ActivePhase 2ACTRN12614001315606

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

A phase II study assessing the intracranial response to nivolumab and nivolumab combined with ipilimumab in patients with melanoma brain metastases

Sponsor

Melanoma Institute Australia

Enrollment

75 participants

Start Date

Oct 23, 2014

Study Type

Interventional

Conditions

Melanoma Melanoma Brain Metastases

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.

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria20

Cohort 1 and 3
equal or greater than 18 years of age.
Written informed consent
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.
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).
No prior localised treatment for brain metastases (eg. surgery or radiotherapy).
Neurologically asymptomatic from brain metastases.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2, and life expectancy greater than 30 days.
Able to undergo MRI with Gadolinium contrast agent.
Adequate haematological, hepatic and renal organ function.
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.
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:
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;
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;
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).

Exclusion Criteria12

Any melanoma brain metastasis greater than 40mm and any leptomeningeal disease, whether asymptomatic or not.
Ocular melanoma.
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.
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.
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.
Any investigational drug or other systemic drug therapy for melanoma within 28 days or 5 half-lives from baseline.
Known to be HIV positive, or a positive test for hepatitis B and C.
Another malignancy or concurrent malignancy unless disease-free for 3 years.
Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient’s safety, consent, or compliance.
Pregnant or breastfeeding females.
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.

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Interventions

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.