Clinical trial NCT05717738: Combined TACE, TKI/Anti-VEGF and ICIs as Conversion Therapy for Advanced Hepatocellular Carcinoma
Official title: Combined Transarterial Chemoembolization, Tyrosine Kinase Inhibitor/ Anti-VEGF Antibody, and Anti-PD-1/ PD-L1 Antibody as Conversion Therapy for Advanced Hepatocellular Carcinoma: a Multicenters, Real-world, Ambispective Cohort Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Hepatocellular Carcinoma Non-resectable
Keywords: Hepatocellular Carcinoma
Downstaging conversion therapy
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
Collaborators: name: Chinese Cooperative Group of Liver Cancer
name: Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province
name: The Second Affiliated Hospital of Fujian Medical University
name: Geneplus-Beijing Co. Ltd.
name: Haplox Biotechnology Co., Ltd.
First posted: 2023-02-08
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with advanced hepatocellular carcinoma which initially unsuitable for the radical therapy, including resection, transplantation, or ablation.

Brief summary: The aim of this study is to the efficacy, prognosis, adverse effects, and factors for predicting therapeutic effects and clinical prognosis of combined therapy of transarterial chemoembolization (TACE), Anti-VEGF antibodies or pan-target anti-angiogenic drugs, and anti-PD-1/ PD-L1 antibody for advanced hepatocellular carcinoma which initially unsuitable for the radical therapy, including resection, transplantation, or ablation.

Detailed description: The multicenter, non-random, open and ambispective real-world cohort study is conducted at 4 research centers, including 3 centers (Hankou, Sino-French New District, and Optical Valley) of Tongji hospital (Wuhan, China) and one in the second affiliated hospital of Fujian Medical University (Quanzhou, China). It is estimated that 300 patients with advanced HCC will be enrolled in these 4 research centers. And it is planned to complete the enrollment within 1 year and it is expected that all enrolled subjects will reach the observation end point in 3 years. Radiological assessments are performed every two cycles over the course of treatment, then every 3 months within the first two years following the completion of treatment and every 6 months thereafter, until PD were recorded. All subjects are followed until death or lost to follow up.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years old
2. Diagnosis of HCC is according to the American Association for the Study of Liver Diseases or European Association for the Study of the Liver guidelines of HCC management;
3. at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or mRESIST criteria.
4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
5. Hepatocellular carcinoma (HCC) was assessed as not suitable for radical resection, liver transplant, or ablation treatment after the assessment of a multidisciplinary team because either: (1) R0 resection was not feasible; (2) remnant liver volume was less than 30% in patients who did not have cirrhosis or 40% in patients with cirrhosis, or the results of an indocyanine green test were higher than 15%; (3) patients had Barcelona Clinic Liver Cancer (BCLC) stage B or BCLC stage C.
6. portal vein involvement (Chen's groups A, or Cheng's type I-II) is allowed: Chen's group A1 or Cheng's type I, tumor thrombus is involved in segmental or sectoral branches of the portal vein or above; Chen's group A2 or Cheng's type II, involvement of the first branch of portal vein.
7. hepatic vein invasion (VV1 to VV2) were allowed.
8. Patients with extrahepatic oligometastasis is allowed: extrahepatic oligometastasis was defined as up to three metastatic lesions in up to two organs with the largest diameter of 3 cm
9. Child-Pugh liver function class A-B7
10. No prior transplantation, TACE, or radioembolization to the liver was allowed. Prior locoregional therapies, such as surgical resection, radiotherapy, radiofrequency ablation, percutaneous ethanol injection or cryoablation, are allowed if the disease have progressed since prior treatment. Local therapy must have been completed at least 4 weeks prior to the baseline scan.
11. Adequate organ and marrow function, as defined below:

(1) Hemoglobin ≥80 g/L (2) Absolute neutrophil count ≥1.5 ×109/L (3) Platelet count ≥50 ×109/L (4) Total bilirubin \< 51 μmol/L (5) Alanine transaminase (ALT) and aminotransferase (AST)≤5×ULN (6) Albumin ≥28 g/L (7) INR ≤1.6 (8) Serum creatinine \< 110 μmol/L 12. Time interval between TACE and systemic therapy within 7 days.

Exclusion Criteria:

1. Prior invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured 2. Severe, active and uncontrolled co-morbidity including but not limited to:

1. Persistent or activity (except the HBV and HCV) infection;
2. symptoms of congestive heart failure and uncontrolled diabetes;
3. uncontrolled hypertension, systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100 mmHg despite anti-hypertension medications ≤ 28 days before randomization or first dose of drug.
4. unstable angina,
5. uncontrolled arrhythmias,
6. active ILD,
7. severe chronic GI disease accompanied by diarrhea,
8. compliance with requirements may limit the research, resulted in significant increase risk of AE or influence Subjects provided psychiatric/social problem status on their ability to provide written informed consent.
9. A history of active primary immunodeficiency or human immunodeficiency virus; (10) Active or previous records of autoimmune disease or inflammatory diseases, including inflammatory bowel disease (e.g., colitis or Crohn's disease\], diverticulitis, except \[diverticulosis\], systemic lupus erythematosus (SLE), sarcoidosis syndrome or Wegener syndrome (e.g., granulomatous vasculitis, gray's disease, rheumatoid arthritis, the pituitary gland inflammation and uveitis\]).

