Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Bevacizumab

Atezolizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Immune Checkpoint Inhibitors

Atezolizumab plus bevacizumab

Hong Jae Chon, MD, PhD

Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related deaths globally and in Korea. Many patients diagnosed at advanced stage, and systemic therapy is mainstay of treatment in patients with advanced HCC.

However, immune-checkpoint inhibitor (ICI) monotherapy did not significantly improve overall survival in phase III studies. According to previous retrospective analyses, ICI treatment in advanced HCC showed different organ-specific responses. The intrahepatic HCC was the least responsive organ to ICI treatment. The failure of phase III trials of ICI monotherapy may have been attributed to different organ-specific response pattern of ICIs.

Combination of atezolizumab plus bevacizumab is expected to overcome the immunosuppressive microenvironment of liver and may enhance intrahepatic response of ICI.

In a previous retrospective analysis of pembrolizumab treated patients with advanced melanoma and NSCLC, patients with liver metastases showed poorer PFS compared with those without liver metastases with reduced ORR. Similar observations have also been reported in metastatic of triple-negative breast cancer patients, there were no responses in patients with liver metastases. Taken together the results of previous studies, hepatic metastases had reduced response to ICI compared with metastases at other organs, regardless of cancer types.

In addition, ICI treatment in advanced HCC showed different organ-specific responses. The poorer response rate in liver to ICI might be affected by liver-specific immunosuppressive microenvironment (TME). To overcome the unfavorable immunosuppressive TME of the liver, combination strategies are needed to achieve enhanced anti-tumor immune responses or alleviated tumor-associated immunosuppression.

Since the cause of death in most HCC patients was hepatic failure due to intrahepatic HCC or underlying liver cirrhosis, the response rate to ICI of intrahepatic tumor lesions is a crucial factor in determining the overall prognosis of advanced HCC.

Therefore, we hypothesize that combination strategy of atezolizumab plus bevacizumab may increase organ specific response in patients with advanced HCC, and may improve survival outcomes accordingly.

Objectives We hypothesize that combination strategy of atezolizumab plus bevacizumab may increase organ specific response in patients with advanced HCC, and may improve survival outcomes accordingly.

Organ-specific Responses to Atezolizumab Plus Bevacizumab in Advanced HCC

Organ-specific Responses to Atezolizumab Plus Bevacizumab in Patients With Advanced Hepatocellular Carcinoma

Organ-specific response rate were established to evaluate the heterogenous responses of different organ systems to immunotherapy in previous analysis. We select the largest lesions representative of involved organs (up to a maximum of two per organ and five total). Lesions of each organ were measured unidimensionally. Each lesion will be evaluated according to RECIST 1.1 (CR, complete disappearance or LN short axis diameter \< 1.0cm; PR, ≥30% reduction; PD, ≥20% increase; SD, neither CR, PR nor PD). New lesions did not always indicate PD, and were added to those of the original target lesions to determine the total tumor burden.

Hoffmann-La Roche

CHA University

Candonilimab 10mg/kg, Bevacizumab 15mg/kg, every 3 week

Candonilimab

Ming Shi, MD

To explore the efficacy and safety of candonilimab plus bevacizumab for patients with advanced hepatocellular carcinoma who progressed on atezolizumab plus bevacizumab.

Atezolizumab plus bevacizumab is the first-line treatent for patients with advanced hepatocellular carcinoma. However, the second-line treatment is absent for patients who progressed on atezolizumab plus bevacizumab. Candonilimab is a humanized bisspecific monoclonal antibody against PD-1/ CTLA-4 IgG1. Candonilimab plus lenvatinib showed strong anti-tumor effect, with objective response of 44%. This single-arm, prospective, phase 2 trial is to explore the efficacy and safety of candonilimab plus bevacizumab for patients with advanced hepatocellular carcinoma who progressed on atezolizumab plus bevacizumab.

Candonilimab Plus Bevacizumab for Patients With Advanced HCC Who Progressed on A+T

Candonilimab Plus Bevacizumab as Second-line Treatment for Patients With Advanced Hepatocellular Carcinoma Who Progressed on Atezolizumab Plus Bevacizumab: a Single Arm, Phase 2 Trial

DCR （Disease Control Rate） include complete response, partial response and stable Disease per RECIST 1.1

OS is the length of time from the date of randomization until death from any cause.

PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor progression or death due to any cause.

Objective response rate (complete response+partial response) per RECIST 1.1

Safety will be evaluated according to the NCI CTCAE Version 4.03. All observations pertinent to the safety of the study medication will be recorded on the CRF and included in the final report.

The blood specimen and needle biopsy specimen would be collected

Shi Ming

Proffessor

Atezolizumab plus bevacizumab is the first-line treatent for patients with advanced hepatocellular carcinoma. However, the second-line treatment is absent for patients who progressed on atezolizumab plus bevacizumab. Candonilimab is a humanized bisspecific monoclonal antibody against PD-1/CTLA-4 IgG1. Candonilimab plus lenvatinib showed strong anti-tumor effect, with objective response of 44%. This single-arm, prospective, phase 2 trial is to explore the efficacy and safety of candonilimab plus bevacizumab for patients with advanced hepatocellular carcinoma who progressed on atezolizumab plus bevacizumab.

Heart and Blood Diseases

Thrombosis

Hematinics

Micronutrients

Anti-Infective Agents

Chlorotrianisene

Liver Extracts

Iodine

Cadexomer iodine

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immunologic Factors

TACE will be performed for the patients after randomization. Iodion-125 seeds will be implanted into the PVTT under CT guidance within 3-7 days after the first TACE.

