STUDY DESIGN
* Screening
\- Assessment of the subject's eligibility to participate as determined by the inclusion/exclusion criteria.
* Biopsy schedule
\- Subjects will be biopsied according to the schedule in Section 7.
* Induction
* The recommended induction dose of ipilimumab is 3 mg/kg administered intravenously over a 90-minute period every 3 weeks for a total of four doses, as tolerated.
* Laboratory evaluations should be performed and the results examined before administration of each ipilimumab dose.
* As durable disease stabilization and/or objective tumor response can be seen after early progression before Week 12, it is recommended that, in the absence of dose-limiting toxicities (eg, serious immune-mediated adverse reactions), all four doses of ipilimumab be administered over the initial 12 weeks even in the setting of apparent clinical progression, providing the subject's performance status remains stable.
* All subjects who enter the induction period, including those who may have discontinued treatment for drug-related AEs and/or who have evidence of clinical progression during the induction period, should obtain a 12-week tumor assessment.
* Based on clinical experience in the ongoing and completed melanoma studies, the following recommendations apply for subject management in light of the Week 12 or later tumor assessments:
* The appearance of new lesions in subjects with other stable or shrinking baseline tumor burden may be experiencing clinical benefit and should continue in follow-up and/or maintenance therapy before alternative anti-cancer agents are considered. These subjects can be seen to have continued tumor shrinkage in follow-up scans.
* As long as overall tumor burden is stable or decreasing, subjects should remain in follow-up and/or maintenance (see below), even in the presence of new lesions.
* Clinical progression warranting alternative anti-cancer treatment should be considered only in subjects whose overall tumor burden appears to be substantially increased and/or in subjects whose performance status is decreased.
* Patients are eligible for retreatment treatments with ipilimumab on this protocol
* Follow-up
\- Subjects will be required to attend a follow-up visit within 90 days of the last ipilimumab treatment.
* Re-treatment
Patients who received ipilimumab at any dose in a prior/parent study and have met each of the following criteria:
* Had no unacceptable toxicity requiring ipilimumab discontinuation; OR
* Patients who permanently discontinued treatment due to select irAEs as follows:
1. Reversible autoimmune hepatitis
2. Medically manageable endocrinopathy
3. Reversible dermatological toxicity AND
* Have experienced documented disease progression after demonstrating expanded clinical benefit.
Expanded clinical benefit is defined as:
* Patients whose disease is responding (partial response, complete response); or
* Patients whose disease was stable more than or equal to 3 months.
* Patients who demonstrated mixed or delayed response.
The mixed or delayed response is defined as follows:
Patients with Mixed Response: defined as at least 50% reduction in the bidimensional size of one or more non-cystic lesions, even in the presence of any new lesions.
Patients with Delayed Response: defined as objective response (PR or CR) following progressive disease, occurring any time after Week 12 in the prior/parent protocol, in patients who have not received therapy with a non ipilimumab anti-cancer agent (approved or experimental) between the PD and objective response.
Patients with select irAEs related to ipilimumab that have completely resolved with immunosuppressive therapy or are adequately controlled with hormone therapy, may be considered for further re-treatment with ipilimumab under this study, at the time of disease progression. The list of completely reversible or medically managed immune-related adverse events (irAEs) eligible for consideration are:
* Reversible autoimmune hepatitis
* Medically managed endocrinopathy
* Reversible dermatological toxicity All other irAEs are not considered eligible for re-treatment, including, but not limited to, greater or equal Grade 3 colitis or diarrhea, or uveitis of any grade.
