A Phase III, Multicenter, Randomized, Open-label Trial to Evaluate the Safety and Efficacy of Systemic Therapy With Regorafenib and Pembrolizumab Versus Locoregional Therapy With Transarterial Chemoembolization or Transarterial Radioembolization, for the First-line Treatment of Intermediate-stage Hepatocellular Carcinoma With Beyond Up-to-7 Criteria
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 45
- 试验地点
- 26
- 主要终点
- Progression-free Survival (PFS) Assessed by the Investigator as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC
研究概览
简要总结
REPLACE is a phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of regorafenib and pembrolizumab (Rego-Pembro) versus transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) for the first-line treatment of hepatocellular carcinoma (HCC or liver cancer). Approximately 496 patients in around 80 clinical sites worldwide will be randomized to receive either:
- Investigational arm: Regorafenib in combination with pembrolizumab
- Control arm: Transarterial chemoembolization (TACE) or transarterial radioembolization (TARE)
In both arms, patients will receive trial treatment until progressive disease, unacceptable toxicity, deterioration of patient's condition that warrants permanent trial treatment discontinuation or other treatment discontinuation criteria is met. After trial treatment discontinuation, subsequent treatment will be administered according to the Investigator's clinical judgment.
详细描述
REPLACE is a phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of systemic therapy with Rego-Pembro versus loco-regional therapy with TACE or TARE, for the first-line treatment of intermediate-stage HCC with beyond up-to-7 criteria. Approximately 496 patients (~248 in each arm) from approximately 80 sites will be randomized in order to power the trial efficiently to measure a clinically meaningful improvement for the primary endpoint, PFS according to mRECIST based on the Investigator´s assessment.
The trial will include patients who have been diagnosed with intermediate-stage HCC by biopsy, cytology or diagnostic imaging, such as dynamic computed tomography (CT) or magnetic resonance imaging (MRI), according to the criteria of the American Association for the Study of Liver Diseases (AASLD). Patients should have at least one measurable lesion per RECIST 1.1, disease not amenable to curative treatment but amenable to loco-regional therapy with TACE (cTACE or DEB-TACE) or TARE, ECOG PS 0-1, Child-Pugh class A, and beyond up-to-7 criteria.
The trial will include the following phases:
- Screening
- Treatment
- Follow-up
Randomized patients will receive either:
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed and dated Patient Informed Consent Form (PICF)
- •≥ 18 years-old at the time of PICF signature
- •Confirmed diagnosis of HCC
- •Intermediate-stage HCC, defined as follows:
- •Multinodular HCC localized to the liver
- •No evidence of MVI or EHS
- •Not amenable to curative treatment
- •Child-Pugh Class A
- •ECOG PS 0 or 1
- •ALBI grade 1 or 2
- •Beyond up-to-seven criteria
- •Disease amenable to TACE or TARE and no contradiction to intra-arterial treatment
- •Measurable disease by CT or MRI as per RECIST 1.1
- •No prior systemic therapy or loco-regional therapy for HCC
- •Adequate hematologic and organ function
- •Willing and able to comply with scheduled visits, treatment plans, laboratory tests and other trial procedures
- •Women of childbearing potential (CBP) must have confirmed negative serum pregnancy test
- •Use of highly-effective contraceptive methods in women of CBP and men
- •Patients with hepatitis C virus (HCV) or hepatitis B virus (HBV) infection are eligible if they meet criteria as defined within the protocol
排除标准
- •No measurable tumor of a diffuse infiltrative HCC type.
- •Fibrolamellar HCC, sarcomatoid HCC or mixed hepatocellular/ cholangiocarcinoma subtypes.
- •Clinically meaningful ascites.
- •Prior treatment with regorafenib, a PD-1, PD-L1/PD-L2, or cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- •Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to randomization.
- •Active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids.
- •Requirement of systemic treatment with either corticosteroids or other immunosuppressive medications ≤ 14 days prior to randomization.
- •Interstitial lung disease, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, or clinically significant acute lung diseases.
- •Cardiovascular conditions as defined within the protocol.
- •Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed ≤ 2 years before randomization.
- •Persistent proteinuria of NCI-CTCAE v5.0 Grade
- •Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.
研究组 & 干预措施
Regorafenib + Pembrolizumab
Investigational arm: regorafenib at a dose of 90 mg orally once per day (on days 1 to 21 of a 28-day cycle), in combination with pembrolizumab 400 mg using a 30-minute intravenous infusion, on day 1 of a 6-week cycle.
干预措施: Regorafenib in combination with pembrolizumab (Drug)
Loco-regional therapy
Control arm: Patients will be treated with TACE or TARE "on-demand" according to site's standard of practice.
干预措施: Loco-regional therapy (Procedure)
结局指标
主要结局
Progression-free Survival (PFS) Assessed by the Investigator as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC
时间窗: up to 3.5 years
PFS, defined as the time (in months) from the date of randomization until the date of progressive disease (PD) or death due to any cause, whichever occurs first. PD will be assessed locally by the Investigator using mRECIST.
次要结局
- Number of Patients with Adverse Events as Assessed by the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 5(up to 3.5 years)
- Progression-free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST Version 1.1(up to 3.5 years)
- Overall Response Rate (ORR) Assessed by Investigator and Blinded Independent Central Review (BICR) as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST Version 1.1(up to 3.5 years)
- Progression-free Survival (PFS) Assessed by the Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(up to 3.5 years)
- Duration of Response (DOR) of Rego-Pembro Versus Loco-regional Therapy(up to 3.5 years)
- Change from Baseline in Health-Related Quality of Life as Assessed by the EuroQol's 5-level EQ-5D Health Questionnaire (EQ-5D-5L)(up to 3.5 years)
- Overall Survival (OS) of Intermediate-Stage HCC (Rego-Pembro versus Loco-regional Therapy)(up to 3.5 years)
- Time to unTACEable Progression (TTUP)(up to 3.5 years)
- Change from Baseline in the Physical Functioning Sub-scale Score and Global Health Status/Quality of Life Scale Score as assessed by European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)(up to 3.5 years)
- Change from Baseline in Health-related Quality of Life in Hepatocellular Carcinoma as Assessed by European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire for HCC (EORTC QLQ-HCC18)(up to 3.5 years)