Vemurafenib and TIL Therapy for Metastatic Melanoma

Study Overview
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Brief Summary
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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.

Official Title
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T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Drug: Vemurafenib
* Drug: Lymphodepleting chemotherapy
* Drug: TIL infusion
* Drug: Interleukin-2


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine, followed by TIL infusion and interleukin-2. | Drug: Vemurafenib<br>* Vemurafenib is used to treat patients with BRAF mutated metastatic melanoma. Patients will start treatment in a dose of 960 BID 7 days before tumor harvest and ends at the day of admission (day -8).<br>* Other names: BRAF inhibitor;Drug: Lymphodepleting chemotherapy<br>* First patients undergo lymphodepleting chemotherapy regimen consisting of cyclophosphamide 60 mg/kg for 2 days and fludarabine 25 mg/m2 for 5 days (constitutes day -7 to -1 of admission).<br>* Other names: fludarabine;Drug: TIL infusion<br>* 7 days after start of vemurafenib treatment, patients undergo surgery to removal of a tumor in order to isolate, activate and expand tumor infiltrating lymphocytes (TIL) to high numbers. In vitro preparation usually takes 4-6 weeks using the young TIL method. On day 0 patients receive an infusion of TIL (1x10e9-2x10e11 cells).<br>* Other names: T cell therapy;Drug: Interleukin-2<br>* After infusion of TILs, patients will receive interleukin-2 infusions according to the decrescendo regimen (18 MIU/m2 for 6 hours, 18 MIU/m2 for 12 hours, 18 MIU/m2 for 24 hours followed by 4,5 MIU/m2 for another 3 x 24 hours)<br>* Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Reported Adverse Events | Determine the safety of the administration of vemurafenib in combination with TIL therapy including lymphodepleting chemotherapy and interleukin-2 treatment by collecting adverse events according to CTCAE v. 4.0. From start of treatment until 24 weeks after T cell infusion. | 0-40 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Related Immune Responses | Number of patients whose infusion product contained anti-tumor reactive T cells by in vitro testing. Anti-tumor reactive T cells is defined by positive staining for two of the three markers (interferon gamma, tumor necrosis factor alpha and CD107a) in an intracellular cytokine staining using flow cytometry. | 0-24 weeks | 
| Objective Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 12 months | 
| Overall Survival | Overall survival (OS), defined as the time from the start of treatment to death, will be described with the Kaplan-Meier curve. | Up to 40 months | 
| Progression Free Survival | Progression-free survival (PFS), defined as the time from start of treatment to disease progression, relapse or death due to any cause, whichever is earlier, will be described with the Kaplan-Meier curve. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Up to 40 months |