A phase II study of nivolumab and nivolumab combined with ipilimumab in patients with melanoma brain metastases (ABC - Anti-PD1 Brain Collaboration Study)

INTERVENTION: Cohorts 1 and 2: Nivolumab 3mg/kg intravenous infusion every 2 weeks, repeated until either of: disease progression, withdrawn consent, unacceptable toxicity or death.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. CONDITION: Melanoma Melanoma Brain Metastases PRIMARY OUTCOME: 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). SECONDARY OUTCOME: 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). 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. 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. Proportion of patients with an overall complete or partial response as measured using bm RECIST 1.1 criteria. Proportion of patients with an overall complete or partial response in extra cranial metastases as measured using bm RECIST. 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. 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. Time from the baseline assessment to the date of extracranial ; progression as measured using bm RECIST 1.1 criteria. Time from the baseline assessment to the date of intracranial ; progression as measured using bm RECIST 1.1 criteria. 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. 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. INCLUSION CRITERIA: Cohort 1 and 3 Inclusion criteria 1. equal or greater than 18 years of age. 2. Written informed consent 5. No prior localised treatment for brain metastases (eg. surgery or radiotherapy). 6. Neurologically asymptomatic from brain metastases. 7. Eastern Cooperative Oncology Grou 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).