Phase II Study of Fruquintinib Combined With Sintilimab and TACE for Inoperable Primary Hepatocellular Carcinoma

The goal of this prospective, interventional clinical trial is to evaluation of fruquintinib in combination with sintulimab and TACE for inoperable primary hepatocellular carcinoma for progression-free survival (PFS).

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Fruquintinib; Drug: Sintilimab; Device: Transcatheter arterial chemoembolization（TACE）

Detailed Description

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, accounting for approximately 745,000 deaths annually and 9.1% of all cancer-related deaths worldwide, with only about 30% of HCC patients having access to curative therapies. Most patients have intermediate to advanced disease and are usually treated with palliative therapy using TACE or systemic therapy (e.g., sorafenib, lenvatinib).

The efficacy of either sorafenib or lenvatinib as a single agent in the treatment of hepatocellular liver cancer remains limited, therefore, exploring combination therapy is one of the current research hotspots. A recent randomized, open, multicenter clinical study (TACTICS) enrolling patients with unresectable HCC showed that PFS was significantly prolonged to 25.2 months in the TACE combined with sorafenib treatment group, compared to 25.2 months in the TACE alone group. PFS was only 13.5 months in the TACE treatment group (HR=0. 59, 95%CI: 0.41-0. 87, P=0. 006). Median TTP was 24.1 months in the combination treatment group and 13.5 months in the TACE treatment group alone (HR=0. 56, 95%CL 0. 38-0. 83, P=0. 004).

Sintilimab, a recombinant fully human IgG4-type PD-1 monoclonal antibody, is an innovative drug developed by Sintilimab (Suzhou) Co. At the end of 2018, Sintilimab was officially approved by the NMPA of china for the treatment of relapsed or refractory classic Hodgkin's lymphoma (cHL) after at least second-line systemic chemotherapy. As a biosimilar to pembrolizumab, sintilimab has great potential to play a role similar to that played by pembrolizumab in primary hepatocellular carcinoma.

Fruquintinib is a potent small molecule VEGFR inhibitor developed by Hutchmed Ltd. with full intellectual property rights, with high kinase selectivity and inhibitory activity only for the VEGFR kinase family (VEGFR1, 2 and 3).On September 5, 2018, the NMPA of china officially approved fruquintinib for patients who have previously received fluorouracil-based, oxaliplatin and irinotecan-based chemotherapy, and for patients with metastatic colorectal cancer (mCRC) who have received prior or are not suitable for prior anti-vascular endothelial growth factor (VEGF) therapy, anti-epidermal growth factor receptor (EGFR) therapy (RAS wild type).

Therefore, based on previous studies, this study intended to select patients with unresectable primary hepatocellular carcinoma, and prospectively observe the efficacy and safety of fruquintinib in combination with sintilimab and TACE in the treatment of unresectable CNLC(China liver cancer staging) 2b-3a patients.

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Guoliang Shao; Phone Number: +8613958183472; Email: shaoguoliang666@hotmail.com
• Study Contact Backup: Name: Hui Zeng; Phone Number: +8613989898089; Email: zenghuiray@zjcc.org.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Recruiting
      • Guoliang Shao
      • Contact: Guoliang Shao; Phone Number: +8613958183472; Email: shaoguoliang666@hotmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age 18-75 years, male or female;
2. Patients diagnosed with primary hepatocellular carcinoma (HCC) based on clinical diagnosis or pathology;
3. Patients diagnosed with Chinese stage IIb-IIIa according to the Primary Liver Cancer Diagnostic and Treatment Protocol (2019 version), and evaluated by the investigator to be unable to undergo surgical treatment, such as resection, ablation or liver transplantation;
4. Imaging reports within 14 days prior to the intervention showed the presence of at least 1 target lesion measurable by CT or MRI, and the lesion is suitable for repeated accurate measurements;
5. Child-Pugh liver function rating: grade A or better B (≤7 points);
6. ECOG score: 0-1;
7. all lesions amenable to phase 1 or 2 (fractionated TACE) TACE therapy;
8. Good organ and bone marrow function. Blood count: WBC>4. 0 × 109/L, Hb>80g/L, PLT>75 ×109/L, NEUT>/ 1.5 × 109/L; coagulation function:International normalized (prothrombin time) ratio(INR) <1.2; liver function indexes: serum albumin (ALB) >3.5 g/dl, serum total bilirubin(TBIL) <1.5 times the upper limit of normal value (excluding biliary obstruction), serum transaminases (ALT and AST)<3 times the upper limit of normal value; renal function: serum myelin (CR) <1.5 times the upper limit of normal value;
9. Patients with positive hepatitis B surface antigen need to have received anti-hepatitis B treatment prior to inclusion in the study;
10. Signed an informed consent form, were compliant and cooperated with the follow-up.

