changes in available treatments for melanoma

This research study is a Phase II clinical trial of an investigational combination of drugs (vemurafenib and aldesleukin) to learn whether the combination works in treating a specific cancer. While both vemurafenib and aldesleukin are approved by the FDA for the treatment of metastatic melanoma, the FDA has not yet approved the combination of vemurafenib and aldesleukin.

Researchers have found that a large number of melanoma cells have mutations in the BRAF gene. It has been shown that vemurafenib blocks the effects of these mutations in the BRAF gene, and, as a result, may help to prevent cancer growth.

Aldesleukin, also referred to as IL-2, is an immunotherapy drug administered via IV infusion that increases the growth of key cells within the immune system that are responsible for targeting cancer cells. Activating more of these key cells, called T-lymphocytes and natural-killer cells, leads to increased cancer cell death.

The BRAF gene is located on a larger pathway called the MAPK pathway. Studies have shown that when a BRAF inhibitor, like vemurafenib is used to block the MAPK pathway, melanocytes, or cancer cells express more proteins on their surfaces, making them easier for T-lymphocytes and natural killer cells to recognize and kill them. This suggests that combining BRAF-targeted therapy with aldesleukin, which activates more of these white blood cells, can lead to an increase in the death of cancer cells.

In this research study, the investigators are looking to see whether the combination of vemurafenib (a BRAF-inhibitor) combined with aldesleukin(an immunotherapy drug) work together to produce a better health outcome in people with metastatic melanoma.

Subjects will take oral vemurafenib twice a day for 2 weeks. Following this lead-in period, subjects will receive aldesleukin via IV infusion on Day 15 of the study. One course of aldesleukin is 12 weeks long; subjects will receive aldesleukin via IV infusion every 8 hours for the first five days. Subjects will be hospitalized for the 5 days that they are receiving aldesleukin.

Week 1 of aldesleukin will be days 15-19 (M-F) of the 12 week cycle. Following Week 1 of therapy, subjects will be discharged from the hospital and only take vemurafenib at home for the following week. Subjects will then come in for one more week of aldesleukin during days 29-33 of the 12 week cycle. This is referred to as Week 2 of aldesleukin.

Subjects will continue to take vemurafenib twice daily during the course of aldesleukin. Their cancer will be evaluated at screening and at Week 12 following the beginning of the first aldesleukin course with a CT scan. After the first cycle, tumors will be evaluated every 8 weeks for the first year, then every 12 weeks for years 2 and 3, every 6 months for year 5, and annually thereafter.

If scans show that the subject's cancer has improved after the first course of aldesleukin, subjects may be allowed to continue on to a second course. In the event of a second course of aldesleukin, subjects will remain on vemurafenib throughout the second course.

Inclusion Criteria:

• Histologically confirmed metastatic or unresectable melanoma with V600E mutation
• Measurable disease
• May have received prior immunotherapy (excluding interleukin 2)
• Life expectancy greater than 3 months
• Recovered from effects of previous surgery and/or traumatic injury
• Must agree to use effective contraception

Exclusion Criteria:

• Pregnant or breastfeeding
• Psychological, familial or other conditions that could hamper compliance with protocol
• Receiving other study agents
• History of carcinomatous meningitis
• Known active brain metastases
• Have received a BRAF inhibitor
• Uncontrolled intercurrent illness
• HIV positive on antiretroviral therapy
• History of a different malignancy within past 5 years (except cervical cancer in situ or basal/squamous cell carcinoma of the skin)
• Active hepatitis B or C
• Have received allogenic bone marrow transplant or organ transplant

All raw analytic data on tumor and blood samples will be shared, upon acceptance of manuscript.

9 months

All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.

The protocol terminated early due to a dramatic change in the treatment landscape for treating BRAF mutant melanoma (e.g. one BRAF/MEK inhibitor combination and two anti-PD1 antibodies were approved by the FDA while this study was open).