Durvalumab/Tremelimumab in Neoadjuvant and Adjuvant Setting in Patients With HCC Treated by by Percutaneous Ablation Procedure in Curative Intent: French Multicenter Phase 2 Therapeutic
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- local recurrence-free survival
研究概览
简要总结
This project is a Phase 2 trial testing the safety and efficacy of treatment with Durvalumab/Tremelimumab in neoadjuvant and Durvalumab in adjuvant setting in patients with BCLC A HCC treated by by percutaneous ablation (PA) procedure in a curative intent.
DUMELEP is a Multicentre, Phase 2 trial
Eligible patients will receive consecutively:
- 1 Durvalumab 1500 mg/Tremelimumab 300 mg infusion in a neoadjuvant setting
- percutaneous ablation procedure in a curative attempt at Day 30
- 11 monthly Durvalumab 1500 mg infusions.
- Classical follow-up during an additional year (every 3 months)
详细描述
Immunotherapy is currently the gold standard for first-line treatment of advanced HCC based of the combination of check-point inhibitors (CPI). The first approved regimen is based on the association of atezolizumab and bevacizumab, an antiangiogenic molecule. More recently, the HIMALAYA trial demonstrated the superiority of durvalumab-tremelimumab over sorafenib, establishing a new first-line option.The combination of Immunotherapy and locoregional treatments in earlier HCC stages may reduce relapse rates. Preliminary data from the IMBRAVE 050 trail reports lower rates of recurrence following HCC percutaneous ablation (PA) or resection associated with atezolizumab and bevacizumab in adjuvant setting.PA procedures and most likely electroporation induce T-cell recruitment that may foster immunomodulation. In particular, radiofrequency ablation (RFA) can lead to stimulation of NK cells with a more differentiated and proactivatory phenotypic profile with general increase of functional activities. As compared with RFA, these local changes of IRE induce more robust systemic effects, including both tumorigenic and immunogenic events. Indeed, the preservation of the tumor microvasculature and extracellular matrix within the coagulated zone would favour infiltration by anti tumoral immune cells. These observations are relevant for development of neoadjuvant and adjuvant immunotherapeutic strategies in the setting of HCC treated by percutaneous ablation, and particularly IRE .
Neoadjuvant and adjuvant trials using these new molecules must now be cautiously designed based on the rigorous selection of special populations and therapeutic indications based on the following criteria:
- Exclusion of early forms of HCC with low probability of recurrence for statistical power issues
- Inclusion of patients with HCC treated in "curative intent" by new PA techniques such as electroporation
- Selective inclusion of patients treated with PA whose immunomodulatory properties are recognized
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 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •* Male or female patients ≥ 18 years of age.
- •* Histological or radiological diagnosis of HCC
- •* Patients with newly diagnosed or recurrent HCC (following a previous curative procedure performed at least 6 months before inclusion) eligible for PA as assessed by multidisciplinary board corresponding to BCLC A stage:
- •* Uninodular HCC ≥ 2 cm and ≤ 5 cm, no macroscopic vascular invasion
- •* Multinodular maximum 3 nodules ≤ 3 cm
- •* Body weight \>30 kg
- •* Liver function status Child-Pugh Class A
- •* Eastern Cooperative Oncology Group (ECOG) -World Health Organisation (WHO) performance status of 0 or 1
- •* Adequate bone marrow, liver and renal function as assessed by the following laboratory tests:
- •* Total bilirubin ≤ 2 mg/dL
- •* Serum creatinine ≤ 1.5 x ULN
- •* Lipase ≤ 2 x ULN
- •* Prothrombine time-international normalized ratio (PT-INR) \< 2.3 and PTT \< 1.5
- •* Glomerular Filtration Rate (GFR) ≥ 30 mL/min/1.73 m2
- •* Life expectancy ≥ 3 months
- •* Female of childbearing potential (WOCBP) or male or female patients of reproductive potential must employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy.
- •* Patients affiliated to a Social Security System
- •* Written informed consent signed (patients must be free from tutelle, curatelle or sauvegarde de justice)
- •* Haemoglobin ≥9.0 g/dL
- •* Absolute neutrophil count (ANC ≥1.0 × 109 /L)
- •* Platelet count ≥75 × 109/L
- •* Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.)
