Neoadjuvant Therapy in Patients With Resectable HCC Screened by a Multimodal Deep Learning Model

Efficacy and Safety of Neoadjuvant HAIC Combined With Tislelizumab and Lenvatinib in Patients With Resectable HCC Screened by a Multimodal Deep Learning Model: a Multicenter Randomized Controlled Trial.

Primary liver cancer is one of the most common malignant tumors in the world, and about 80%~90% of primary liver cancers are pathologically characterized as hepatocellular carcinoma (HCC). Radical surgery is the main method for patients with HCC to obtain long-term survival. However, there is no consensus on surgical treatment for patients with BCLC-stage B or C HCC. New tools are urgently needed to guide the choice of treatment options.

Study Overview

• Status: Not yet recruiting
• Conditions: HCC
• Intervention / Treatment: Procedure: Hepatic arterial infusion chemotherapy; Drug: Lenvatinib; Drug: Tislelizumab; Procedure: Liver resection; Drug: Tislelizumab

Detailed Description

Primary liver cancer is one of the most common malignant tumors in the world, and about 80%~90% of primary liver cancers are pathologically characterized as hepatocellular carcinoma (HCC). Radical surgery is the main method for patients with HCC to obtain long-term survival. However, there is no consensus on surgical treatment for patients with BCLC-stage B or C HCC. Transarterial chemoembolization and systemic medication were the first line of treatment for this patients. In eastern countries, such as China, BCLC-B is further categorized into stages IIa and IIb, and surgical resection is recommended as the first-line treatment option for stage IIa, while surgical resection can also be considered for stage IIb. Moreover, many studies have found that patients with BCLC-C stage tumors can also benefit from surgery and the overall prognosis were better than non-surgical treatment. However, the rate of postoperative recurrence is higher than that of early HCC. To address this issue, new tools are urgently needed to guide the selection of appropriate treatment regimens to reduce the risk of postoperative recurrence and improve overall survival.

Our multidisciplinary team used deep learning technology to construct an artificial intelligence prediction model of neoadjuvant therapy (Neoadj-Net) benefit based on pre-treatment genetic testing data, digital pathology slides and imaging data (enhanced MRI) of 536 intermediate-stage HCC patients treated with HAIC in combination with lenvatinib and PD-1 monoclonal antibody in six centers, and external center data validated the model's good ability to identify the beneficiary population of the combination regimen ( AUC 0.89, Accuracy 0.86). This study is to explore the effectiveness and safety of Neoadj-Net in reducing postoperative recurrence by observing the benefit of the combined neoadjuvant regimen in patients who are potentially benefited from neoadjuvant therapy and direct surgery from the perspective of precision therapy.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: WanGuang Zhang; Phone Number: 13886195965; Email: wgzhang@tjh.tjmu.edu.cn
• Study Contact Backup: Name: xiaoping Chen; Phone Number: 027-83663400; Email: chenxpchenxp@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18-75.
2. No previous local or systemic treatment for hepatocellular carcinoma.
3. Child-Pugh liver function score ≤ 7.
4. ECOG PS 0-1.
5. No serious organic diseases of the heart, lungs, brain, kidneys, etc.
6. Enhanced MRI determines that the tumor stage is BCLC B or C without distant metastasis, and is technically resectable.
7. Pathologic type of hepatocellular carcinoma confirmed by puncture biopsy.
8. Multimodal Deep Learning Model Screening Based on Pathology, Imaging, and Genetic Data Suggests Benefit from HAIC in Combination with Lenvatinib and PD-1 inhibitors.

