Adoptive TIL Therapy With Low-dose IFN-alpha Plus Anti-PD1 in Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Incidence of treatment-related serious adverse events as assessed by CTCAE 4.0 criteria
研究概览
简要总结
The ACTME study is an investigator initiated, single center phase I/II clinical trial for patients with progressive unresectable stage III or stage IV melanoma. The trial consists of both a phase I part to determine safety and feasibility and a phase II part to evaluate first clinical activity of IFN-alpha, nivolumab and TIL. The treatment with IFN-alpha will be added after the combination of TIL and nivolumab has proven to be safe.
详细描述
The ACTME is an investigator initiated, single center phase I/II clinical trial for patients with progressive unresectable stage III or stage IV melanoma.
Patients are conditioned by low-dose IFN-alpha and treated with ACT and PD-1 antibodies. With this approach the investigators hope to solve 4 of the most important aspects curtailing the efficacy of current immunotherapies in metastatic melanoma:
- the lack of sufficient numbers of activated tumor-reactive T cells in patients by providing ACT; and
- the inhibition of T-cell effector function through PD-1 signalling by administration of nivolumab; as well as
- the toxicity of high-dose IL-2, and
- long term hospitalization of patients due to the conditioning-regimen used in most ACT protocols by replacing it with low-dose IFN-alpha treatment.
The trial consists of both a phase I part to determine safety and feasibility and a phase II part to evaluate first clinical activity of IFN-alpha, nivolumab and TIL.
The treatment with IFN-alpha will be added after the combination of TIL and nivolumab has proven to be safe in the first cohort of the phase I part of the trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Histologically or cytologically proven metastatic skin melanoma
- •Melanoma must be at one of the following AJCC 2009 stages:
- •Unresectable (or residual) regional metastatic melanoma, i.e. in terms of AJCC 2009 classification unresectable stage III melanoma, or
- •Stage IV melanoma, i.e. distant metastatic disease (any T, any N, M1a, M1b or M1c), and normal LDH
- •Patients have failed on standard treatment options
- •Patients with brain metastases have to be neurologically stable for at least 2 months and should not use dexamethasone
- •Presence of measurable progressive disease according to RECIST version 1.1
- •Expected survival of at least 3 months
- •WHO performance status ≤1
- •Within the last 2 weeks prior to study day 1, vital laboratory parameters should be within normal range, except for the following laboratory parameters, which should be within the ranges specified:
- •Lab Parameter Range Hemoglobin ≥ 6,0 mmol/l Granulocytes ≥ 1,500/µl Lymphocytes ≥ 700/µl Platelets ≥ 100,000/µl Creatinine clearance ≥ 60 min/ml Serum bilirubin ≤ 40 µmol/l ASAT and ALAT ≤ 5 x the normal upper limit LDH ≤ 2 x the normal upper limit
- •Viral tests must be performed at least 30 days before surgery:
- •Negative for HIV type 1/2, HTLV and TPHA
- •No HBV (hepatitis B virus) antigen or antibodies against HBc in the serum
- •No antibodies against HCV (hepatitis C virus) in the serum
- •Able and willing to give valid written informed consent.
- •Progressive disease on prior treatment with f.e. BRAF-inhibitors, MEK-inhibitors or immunotherapy, including anti-PD1 treatment. Systemic therapy must have been discontinued for at least four weeks before start of study treatment.
排除标准
- •Patients with brain metastases who are neurologically unstable and/or use dexamethasone
- •Clinically significant heart disease (NYHA Class III or IV)
- •Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders, or other conditions requiring concurrent medications not allowed during this study
- •Active immunodeficiency disease, autoimmune disease requiring immune suppressive drugs or autoimmune adverse events following treatment with checkpoint inhibitors. Vitiligo is not an exclusion criterion
- •Subjects with a condition requiring systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy within 14 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids, and adrenal replacement therapy are allowed.
- •Other malignancy within 2 years prior to entry into the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma
- •Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study
- •Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the associated with the participation, study drug administration, or would impair the ability of the patient to receive protocol therapy
- •Lack of availability for follow-up assessments
- •Pregnancy or breastfeeding
- •Known allergy to penicillin or streptomycin (used during the culturing of T cells)
研究组 & 干预措施
Treatment with nivolumab plus TIL
In the first cohort the subcutaneous IFN-alpha injections will be omitted and the combination of nivolumab and TIL is given.
- Nivolumab is given 3mg/kg i.v. once every two weeks and starts 4 weeks before the first TIL infusion
- TILs are given at a dose ranging between 2.5-7.5x10^8 T cells i.v. once every three weeks, three times per cycle.
干预措施: Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha (Drug)
Treatment with Nivolumab plus TIL and IFN-alpha
In the second cohort of the first phase and the second phase of the trial patients will be treated with subcutaneous IFN-alpha injections in combination with TIL and nivolumab.
- IFN-alpha is given at a fixed dose of 3 million IU s.c. every day, for 11 weeks, starting one week before the first TIL infusion
- Nivolumab is given 3mg/kg i.v. once every two weeks and starts 4 weeks before the first TIL infusion
- TILs are given at a dose ranging between 2.5-7.5x10^8 T cells i.v. once every three weeks, three times per cycle.
干预措施: Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha (Drug)
结局指标
主要结局
Incidence of treatment-related serious adverse events as assessed by CTCAE 4.0 criteria
时间窗: 14 weeks after start of treatment
To evaluate the safety and toxicity of ACT with nivolumab, followed by evaluating the safety and toxicity of IFN-alpha, and nivolumab plus ACT according to the common terminology criteria of adverse events (CTCAE) 4.0 criteria. Treatment related adverse events grade 3 or less and SAE related to treatment that do not result in treatment termination are considered acceptable for continuation of the study. * Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. * Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL * Grade 3: Severe or medically significant but not immediately life-threatening hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL * Grade 4: Life-threatening consequences; urgent intervention indicated * Grade 5: Death related to AE
次要结局
- Evaluation of disease control rate according to RECIST 1.1 criteria(14 weeks after first nivolumab infusion)
- Evaluation of disease control rate according to immune RECIST response criteria(14 weeks after first nivolumab infusion)
- To study the potential working mechanisms of the different treatment compounds. Therefore, blood will be drawn to analyse changes in circulating immune cells and their function during treatment.(Within 5 years after first inclusion)
- To establish a possible prognostic biomarker profile in patients tumor material, blood, serum and TILs used for infusion(Within 5 years after first inclusion)
- To characterize the infusion product(Within 5 years after first inclusion)
- To analyse potential correlations between the clinical response and hypothesis related immune parameters(Within 5 years after first inclusion)
- To analyse the overall survival following treatment(Within 5 years after first inclusion)
研究者
HW Kapiteijn
Principal Investigator
Leiden University Medical Center