Background:

Adoptive T cell therapy with tumor infiltrating lymphocytes (TILs) has been reported to induce durable clinical responses in patients with metastatic melanoma. From patients own tumor material T cells are extracted, expanded and activated in vitro in a 4-6 weeks culture period. Before TIL infusion patients are preconditioned with a lymphodepleting chemotherapeutic regimen. After TIL infusion, patients are treated with IL-2 to support T cell activation and expansion in vivo.

The BRAF inhibitor is an approved treatment of metastatic melanoma and functions by selectively inhibiting the BRAF mutated enzyme, consequently halting the proliferation of tumor cells. Furthermore, in vitro tests have shown that vemurafenib has immunomodulatory effects that are hypothesized to synergize with TIL therapy, which has been confirmed in animal studies.

Objectives:

• To evaluate safety and feasibility when combining vemurafenib and ACT with TILs.
• To evaluate treatment related immune responses
• To evaluate clinical efficacy

Design:

• Patients will be screened with a physical exam, medical history, blood samples and ECG.
• Patients will start vemurafenib 960 mg BID and will continue during TIL preparation.
• 7 days after start of vemurafenib, patients will undergo surgery to harvest tumor material for TIL production.
• Patient stops vemurafenib and is admitted day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7.
• On day 0 patients receive TIL infusion and shortly after starts IL-2 infusion continually following the decrescendo regimen.
• The patients will followed until progression or up to 5 years.

Inclusion Criteria:

• Histologically confirmed unresectable stage III or stage IV metastatic melanoma.
• Metastasis available for surgical resection (about 2 cm3) and residual measureable disease after resection.
• Pathologically verified BRAF mutation.
• ECOG performance status 0-1.
• Life expectancy ≥ 3 months.
• No significant toxicity (CTC ≤ 1) from prior treatments.
• Adequate renal, hepatic and hematologic function.
• Women of childbearing potential (WOCBP) and men in a sexual relationship with a WOCBP must be using an effective method of contraception during treatment and for at least 6 months after completion of treatment.
• Able to comprehend the information given and willing to sign informed consent.

Exclusion Criteria:

• Other malignancies, unless followed for ≥ 5 years with no sign of disease, except squamous cell carcinoma or adequately treated carcinoma in situ colli uteri.
• Cerebral metastasis. Patients with previously treated CNS metastasis can participate if surgically removed or treated with stereotactic radiotherapy if stable > 28 days after treatment measured by MRI. Patients with asymptomatic and untreated CNS metastasis can participate based on investigators evaluation.
• Patients with ocular melanoma.
• Previous treatment with a BRAF inhibitor.
• Severe allergies, history of anaphylaxis or known allergies to drugs administered.
• Serious medical or psychiatric comorbidity.
• QTc ≥ 450 ms.
• Clearance < 70 ml/min.
• Acute or chronic infection with e.g. HIV, hepatitis, tuberculosis
• Active autoimmune disease.
• Pregnant og nursing women.
• Need for immunosuppressive treatment, e.g. corticosteroids or methotrexate.
• Concomitant treatment with other experimental drugs.
• Patients with uncontrolled hypercalcemia
• More than four weeks must have elapsed since any prior systemic therapy at the time of treatment

Adverse events were collected from start of treatment until 24 weeks after T cell infusion.

Adverse events were collected continually and as a minimum systematically at baseline, each treatment visit and at follow-up visits until 24 weeks after T cell infusion.