Exclusion Criteria:

1. Pregnant and lactating women.
2. Suffering from a condition that interferes with the absorption, distribution, metabolism, or clearance of the study drug (e.g., severe vomiting, chronic diarrhea, intestinal obstruction, impaired absorption, etc.).
3. A history of gastrointestinal bleeding within the previous 4 weeks or a definite predisposition to gastrointestinal bleeding (e.g., known locally active ulcer lesions, fecal occult blood ++ or more, or gastroscopy if persistent fecal occult blood +) that has not been targeted, or other conditions that may have caused gastrointestinal bleeding (e.g., severe fundoplication/esophageal varices), as determined by the investigator.
4. Active infection.
5. Other significant clinical and laboratory abnormalities that affect the safety evaluation.
6. Inability to follow the study protocol for treatment or follow up as scheduled.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant therapy group; Patients in the neoadjuvant group received neoadjuvant therapy prior to surgery (two cycles of HAIC combined with Tislelizumab and Lenvatinib), and adjuvant therapy (Tislelizumab for 8 cycles) after surgery.	Procedure: Hepatic arterial infusion chemotherapy; Patients in the neoadjuvant group received two cycles of neoadjuvant hepatic arterial infusion chemotherapy (HAIC, adoption of the FOFOLX6 program, Folinic acid+5-fluorouracil+Oxaliplatin, 21 days between second HAIC treatments with a window of ±3 days); Drug: Lenvatinib; Patients in the neoadjuvant therapy group received Lenvatinib before surgery(Len was started before HAIC treatment, discontinued during HAIC treatment, and discontinued approximately two weeks before surgery, Oral 8 mg or 12mg once a day depending body weight).; Drug: Tislelizumab; Patients in the neoadjuvant therapy group received two cycles of Tislelizumab therapy before surgery (First treatment with Tislelizumab was started 0-1 days after HAIC, 200 mg IV, followed by a second treatment 21 days later); Procedure: Liver resection; Patients in the neoadjuvant therapy group were evaluated for tumor status and surgical safety after neoadjuvant therapy, and eligible patients subsequently underwent surgical resection. Patients in the direct surgery group underwent liver resection.; Drug: Tislelizumab; Given the high risk of postoperative recurrence, patients in both groups received adjuvant Tis therapy (every 21 days for 8 cycles) starting about one month after surgery.
Active Comparator: Direct liver resection group; Patients in the control group underwent liver resection directly and received adjuvant therapy (Tislelizumab for 8 cycles) after surgery.	Drug: Tislelizumab; Patients in the neoadjuvant therapy group received two cycles of Tislelizumab therapy before surgery (First treatment with Tislelizumab was started 0-1 days after HAIC, 200 mg IV, followed by a second treatment 21 days later); Procedure: Liver resection; Patients in the neoadjuvant therapy group were evaluated for tumor status and surgical safety after neoadjuvant therapy, and eligible patients subsequently underwent surgical resection. Patients in the direct surgery group underwent liver resection.; Drug: Tislelizumab; Given the high risk of postoperative recurrence, patients in both groups received adjuvant Tis therapy (every 21 days for 8 cycles) starting about one month after surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median event-free survival (EFS)	EFS is defined as the time from randomization to disease recurrence and/or disease progression or death from any cause.	From date of randomization until the date of first documented recurrence or date of death from any cause, whichever came first, assessed up to 60 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Assessment	Any adverse event during treatment that is incompatible with the therapeutic purpose of the medication.The incidence and severity of adverse events and serious adverse events as assessed by CTCAE v5.0.	Baseline up to 12 months
Overall Survival (OS)	OS is defined as the time from randomization to death from any cause	From date of randomization until the date of death from any cause, assessed up to 60 months.

Collaborators and Investigators

• Sponsor: Chen Xiaoping

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: May 14, 2024
• First Submitted That Met QC Criteria: May 17, 2024
• First Posted (Actual): May 20, 2024

Study Record Updates

• Last Update Posted (Actual): May 20, 2024
• Last Update Submitted That Met QC Criteria: May 17, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: recurrence; Hepatocellular carcinoma; Deep learning; Neoadjuvant tehrapy
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Lenvatinib; Tislelizumab
• Other Study ID Numbers: Neoadj-Net01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No