A Two-arm Multi-stage (TAMS) Seamless Phase II/III Randomised Trial of Nivolumab in Combination With TACE/TAE for Patients With Intermediate Stage HCC
试验速览
- 阶段
- 2 期
- 状态
- 暂停
- 入组人数
- 522
- 试验地点
- 2
- 主要终点
- Overall Survival - phase III primary outcome
研究概览
简要总结
This study evaluates the addition of nivolumab to TACE/TAE in the treatment of patients with intermediate stage hepatocellular carcinoma. All patients will receive TACE/TAE and half will receive nivolumab.
详细描述
A significant proportion of HCC patients present with, or progress to, intermediate stage disease and these patients are typically treated with transarterial chemo-embolisation (TACE) or transarterial embolisation (TAE).
However, since TACE/TAE is generally a palliative therapy, it provides a potential backbone for the addition of effective systemic therapies with the aim of improving survival outcomes. Since TACE may liberate an abundance of tumour antigens and 'danger' signals, it may lend itself to combination with immunotherapeutic strategies.
Nivolumab is a human monoclonal antibody. Nivolumab targets the programmed death-1 PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histological diagnosis of HCC and at least one uni-dimensional lesion measurable according to RECIST 1.1 criteria by CT-scan or MRI.
- •Not a candidate for surgical resection or liver transplantation
- •Aged ≥16 years and estimated life expectancy >3 months
- •ECOG performance status 0-1
- •Adequate haematological function:
- •Absolute neutrophil count ≥1.0x109/L
- •Platelet count ≥60x109/L
- •Bilirubin ≤50 μmol/L, AST,ALT and ALP ≤5 x ULN
- •Adequate renal function; Creatinine ≤ 1.5ULN (Using Cockcroft-Gault Formula)
- •Child-Pugh A (score ≤6) (Appendix D)
- •HAP score A, B or C (Appendix E)
- •No contra-indications to T-cell checkpoint inhibitor therapy (use of immunosuppressive drugs including steroids at dose equivalent to prednisolone >10mg/day unless used as replacement therapy; organ transplantation; subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, lichen planus or other conditions not expected to recur in the absence of an external trigger are permitted to enrol).
- •Women of child-bearing potential should have a negative pregnancy test prior to study entry. Both men and women must be using an adequate contraception method, which must be continued for 5 months after completion of treatment for women and 7 months for men
- •Written informed consent
排除标准
- •Extrahepatic metastasis
- •Prior embolisation, systemic or radiation therapy for HCC
- •Any contraindications for hepatic embolisation procedures including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis
- •Investigational therapy or major surgery within 4 weeks of trial entry
- •History of variceal bleeding within the past 4 weeks
- •Child-Pugh cirrhosis B or C (score ≥7)
- •HAP score D
- •Hepatic encephalopathy
- •Ascites refractory to diuretic therapy
- •Documented occlusion of the hepatic artery or main portal vein5
- •Hypersensitivity to intravenous contrast agents
- •Active clinically serious infection > Grade 2 NCI-CTC
- •Pregnant or lactating women
- •Known history of HIV infection
- •HBV chronic infection with HBV DNA > 500IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated.
- •History of second malignancy except those treated with curative intent more than three years previously without relapse and non-melanotic skin cancer or cervical carcinoma in situ
- •Evidence of severe or uncontrolled systemic disease, or laboratory finding that in the view of the Investigator makes it undesirable for the patient to participate in the trial
- •Psychiatric or other disorder likely to impact on informed consent
- •Patient is unable and/or unwilling to comply with treatment and study instructions
- •Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity
- •Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or antifungal therapy within 7 days prior to administration of study medication
- •Positive test for latent TB or evidence of active TB
- •Hypersensitivity to any of the active substances or excipients
- •Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment
- •Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration
- •Any uncontrolled inflammatory GI disease including Crohn's Disease and ulcerative colitis
- •Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol
研究组 & 干预措施
TACE/TAE Alone
Transarterial Chemoembolisation (TACE) and/or Transarterial Embolisation (TAE) Alone.
干预措施: TACE/TAE (Procedure)
TACE/TAE and Nivolumab
As above for TACE/TAE. Nivolumab adminstered as a flat dose of 480mg IV.
干预措施: Nivolumab and TACE/TAE (Drug)
TACE/TAE and Nivolumab
As above for TACE/TAE. Nivolumab adminstered as a flat dose of 480mg IV.
干预措施: TACE/TAE (Procedure)
结局指标
主要结局
Overall Survival - phase III primary outcome
时间窗: The time until death. Patients discontinuing the study, lost to follow-up or still alive at the end of the study will be censored at the last know date alive, this can be assessed up until 2 years after the last patient.
Measured in days
Time to TACE Progression (TTTP) - phase II primary outcome
时间窗: The time to confirmatory scan 4 weeks after progression this can be assessed up until 2 years after the last patient is randomised
Measured in days
次要结局
- Safety and Toxicity: the number and percentage of patients reporting a Serious Adverse Event (SAE) and Grade 3 or higher Adverse Event (AE)(Through study completion)
- Time to Progression(Time to date of progression confirmed by RECIST1.1 assessed up until 2 years after the last patient is randomised)
- Radiological response rate(Through study completion)
- Progression Free Survival(Time to progression or death. Assessed up until 2 years.)
- QOL: EORTC QLQ-C30(baseline, pre - TACE (first treatment) and 12 weekly thereafter until end of treatment. Assessed up until 2 years after the last patient is randomised)