T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Number of Reported Adverse Events
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-
- •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.
排除标准
- •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
研究组 & 干预措施
A
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.
干预措施: Interleukin-2 (Drug)
A
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.
干预措施: Vemurafenib (Drug)
A
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.
干预措施: Lymphodepleting chemotherapy (Drug)
A
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.
干预措施: TIL infusion (Drug)
结局指标
主要结局
Number of Reported Adverse Events
时间窗: 0-40 weeks
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.
次要结局
- Progression Free Survival(Up to 40 months)
- Overall Survival(Up to 40 months)
- Treatment Related Immune Responses(0-24 weeks)
- Objective Response Rate(Up to 12 months)
研究者
Inge Marie Svane
Professor, MD
Herlev Hospital