(11) A history of hepatic decompensation, including refractory ascites, gastrointestinal bleeding, or hepatic encephalopathy; 3. Known to produce allergic or hypersensitive reactions to any study drug or any excipient thereof; 4. Significant clinical gastrointestinal bleeding or a potential risk of bleeding was identified by the investigator during the 30 days prior to study entry.

5. Tumors of the central nervous system, including metastatic brain tumors; 6. Pregnant women or breast-feeding patients; 7. Has received anti-tumor system therapy for HCC. Non-anti-tumor purpose combined hormone therapy (e.g., hormone replacement therapy) is excluded.

8. Is currently using, or has used an immunosuppressive drug within 14 days prior to the first dose of the investigational drug. This standard has the following exceptions: (1) intranasal, inhaled, topical or topical steroids. (e.g., intraarticular) (2) Systemic corticosteroid therapy not exceeding 10 mg/ day of prednisone; (3) prophylactic use of steroids for hypersensitivity. (e.g., CT scan pretherapy medication) 9. A live attenuated vaccine was administered within 30 days prior to the first administration of the study drug. Note: If enrolled, patients shall not receive live attenuated vaccine within 30 days of receiving study drug therapy and after the last administration of study drug.

10. Extrahepatic vascular involvement or thrombosis: main trunk of portal vein and superior mesenteric vein (Cheng's type III and IV) or inferior vena cava (IVC) (VV3).

Primary outcomes:
measure: Number of Patients Amendable to Curative Surgical Interventions
timeFrame: from the date of first treatment to the date of last treatment, an average of 3 years
Secondary outcomes:
measure: Response Rate measured by mRECIST criteria
timeFrame: from the date of first treatment to radiographically documented progression according to mRECIST v1.1, assessed up to 3 years
measure: Time to progression (TTP)
timeFrame: from the date of first treatment to radiographically documented progression according to mRECIST1.1, assessed up to 3 years
measure: Time to intrahepatic tumor progression (TTITP)
timeFrame: from the date of first treatment to radiographically documented intrahepatic tumor progression according to mRECIST 1.1, assessed up to 3 years
measure: Progression-free survival (PFS)
timeFrame: from the date of first treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause, whichever occurs first, assessed up to 3 years
measure: Overall survival (OS)
timeFrame: from the date of first treatment to the date of death from any cause, assessed up to 5 years
measure: Incidence of Study-Related Adverse Events
timeFrame: from the date of first treatment to 90 days after last treatment, around 3 years and 90 days
measure: Pathological response
timeFrame: from the date of first treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause, whichever occurs first, assessed up to 5 years.
measure: Disease control rate
timeFrame: from the date of first treatment to radiographically documented response according to mRECIST 1.1, assessed up to 3 years.
measure: Duration of response
timeFrame: from the date of first documented evidence of CR or PR to first documented sign of PD or death from any cause according to mRECIST 1.1, assessed up to 3 years
measure: Quality of Life (QoL) after treatment
timeFrame: 3 year
Other outcomes:
Locations:
city: Quanzhou
country: China
facility: The Second Affiliated Hospital of Fujian Medical University
state: Fujian
city: Wuhan
country: China
facility: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Optical Valley branch of Tongji hospital
state: Hubei
city: Wuhan
country: China
facility: Sino-French branch of Tongji hospital
state: Hubei
Study officials:
affiliation: Tongji Hospital
name: Ze-yang Ding, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chiang CL, Chiu KWH, Chan KSK, Lee FAS, Li JCB, Wan CWS, Dai WC, Lam TC, Chen W, Wong NSM, Cheung ALY, Lee VWY, Lau VWH, El Helali A, Man K, Kong FMS, Lo CM, Chan AC. Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Feb;8(2):169-178. doi: 10.1016/S2468-1253(22)00339-9. Epub 2022 Dec 15.
citation: Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.
citation: Luo L, He Y, Zhu G, Xiao Y, Song S, Ge X, Wang T, Xie J, Deng W, Hu Z, Shan R. Hepatectomy After Conversion Therapy for Initially Unresectable HCC: What is the Difference? J Hepatocell Carcinoma. 2022 Dec 22;9:1353-1368. doi: 10.2147/JHC.S388965. eCollection 2022.