## Protocol Section
### Identification Module
**NCT ID:** NCT06143579

**Brief Title:** A Study of HAIC Combined With Lenvatinib and Envolizumab in Potentially Resectable Hepatocellular Carcinoma

**Official Title:** FOLFOX-Hepatic Arterial Infusion Chemotherapy (HAIC) Combined With Lenvatinib and Envolizumab in Potentially Resectable Hepatocellular Carcinoma:A Single-arm, Open-label, Single Center, Phase II Trial

#### Organization Study ID Info
**ID:** B2023-561-01
#### Organization
**Class:** OTHER
**Full Name:** Sun Yat-sen University
### Status Module
#### Completion Date
**Date:** 2026-12-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-11-22

**Type:** ACTUAL

**Last Update Submit Date:** 2023-11-16

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2025-03-03

**Type:** ESTIMATED

#### Start Date
**Date:** 2023-12-15

**Type:** ESTIMATED

**Status Verified Date:** 2023-11

#### Study First Post Date
**Date:** 2023-11-22
**Type:** ACTUAL
**Study First Submit Date:** 2023-11-16
**Study First Submit QC Date:** 2023-11-16
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Sun Yat-sen University

#### Responsible Party

**Investigator Affiliation:** Sun Yat-sen University

**Investigator Full Name:** Zhongguo Zhou

**Investigator Title:** Clinical Professor

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** This is a single term, open label, single Center, Phase II Trial. The study is to explore the efficacy and safety of FOLFOX-HAIC combined with Lenvatinib and Envolizumab in the treatment of patients with potentially resectable HCC.

**Detailed Description:** At present, surgery is the preferred modality for the treatment of HCC patients with radical cure and long-term survival. However, 70% to 80% of HCC is advanced, and only 15% to 30% of patients are able to undergo surgical resection. For unresectable HCC, transformation therapy is currently used, and the response rate can be effectively increased through the "TKI plus IO" or "TKI plus IO and local therapy" regimen. For locally advanced HCC (stage III-IV), HAIC or HAIC + systemic therapy is recommended. And the first-line treatment of advanced HCC, TKI (Lenvatinib, Donafenib) or IO combined TKI are recommended. For patients with potentially resectable HCC, there are currently few explorations, and more effective treatment options and evidence-based medical evidence are needed. Therefore, this study investigated the efficacy and safety of FOLFOX-HAIC combined with Lenvatinib and Envolizumab in the treatment of patients with potentially resectable HCC, and explored the relationship between biomarkers, prognostic factors and efficacy.

### Conditions Module

**Conditions:**

- Potentially Resectable Hepatocellular Carcinoma

**Keywords:**

- HAIC

- Lenvatinib

- Envolizumab

- PD-L1

- TKI

- potentially resectable HCC

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 48

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** FOLFOX-HAIC + Lenvatinib + Envolizumab

**Intervention Names:**

- Drug: FOLFOX-HAIC+Lenvatinib+Envolizumab

**Label:** Treatment

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Treatment

**Description:** FOLFOX-HAIC: Oxaliplatin 130 or 85 mg/m2; leucovorin 200 mg/m2; fluorouracil 400 mg/m2 intravenous bolus followed by fluorouracil 2400 mg/m2 continuous infusion over 23 hours, Q3W, 2 to 4 cycles;

Lenvatinib: 8 mg/day (BW \< 60 kg) or 12 mg/day (BW ≥ 60 kg), PO, 3-4 cycles;

Envolizumab: 300 mg, SC, Q3W, 3-4 cycles.

**Name:** FOLFOX-HAIC+Lenvatinib+Envolizumab

**Other Names:**

- KN035

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Defined as the proportion of patients with AE, treatment-related AE (TRAE), immune-related AE (irAE), serious adverse event (SAE), assessed by NCI CTCAE v5.0

**Measure:** AEs

**Time Frame:** Up to 60 days after last treatment or 30 days after surgery

**Description:** Defined as proportion of patients who have a best response of CR or PR

**Measure:** Overall response rate (ORR)

**Time Frame:** At the end of Cycle 4 (each cycle is 21 days)

#### Secondary Outcomes

**Description:** According to post-operative pathology, the proportion of tumor necrosis, viable. tumor cells, and tumor infiltrating lymphocytes indicated by surgical resected specimens.

