## Protocol Section
### Identification Module
**NCT ID:** NCT06420440

**Brief Title:** Neoadjuvant Therapy in Patients With Resectable HCC Screened by a Multimodal Deep Learning Model

**Official Title:** 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.

#### Organization Study ID Info
**ID:** Neoadj-Net01
#### Organization
**Class:** OTHER
**Full Name:** Tongji Hospital
### Status Module
#### Completion Date
**Date:** 2027-05-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-20

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-17

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-05-31

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-20
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-14
**Study First Submit QC Date:** 2024-05-17
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Chen Xiaoping

#### Responsible Party

**Investigator Affiliation:** Tongji Hospital

**Investigator Full Name:** Chen Xiaoping

**Investigator Title:** Professor

**Type:** SPONSOR_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

### Description Module

**Brief Summary:** 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.

**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.

### Conditions Module

**Conditions:**

- HCC

**Keywords:**

- Hepatocellular carcinoma

- Neoadjuvant tehrapy

- recurrence

- Deep learning

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 160

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 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.

**Intervention Names:**

- Procedure: Hepatic arterial infusion chemotherapy

- Drug: Lenvatinib

- Drug: Tislelizumab

- Procedure: Liver resection

**Label:** Neoadjuvant therapy group

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Patients in the control group underwent liver resection directly and received adjuvant therapy (Tislelizumab for 8 cycles) after surgery.

**Intervention Names:**

- Procedure: Liver resection

- Drug: Tislelizumab

**Label:** Direct liver resection group

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Neoadjuvant therapy group

**Description:** 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)

**Name:** Hepatic arterial infusion chemotherapy

**Type:** PROCEDURE

#### Intervention 2

**Arm Group Labels:**

- Neoadjuvant therapy group

**Description:** 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).

**Name:** Lenvatinib

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Neoadjuvant therapy group

**Description:** 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)

**Name:** Tislelizumab

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Direct liver resection group

- Neoadjuvant therapy group

**Description:** 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.

**Name:** Liver resection

**Type:** PROCEDURE

#### Intervention 5

**Arm Group Labels:**

- Direct liver resection group

- Neoadjuvant therapy group

**Description:** 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.

**Name:** Tislelizumab

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** EFS is defined as the time from randomization to disease recurrence and/or disease progression or death from any cause.

**Measure:** Median event-free survival (EFS)

**Time Frame:** 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 Outcomes

**Description:** 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.

**Measure:** Safety Assessment

**Time Frame:** Baseline up to 12 months

**Description:** OS is defined as the time from randomization to death from any cause

**Measure:** Overall Survival (OS)

**Time Frame:** From date of randomization until the date of death from any cause, assessed up to 60 months.

### Eligibility Module

**Eligibility Criteria:** 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.

**Maximum Age:** 75 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** wgzhang@tjh.tjmu.edu.cn

**Name:** WanGuang Zhang

**Phone:** 13886195965

**Role:** CONTACT

**Contact 2:**

**Email:** chenxpchenxp@163.com

**Name:** xiaoping Chen

**Phone:** 027-83663400

**Role:** CONTACT

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: All

- Name: All Conditions

- Abbrev: BC06

- Name: Digestive System Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

### Condition Browse Module - Browse Leaves

- ID: M5534

- Name: Carcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M9613

- Name: Carcinoma, Hepatocellular

- Relevance: LOW

- As Found: Unknown

- ID: M14850

- Name: Recurrence

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Ancestors

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000047428

- Term: Protein Kinase Inhibitors

- ID: D000004791

- Term: Enzyme Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000074322

- Term: Antineoplastic Agents, Immunological

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Micro

- Name: Micronutrients

- Abbrev: Hemat

- Name: Hematinics

- Abbrev: Vi

- Name: Vitamins

### Intervention Browse Module - Browse Leaves

- ID: M353738

- Name: Lenvatinib

- Relevance: HIGH

- As Found: Primary care

- ID: M137899

- Name: Tislelizumab

- Relevance: HIGH

- As Found: Meet

- ID: M6191

- Name: Leucovorin

- Relevance: LOW

- As Found: Unknown

- ID: M8600

- Name: Fluorouracil

- Relevance: LOW

- As Found: Unknown

- ID: M29233

- Name: Levoleucovorin

- Relevance: LOW

- As Found: Unknown

- ID: M1674

- Name: Oxaliplatin

- Relevance: LOW

- As Found: Unknown

- ID: M8618

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: M11110

- Name: Liver Extracts

- Relevance: LOW

- As Found: Unknown

- ID: M25820

- Name: Protein Kinase Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M1346

- Name: Antineoplastic Agents, Immunological

- Relevance: LOW

- As Found: Unknown

- ID: T447

- Name: Folinic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T446

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T448

- Name: Folate

- Relevance: LOW

- As Found: Unknown

- ID: T475

- Name: Vitamin B9

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000531958

- Term: Lenvatinib

- ID: C000707970

- Term: Tislelizumab

### Misc Info Module

- Version Holder: 2024-05-31