Exclusion Criteria:

1. Hepatobiliary cell carcinoma, sarcomatoid hepatocellular carcinoma, mixed cell carcinoma and fibrous lamellar hepatocellular carcinoma;
2. With portal trunk or vena cava invasion;
3. Having received interventional treatment such as TACE within 2 years
4. Combined with medical contraindications that preclude any contrast-enhanced imaging (CT or MRI);
5. Previous systemic therapy;
6. Uncontrollable ascites, hepatic encephalopathy or bleeding esophagogastric fundic varices;
7. Hypertension that cannot be reduced to within normal limits with antihypertensive medication (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg);

8. Suffering from myocardial ischemia or myocardial infarction of grade II or higher, poorly controlled arrhythmia of grade II or higher myocardial ischemia or infarction, poorly controlled arrhythmia (QTc interval greater than or equal to 450 ms, QTc interval calculated in Fridericia metric).

   (calculated in Fridericia formula);

9. History of gastrointestinal bleeding within the past 3 months or a clear tendency of gastrointestinal bleeding, such as: esophageal varices at risk of bleeding, locally active ulcer lesions, fecal occult blood (++);
10. Pregnant or breastfeeding women; patients of childbearing potential who are unwilling or unable to use effective contraceptive measures
11. HIV-infected patients;
12. Those suspected of being allergic to the study drug;
13. Other circumstances that, in the judgment of the investigator, may affect the conduct of the clinical study and the determination of the study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: treatment; Fruquintinib+sintilimab+TACE	Drug: Fruquintinib; Fruquintinib:5 mg capsule orally once daily on day 1-21 in 28-day cycles； Drug: Sintilimab; Sintilimab: 200 mg i.v. every 3 weeks; Device: Transcatheter arterial chemoembolization（TACE）; Transcatheter arterial chemoembolization（TACE）

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival(PFS)	Progression free survival period refers to the period from the beginning of treatment to the time when patients with cancer progress is observed or death occurs for any reason.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Object response rate(ORR)	The proportion of patients whose tumor volume reduction reaches the predetermined value and can maintain the minimum time limit. It is the sum of the proportion of complete response (CR) and partial response(PR).	Change from baseline tumor volume at 6 months
Time to response(TTR)	Time to response	through study completion, an average of 1 year
Disease control rate(DCR)	It is the sum of the proportion of complete response (CR), partial response(PR) and stable disease(SD).	1 year
Overall survival(OS)	(OS) is defined as the time from the patient's first dose of study drug until any cause of their death.	1 year
Time to progression(TTP)	Time from the beginning of treatment to the objective progression of tumor	24 months

Collaborators and Investigators

• Sponsor: Zhejiang Cancer Hospital
• Investigators: Principal Investigator: Guoliang Shao, Zhejiang Cancer Hospital Hangzhou, Zhejiang, China

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2021
• Primary Completion (Estimated): December 23, 2024
• Study Completion (Estimated): December 23, 2024

Study Registration Dates

• First Submitted: July 10, 2023
• First Submitted That Met QC Criteria: August 1, 2023
• First Posted (Actual): August 2, 2023

Study Record Updates

• Last Update Posted (Actual): August 2, 2023
• Last Update Submitted That Met QC Criteria: August 1, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: IRB-2021-385

Drug and device information, study documents

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