**Measure:** Pathological complete response (pCR)

**Time Frame:** At the end of the surgery

**Description:** Survival tumor ≤10% after surgery

**Measure:** Major Pathological Response(MPR)

**Time Frame:** At the end of the surgery

**Description:** The tumor was completely removed during surgery, and the resection margin was negative when observed microscopically without residual components of the tumor

**Measure:** R0 resection rate

**Time Frame:** At the end of the surgery

**Description:** Subjects underwent radical resection from the start until the date of the first documented tumor into recurrence or death from any cause in, whichever occurred first within 1 year after surgery

**Measure:** 1-year recurrence-free survival(RFS) rate

**Time Frame:** Up to one years

**Description:** Subjects underwent radical resection from the start until the date of the first documented tumor into recurrence or death from any cause, whichever occurred first

**Measure:** Recurrence-free survival(RFS)

**Time Frame:** Up to two years

**Description:** Defined as the time from enrollment to death from any cause

**Measure:** Overall survival (OS)

**Time Frame:** Up to two years

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Patients who have signed ICF and are able to perform follow-up visits and relevant procedures required in the protocol;
2. Age ≥ 18 years (at the time of signing the ICF);
3. Clinically, histologically or pathologically confirmed hepatocellular carcinoma without extrahepatic metastases;
4. No previous treatment containing PD- (L) 1 inhibitor and Lenvatinib;
5. Potentially resectable HCC: (1)At least one measurable lesion (according to RECIST 1.1 criteria); (2)Patients with stage IIb/IIIa (equivalent to BCLC B/C) with portal vein tumor thrombus (according to Japanese PVTT grading criteria Vp3-Vp4) or more than three tumor nodules; (3)According to the assessment of the site multidisciplinary team (MDT), like surgical resection is not currently the treatment of choice;
6. ECOG score: 0 \~ 1;
7. Child-Pugh score of ≤ 7
8. Estimated survival of more than 6 months;
9. Vital organ function meets the following requirements: (1) Blood routine: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; Platelet count (PLT) ≥ 100 × 109/L; Hemoglobin (HGB) ≥ 90 g/L; (2) Liver function: Serum creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN) or clearance of creatinine ≥ 50 mL/min (Cockcroft-Gault formula); Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ≤ 2.5 × upper limit of normal (ULN); (3) Kidney function: Urine protein \< 2 +; if urine protein ≥ 2 +, 24-h urine protein quantitation test result should be ≤ 1 g;
10. Normal coagulation function, no active bleeding and thrombosis (1) International normalized ratio (INR) ≤ 1.5 × ULN; (2) Active partial thromboplastin time (APTT) ≤ 1.5 × ULN; (3) Prothrombin time (PT) ≤ 1.5 × ULN;
11. Female patients of childbearing age or male patients with female sexual partners of childbearing age should take effective contraceptive measures during study treatment and for 3 months after the end of study treatment; serum or urine HCG tests must be negative and must be non-lactating within 7 days before study enrollment;
12. Patients should be compliant and cooperative with safety and survival follow-up.

Exclusion Criteria:

1. Participate in other interventional clinical studies;
2. Previous or concurrent other malignancies;
3. History of liver transplantation or undergo liver transplantation;
4. History of hypersensitivity to macromolecular protein preparations, the study drug or any of the excipients;
5. Active autoimmune disease or history of autoimmune diseases (such as the following, but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, previous thyroid surgery); Require bronchodilators for medical intervention of asthma; the patient has vitiligo or has complete remission of asthma in childhood, no intervention is required after adults can be included;
6. Use immunosuppressive agents, or systemic or absorbable local hormone therapy to achieve immunosuppressive purposes (dose \> 10 mg/day prednisone or other effective hormones), and continue to use within 2 weeks before enrollment;
7. Uncontrolled cardiac clinical symptoms or diseases, for example: (1) NYHA class 2 or higher heart failure;(2) Unstable angina pectoris; (3) Myocardial infarction within 1 year; (4) Clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention;
8. Use traditional Chinese medicine immunomodulator within 2 weeks before enrollment;
9. Severe active infection or unexplained fever \> 38.5 degrees during screening and before the first dose (subjects can be enrolled due to tumor-induced fever at the investigator discretion);
10. Congenital or acquired immunodeficiency: (1)HIV infection; (2)Active hepatitis (hepatitis B reference: HBV DNA ≥ 1000 IU/mL; hepatitis C reference: HCV RNA ≥ 1000 IU/mL); chronic hepatitis B virus carriers, HBV DNA \< 2000 IU/ml, must receive concurrent antiviral therapy during the trial to be enrolled;
11. Live vaccines less than 4 weeks prior to study medication or likely during the study;
12. History of psychiatric drug abuse, alcoholism, or drug abuse;
13. Chinese herbal medicine within 4 weeks prior to first treatment;
14. Factors that may cause forced halfway termination of this study, such as other serious diseases (including mental illness) requiring concomitant treatment, serious laboratory abnormalities, accompanied by family or social factors, which may affect the subject' s safety, the collection of data and samples, or other circumstances which are unsuitable for subject enrollment as judged by the investigator.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** zhouzhg@sysucc.org.cn

**Name:** Zhongguo Zhou

**Role:** CONTACT

**Contact 2:**

**Email:** lichq@sysucc.org.cn

**Name:** Chaoqun Li

**Phone:** +86 20-87343879

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** Sun Yat-sen University

**Name:** Zhongguo Zhou

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**Citation:** Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Li X, Wang L, Wang L, Liu Y, Liu J, Zhang M, Qi J, Yu S, Afshin A, Gakidou E, Glenn S, Krish VS, Miller-Petrie MK, Mountjoy-Venning WC, Mullany EC, Redford SB, Liu H, Naghavi M, Hay SI, Wang L, Murray CJL, Liang X. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019 Sep 28;394(10204):1145-1158. doi: 10.1016/S0140-6736(19)30427-1. Epub 2019 Jun 24. Erratum In: Lancet. 2020 Jul 4;396(10243):26.

**PMID:** 31248666

**Citation:** Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023 Jan;73(1):17-48. doi: 10.3322/caac.21763.

**PMID:** 36633525

**Citation:** Akateh C, Black SM, Conteh L, Miller ED, Noonan A, Elliott E, Pawlik TM, Tsung A, Cloyd JM. Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma. World J Gastroenterol. 2019 Jul 28;25(28):3704-3721. doi: 10.3748/wjg.v25.i28.3704.

**PMID:** 31391767

**Citation:** Zhang T, Zhang L, Xu Y, Lu X, Zhao H, Yang H, Sang X. Neoadjuvant therapy and immunotherapy strategies for hepatocellular carcinoma. Am J Cancer Res. 2020 Jun 1;10(6):1658-1667. eCollection 2020.

**PMID:** 32642282

**Citation:** Papadopoulos KP, Harb W, Peer CJ, Hua Q, Xu S, Lu H, Lu N, He Y, Xu T, Dong R, Gong J, Liu D. First-in-Human Phase I Study of Envafolimab, a Novel Subcutaneous Single-Domain Anti-PD-L1 Antibody, in Patients with Advanced Solid Tumors. Oncologist. 2021 Sep;26(9):e1514-e1525. doi: 10.1002/onco.13817. Epub 2021 May 27.

**PMID:** 33973293

**Citation:** Chen M, Jiang M, Wang X, Shen L, Li J. Envafolimab - first PD-1/PD-L1 antibody to be administered by subcutaneous injection for microsatellite instability-high or deficient mismatch repair advanced solid tumors. Expert Opin Biol Ther. 2022 Oct;22(10):1227-1232. doi: 10.1080/14712598.2022.2125799. Epub 2022 Sep 20.

**PMID:** 36124972

**Citation:** Shimizu T, Nakajima TE, Yamamoto N, Yonemori K, Koyama T, Kondo S, Sunakawa Y, Izawa N, Horie Y, Xiang S, Xu S, Qin L, Gong J, Liu D. Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors. Invest New Drugs. 2022 Oct;40(5):1021-1031. doi: 10.1007/s10637-022-01287-7. Epub 2022 Aug 6.

**PMID:** 35932387

**Citation:** Huang X, Xu L, Ma T, Yin X, Huang Z, Ran Y, Ni Y, Bi X, Che X. Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study. Front Oncol. 2021 Nov 16;11:751159. doi: 10.3389/fonc.2021.751159. eCollection 2021.

**PMID:** 34868952

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009375

- Term: Neoplasms, Glandular and Epithelial

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000000230

- Term: Adenocarcinoma

- ID: D000008113

- Term: Liver Neoplasms

- ID: D000004067

- Term: Digestive System Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000004066

- Term: Digestive System Diseases

- ID: D000008107

- Term: Liver Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: All

- Name: All Conditions

- Abbrev: BC06

- Name: Digestive System Diseases

### Condition Browse Module - Browse Leaves

- ID: M5534

- Name: Carcinoma

- Relevance: HIGH

- As Found: Carcinoma

- ID: M9613

- Name: Carcinoma, Hepatocellular

- Relevance: HIGH

- As Found: Hepatocellular Carcinoma

- ID: M12320

- Name: Neoplasms, Glandular and Epithelial

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M3585

- Name: Adenocarcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M11113

- Name: Liver Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M8886

- Name: Gastrointestinal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7256

- Name: Digestive System Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7255

- Name: Digestive System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M8883

- Name: Gastrointestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M11107

- Name: Liver Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000002277

- Term: Carcinoma

- ID: D000006528

- Term: Carcinoma, Hepatocellular

### 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

### Intervention Browse Module - Browse Branches

- Abbrev: Micro

- Name: Micronutrients

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: ANeo

- Name: Antineoplastic Agents

### Intervention Browse Module - Browse Leaves

- ID: M6191

- Name: Leucovorin

- Relevance: LOW

- As Found: Unknown

- ID: M8600

- Name: Fluorouracil

- Relevance: LOW

- As Found: Unknown

- ID: M353738

- Name: Lenvatinib

- Relevance: HIGH

- As Found: Fibrillation

- ID: M1674

- Name: Oxaliplatin

- 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

### Intervention Browse Module - Meshes

- ID: C000531958

- Term: Lenvatinib

### Misc Info Module

- Version Holder: 2024-05-24
