Anti-angiogenic Agents Plus Anti-PD-1 Antibodies for uHCC

Combination Therapy With Anti-angiogenic Agents and Anti-PD-1 Antibodies for Unresectable or Advanced Hepatocellular Carcinoma: a Cohort Study

Combination treatment with antiangiogenic agents and anti-programmed cell death protein 1 (PD-1) antibodies have shown high anti-tumor efficacy for patients with unresectable or advanced hepatocellular carcinoma (uHCC). In this single-center cohort study, we are aiming to (1) evaluate the clinical effectiveness in real-world patients, especially for Chinese patients, most of whom were with hepatitis B virus infection; (2) predict clinical effectiveness with clinicopathological features; (3) predict clinical effectiveness with histologic features and blood samples.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Anti-angiogenic agents plus anti-PD-1/PD-L1 antibodies

Detailed Description

Combination treatment with antiangiogenic agents and anti-programmed cell death protein 1 (PD-1) antibodies have shown high anti-tumor efficacy for patients with unresectable or advanced hepatocellular carcinoma (uHCC). In this single-center cohort study, we are aiming to:

1. To evaluate the clinical effectiveness in real-world patients, especially for Chinese patients most of whom were with hepatitis B virus infection.
2. To predict clinical effectiveness with clinicopathological features, such as lab examinations (at baseline and dynamic changes), radiological features (radiomics study at the baseline);
3. To predict clinical effectiveness with histologic features, such as PD-L1 expression, ctDNA, and peripheral immune cell subtypes.
4. To evaluate the clinical effectiveness of second- or third-line therapies, including TACE, HAIC, and interferon, for those who lost clinical benefit or who were intolerant to the combination therapy.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

• Study Contact: Name: Xiao-Dong Zhu; Phone Number: +862164037181; Email: zhuxiaodong@gmail.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Zhongshan Hospital, Fudan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Unresectable or advanced HCC patients who received the combination therapy with an anti-angiogeic agent and an anti-PD-1/PD-L1 agent.

Description

Inclusion Criteria:

1. Documented diagnosis of HCC confirmed by histology/cytology or clinical diagnosis of HCC by Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2019 edition) criteria.
2. Unresectable or advanced disease at the investigator's discretion. The advanced stage was BCLC C stage or China Liver Cancer Stage IIIa or IIIb.
3. Child-Pugh class A or B7.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
5. Subjects received combination therapy with an anti-angiogenic agent and an anti-PD-1/PD-L1 antibody, received at least one imaging evaluation, and signed an Informed Consent Form. Anti-angiogenic agents include sorafenib, lenvatinib, apatinib, and bevacizumab; anti-PD-1/PD-L1 antibodies include pembrolizumab, nivolumab, sintilimab, toripalimab, camrelizumab, tislelizumab, and atezolizumab.
6. Adequate hematologic and end-organ function.

Exclusion Criteria:

1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
2. History of malignancy other than HCC within 5 years prior to the therapy, with the exception of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or papillary thyroid carcinoma.
3. History of organ transplantation or hepatic encephalopathy.
4. Allergic to anti-angiogenic agents or anti-PD-1/PD-L1 agents.
5. History of gastrointestinal perforation and/or fistula within the 6 months, a history of intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection, Crohn's disease, ulcerative colitis, or chronic diarrhea within 6 months.
6. Active autoimmune disease requiring systemic therapy within 2 years prior to the first dose, allowing the use of alternative therapies (e.g., thyroxine, insulin, or physiologic corticosteroids for adrenal or pituitary insufficiency); history of primary immunodeficiency; presence of only autoimmune antibody-positive subjects. The presence of autoimmune disease needs to be confirmed at the investigator's discretion.
7. Uncontrollable hypertension, SBP >140 mmHg or DBP >90 mmHg after optimal medical therapy, hypertensive crisis, or history of hypertensive encephalopathy.
8. Subjects had a bleeding event in the past 6 months due to esophageal or gastric fundus varices induced by portal venous hypertension; subjects have undergone a gastrointestinal endoscopy within 3 months prior to the first dose to diagnose the presence of severe (G3) varices; subjects had a high risk of bleeding as assessed by the investigator.
9. Subject requests withdrawal of informed consent.
10. Other conditions that the investigator deems inappropriate for participation in this study.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Combinational therapy; Participants who receive systemic treatment with an anti-angiogenic agent, including sorafenib, lenvatinib, apatinib, and bevacizumab, in combination with an anti-PD-1/PD-L1 antibody, including pembrolizumab, nivolumab, sintilimab, toripalimab, camrelizumab, tislelizumab, and atezolizumab.	Drug: Anti-angiogenic agents plus anti-PD-1/PD-L1 antibodies; Combination therapies with an anti-angiogenic agent (tyrosine kinase inhibitor or VEGF/VEGFR antibody) and an anti-PD-1/PD-L1 antibody.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response	Subjects with complete response or partial response	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response	the interval between the time of partial or complete response to the time of progressive disease	up to 2 years
Progression free survival	the interval between the time of treatment initiation to the time of progressive disease or patient death	up to 2 years
Overall survival	the interval between the time of treatment initiation to the time of patient death	up to 2 years
Ratio of R0 resection	The ratio of patients who underwent R0 resection to patients received combination therapy	up to 2 years
Recurrence-free survival	the interval between the time of surgical resection to the time of disease recurrence or patient death for those who underwent surgery	up to 5 years
Time to deterioration in patient-reported quality of life, physical functioning, and role functioning	Quality of life, physical functioning, and role functioning was determined by EORTC QLQ-C30 and QLQ-HCC18 questionnaires.	up to 2 years

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital
• Investigators: Principal Investigator: Hui-Chuan Sun, MD, PhD, Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2020
• Primary Completion (Anticipated): July 31, 2022
• Study Completion (Anticipated): July 31, 2023

Study Registration Dates

• First Submitted: November 19, 2020
• First Submitted That Met QC Criteria: November 19, 2020
• First Posted (Actual): November 20, 2020

Study Record Updates

• Last Update Posted (Actual): July 26, 2021
• Last Update Submitted That Met QC Criteria: July 23, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: lenvatinib; PD-1 antibody; anti-angiogenic; PD-L1 antibody
• 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; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibodies; Angiogenesis Inhibitors
• Other Study ID Numbers: COMOHCC

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