b. Number of patients who discontinue any study treatment due to intolerable or serious adverse events. c. Number and nature of serious adverse events and events of clinical interest using CTCAE criteria.
15. a. Correlation of the PD-L1 status, immune markers, genomics and other biomarkers of response and resistance in tumour tissue (extracranial and intracranial sites if possible, available and applicable) at baseline and at subsequent disease progression.
16. b. Correlation of lymphocyte, T cell subsets, myeloid derived suppressor cells, genomic and other biomarkers in blood at baseline, at the commencement of radiotherapy (and conclusion of radiotherapy if fractionated), at complete or partial response and at subsequent disease progression. c. Investigation of histological features and biomarkers in brain tissue, if removed at biopsy or surgery.
17. d. Investigation of the gut microbiome composition, diversity and abundance and correlation with baseline self-reported dietary habits, the response to immunotherapy and immune-related gastrointestinal toxicity. e. Correlation of gastrointestinal mucosal integrity with bacterial composition in stool samples, RECIST response and immune related adverse events.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Melanoma Institute Australia

Sponsor organisation

Melanoma Institute Australia

Address

40 Rocklands Road

City

Wollstonecraft

Postcode

2065

Country

Australia

Scientific contact point

Organisation

Melanoma Institute Australia

Contact name

Maria Gonzalez

Public contact point

Organisation

Melanoma Institute Australia

Contact name

General enquiries

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications