A Study to Evaluate Efficacy and Safety of Hepatic Resection for Liver Cancer With PVTT, HVTT or IVCTT After Initial Ate/Bev

Venous Thrombosis Clinical Trial

Official title: A Multicenter, Randomized, Open-label Study Evaluating the Efficacy and Safety of Hepatic Resection for Hepatocellular Carcinoma With Venous Thrombosis After Initial Atezolizumab Plus Bevacizumab Treatment

Status Recruiting

Clinical Trial Summary

The treatment strategies for HCC with PVTT is still controversial, and differ substantially between the west and the east. According to western guidelines, including those of the EASL, BCLC, and AASLD, PVTT is regarded as a contra-indication to initial surgery or transarterial chemoembolization.

At present, there is still no consensus on the diagnosis and treatment standards of HCC with HVTT/IVCTT. European and American guidelines for liver cancer use The Barcelona Clinic Liver Cancer (BCLC) staging as the standard and classify liver cancer with HVTT/IVCTT into the advanced stage. Molecular targeted drugs such as sorafenib and lenvatinib are recommended to the patients in this phase as first-line treatment drugs and methods. In this regard, experts in China and Southeast Asian countries still have different opinions. They believe that surgery, transarterial chemoembolization (TACE), radiotherapy, and combined treatment with multiple treatment methods can achieve more satisfactory results.

HCC with VTT consists of heterogeneous populations with different disease behaviors and prognoses. As a result of recent concept evolution and advances in surgical techniques and perioperative management, emerging evidence shows that selected patients with PVTT may benefit from more aggressive treatment modalities, which are recommended for by Chinese, Japanese, South Korean, and Asia Pacific clinical practice guidelines. A national survey from Japan showed median overall survival with liver resection treatment to be 1.77 years longer than with nonresection therapies, which included TACE, radiotherapy, sorafenib, or conservative treatment (2.87 years vs 1.10 years, respectively; p<0.001). After propensity-score matching of patient baseline characteristics, median overall survival since diagnosis in the liver resection group was 0.88 years longer than in the non-resection group. In a large-scale, multicentre, propensity-score matched analysis from China, surgery was the best treatment for patients with Cheng's type I and II PVTT with Child-Pugh A and selected B liver function. Median overall survival after liver resection (745 of 1580 patients) was 15.9 months (95% CI 13.3-18.5 months) for Cheng's type I PVTT and 12.5 months (10.7-14.3 months) for Cheng's type II PVTT. Thus, aggressive surgical resection in selected patients with HCC with vascular invasion, as proposed by several tertiary health-care centers in the east, seems to be reasonable.

Currently, there are no dedicated clinical trials to study the value of hepatic resection in this population. Furthermore, cumulative evidence indicates that long-term overall survival after hepatic resection alone remains unsatisfactory because of the high rate of tumor recurrence and correspondingly low rate of disease-free survival. The combination of perioperative therapies may be more efficacious to improve the prognosis in selected population. More high-level evidence of novel multimodality treatment should be generated.

This trial will enroll HCC patients with PVTT CNLC Stage IIIa, who have no prior anti-cancer treatment. Given the poor prognosis and limited treatment options for these patients, this population is considered appropriate for trials of more aggressive and novel therapeutic candidates in the initial treatment setting. The benefit risk profile for hepatic resection combined with perioperative atezo/bev in this patient population is expected to be favorable.

Clinical Trial Description

This is a multicenter, open-label, two-arm, randomized study designed to evaluate the efficacy and safety of surgical resection plus peri-operative atezo/bev compared with continuous systemic atezo/bev in HCC patients with VTT and without EHS.

Initially eligible patients will be enrolled into induction phase, during which they will receive 3 cycles of atezo/bev and 1 cycle of atezo alone as primary systemic therapy. Tumor response assessment using computed tomography (CT) and/or magnetic resonance imaging (MRI) will be conducted by the Independent-Review Facility (IRF) according to RECIST v1.1 after cycle 2 and cycle 4.

Only those patients who are assessed as partial response (PR) or stable disease (SD) and considered suitable for curative hepatic resection will be randomized in a 1:1 ratio to one of the following two arms:

• Arm A (experimental arm): hepatic resection with post-operative atezolizumab 1200mg and bevacizumab 15mg/kg, both administered by IV infusion on Day 1 of each 21-day cycle

• Arm B (control arm): atezolizumab 1200mg and bevacizumab 15mg/kg, both administered by IV infusion on Day 1 of each 21-day cycle

Randomization will be performed after the second tumor assessment and stratified according to the following stratification factors:

• Tumor response: target lesion reduction (maximum diameter reduction ≥10% compared with the entry baseline) vs non-reduction

• Eastern Cooperative Oncology Group (ECOG) performance status: 0 vs 1 Those patients who are assessed as disease progression (PD) or complete response (CR) and/or not suitable for curative hepatic resection will be excluded from randomization and treated according to local practice (Patients without PD may continue atezo/bev treatment at investigators' discretion).

In Arm A, hepatic resection surgery will be performed 0-2 weeks after the randomization. Surgical approaches will be tailored to the individual patient according to local standards with the goal of achieving R0 resection. The first administration of postoperative atezo/bev treatment is recommended to start within 4-6 weeks after surgery, requiring full recovery from the surgery prior to post-operative atezo/bev treatment, including:

• Adverse events emerged from prior treatment, if any, should have been recovered to meet the requirements of atezo/bev treatment according to investigator's judgement.

• No significant medical events (e.g., gastrointestinal [GI] bleeding, cardiac events, hepatorenal syndrome, biliary fistula, serious infection, etc.) during or after the surgery procedure Treatment with atezo/bev will continue until loss of clinical benefit (determined by the investigator), or unacceptable toxicity, withdrawal of ICF, death, or the study is terminated by the Sponsor, whichever occurs first. For Arm A, whether to continue atezo/bev treatment will be determined by the investigator at the end of the 12-month treatment period if none of the above occurs.

Tumor assessments will be performed in induction phase after cycle 2 and cycle 4 (randomization baseline), and in treatment period at regular intervals (Arm A will receive tumor assessment at the first dose of postoperative treatment (±3 days）and every 9 weeks (±7 days）thereafter. Arm B every 9 weeks (±7 days）thereafter ). Additional scans will be performed as clinically indicated. Following completion or discontinuation of the treatment, information on recurrence or disease progression, survival and subsequent anti-cancer therapies will be collected until death, loss to follow-up, withdrawal of ICF or study termination by Sponsor, whichever occurs first. In the absence of disease recurrence or progression, tumor assessments should continue regardless of whether patients start a new anti-cancer therapy, until documented treatment failure events, withdrawal of ICF or study termination. All patients will be followed for survival unless consent is withdrawn.

Patients who withdraw from the study will not be replaced. An IRF will be used to enable centralized, independent reviews of images and other clinical data (e.g., histopathology, tumor markers etc.) used for assessment of HCC response, recurrence and disease progression. IRF reviews will be performed prior to the pre-specified efficacy analyses. IRF membership and procedures will be detailed in an IRF Charter. ;

Related Conditions & MeSH terms

• Thrombosis
• Venous Thrombosis

• NCT number: NCT04649489
• Study type: Observational
• Source: Fudan University
• Contact: Jia Fan
• Phone: +86-21-64041990
• Email: fan.jia@zs-hospital.sh.cn
• Status: Recruiting
• Start date: April 19, 2021
• Completion date: March 31, 2028