- •* AST (SGOT) and ALT (SGPT) ≤5x ULN
- •* Measured creatinine clearance (CL) must not exceeded 40 mL/min. For the estimation of glomerular filtration rate (eGFR), the Cockcroft-Gault equation was applied in patients aged ≤65 years, while the MDRD equation was used for those older than 65 years
- •* Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- •* At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at pre inclusion/inclusion. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to inclusion
- •* Patients with HCV infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody) must be managed per local institutional practice for the study and for 6 months after the last dose of study treatment.
- •* Antiviral therapy in case of HBV active infection or inactive carriage
- •Non inclusion criteria
- •* Patients with contraindications to PA procedure (Pacemakers or patients who have a history of cardiac arrhythmias or irregular heartbeats considered as contraindication to IRE, ascites, Coagulopathy, Ongoing infection)
- •* Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate
- •* Prior liver transplantation
- •* Prior systemic treatment for HCC, in particular agents targeting T-cell costimulation or checkpoint pathways (including those targeting PD-1, PD-L1 or PD-L2, CD137, or cytotoxic T-lymphocyte antigen \[CTLA-4\]).
- •* Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention
- •* Past or concurrent history of neoplasm other than HCC, except for in situ carcinoma of the cervix uteri and/or non-melanoma skin cancer and superficial bladder tumors. Any cancer curatively treated \> 3 years prior to study entry is permitted
- •* Major surgical procedure or significant traumatic injury within 28 days before enrolment (note: local surgery for isolated lesions for palliative purposes is acceptable)
- •* Congestive heart failure New York Heart Association (NYHA) ≥ class 2
- •* Unstable angina or myocardial infarction within the past 6 months before enrolment
- •* Grade 3 (severe) hypertension ≥180 and/or ≥110 mmHG (systolic and diastolic, according to National Heart Foundation 2016)
- •* Patients with phaeochromocytoma
- •* Refractory ascites according to EASL guidelines definition (ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to sodium restriction and diuretic treatment)
- •* Persistent proteinuria of NCI-CTCAE version 5.0 ≥ Grade 3
- •* Ongoing infection \> Grade 2 according to NCI-CTCAE version 5.0.
- •* Clinically significant bleeding NCI-CTCAE version 5.0 ≥ Grade 3 within 30 days before enrolment
- •* Any psychological, familial, sociological, geographical or illness or medical condition that could jeopardize the safety of the patient and/or his compliance with the study protocol and follow-up procedure
- •* Known history of human immunodeficiency virus (HIV) infection
- •* Non-healing wound, ulcer or bone fracture
- •* Known hypersensitivity to the study drug or excipients in the formulation
- •* Any malabsorption condition
- •* Breast feeding
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排除标准
- 未提供
研究组 & 干预措施
Durvalumab/Tremelimumab
Durvalumab/Tremelimumab in neoadjuvant and Durvalumab in adjuvant setting
干预措施: Durvalumab/Tremelimumab in neoadjuvant and Durvalumab in adjuvant setting (Drug)
结局指标
主要结局
local recurrence-free survival
时间窗: 12 months after PA procedure
Local recurrence is defined as the emergence of irregular areas enhanced at arterial phase followed by wash out at portal phase observed next to the ablation zone
次要结局
- Changes of tumorous and non-tumorous perfusion parameters(one month of neoadjuvant treatment)
- Changes of size of nodules following neoadjuvant course(one month of neoadjuvant treatment)
- Incidences of intra segmental/ extra segmental distant recurrence(Throughout the study, an average of 30 months)
- Treatment-related adverse events(Throughout the study, an average of 30 months)
- Timeframe of PA performance(one month of neoadjuvant treatment)
- Compliance to neoadjuvant and adjuvant treatments(during one cycle neoadjuvant treatment and 11 months starting after the PA evaluation)
- Safety of Durvalumab/Tremelimumab infusions(Throughout the study, an average of 30 months)
- Overall survival(12 months after PA procedure)