Atezolizumab/bevacizumab (1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks) will be started at 3-7 days after the first TACE and I-125 Seeds Brachytherapy.

TACE and iodion-125 seeds implantation can be repeated on demand during follow-up based on the evaluation of laboratory and imaging examination.

TACE will be performed for the patients after randomization. Atezolizumab/bevacizumab (1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks) will be started at 3-7 days after the first TACE.

TACE can be repeated on demand during follow-up based on the evaluation of laboratory and imaging examination.

Iodine125 seed implantation into the PVTT was conducted 3-7 days after TACE when the results of the liver function tests were comparable to those obtained before TACE. Pre-procedural planning was conducted using a three-dimensional conformal radiation therapy treatment planning system (TPS) to determine the number of Iodine125 seeds required, the target location for implantation, the best percutaneous puncture site and the access route. The targeted zone for implantation was the tumour thrombosis in the segmental portal vein, left/right portal vein. Implantation was guided by CT, and the Iodine125 seeds were implanted into the PVTT using 18 G needles and the implantation gun that housed the Iodine125 seeds in the cartridge chamber.

I-125 Seeds Brachytherapy in PVTT

TACE: cTACE (conventional TACE) or dTACE (drug-eluting beads TACE).

Transcatheter arterial chemoembolization

Atezolizumab/bevacizumab (1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks) .

Atezolizumab plus Bevacizumab

Mingsheng Huang, M.D. & Ph.D.

Luwen Mu, M.D.

The present study aimed to assess the effectiveness of the combination treatment of Atezolizumab/Bevacizumab, transcatheter arterial chemoembolization (TACE) and I-125 Seeds Brachytherapy (TACE-AB-I) in patients with advanced hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). The investigators confirmed that the combination therapy yielded better survival data than the combined administration of Atezolizumab/Bevacizumab and TACE (TACE-AB) in patients with advanced HCC and Type I/II PVTT (Based on Cheng's PVTT classification).

This is a multicenter, open-label trial, randomized controlled to evaluate the efficacy and safety of TACE-AB-I compared with TACE-AB for the treatment of HCC with branch PVTT. 234 HCC patients with branch PVTT will be enrolled in this study. The Patients will be treated with TACE-AB-I or TACE-AB using a 1:1 randomization scheme. TACE will be performed for the patients after randomization. Atezolizumab/bevacizumab (1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks) will be started at 3-7 days after the first TACE and I-125 Seeds Brachytherapy and last until disease progresses, intolerable toxicity, withdrawal of informed consent, loss of follow-up, death, or other circumstances that require termination of treatment, whichever occurs first. For patients in the TACE-AB-I arm, iodion-125 seeds will be implanted into the PVTT (according to the pre-operative planning) under CT guidance within 3-7 days after the first TACE. TACE and iodion-125 seeds implantation can be repeated on demand during follow-up based on the evaluation of laboratory and imaging examination.

This is a multicenter, open-label trial, randomized controlled trial to evaluate the efficacy and safety of TACE-AB-I compared with TACE-AB for the treatment of HCC with branch PVTT.

TACE Plus Atezolizumab/Bevacizumab and I-125 Seeds Brachytherapy for HCC With Branch PVTT

TACE Plus Atezolizumab/Bevacizumab and I-125 Seeds Brachytherapy for HCC With Branch PVTT: A Phase III, Randomized Clinical Trial

Time from randomization to death from any cause.

Time from randomization to disease progression (mRECIST) or death from any cause, whichever occurred first.

The percentage of patients who had a best overall tumor response rating of CR and PR (mRECIST).

The time from randomization until the date that complete portal vein occlusion was confirmed (if the portal vein is patent at diagnosis).

Number of patients with AE, treatment-related AE (TRAE), AE of special interest (AESI), serious adverse event (SAE), assessed by NCI CTCAE v5.0.

Sun Yat-sen University

Fifth Affiliated Hospital, Sun Yat-Sen University

Second Affiliated Hospital of Guangzhou Medical University

Maoming People's Hospital

Shandong Provincial Third Hospital

Third Affiliated Hospital, Sun Yat-Sen University

The director of Department of Interventional Radiology

1200 mg of atezolizumab plus 15 mg/kg of body weight of bevacizumab intravenously every 3 weeks

atezolizumab plus bevacizumab

Hong Jae Chon, MD,PhD

Hongjae Chon, MD,PhD

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, and HCC is more frequently observed in Asia, including South Korea. As HCC is often accompanied by chronic hepatitis B or C virus and liver cirrhosis, treatment of HCC consider not only the tumor but also various factors such as liver function and the patient's performance status. Local treatment and surgery are possible in the early stages of HCC. However, it has a high recurrence rate even after curative surgeries due to underlying cirrhosis and the tumor microenvironment.

Although several studies have investigated gene mutations and differences in treatment response in advanced HCC through next-generation sequencing (NGS), studies on transcriptome analysis of advanced HCC through RNA-sequencing are hard to find, with a need for future research into precise classification and clinical significance of HCC based on multi-omics data.

to establish multi-omics data and discover biomarkers highly associated with treatment response in HCC patients

Predictive Biomarkers in Patients With Advanced Hepatocellular Carcinoma Treated With Systemic Therapy

Biomarker Discovery Through Multiomics Study in Advanced Hepatocellular Carcinoma Patients Who Received Atezolizumab and Bevacizumab Combination Therapy

tumor samples from patients with hepatobiliary cancers (incidence of genetic alteration, association with treatment response and survival duration)

blood samples from patients with hepatobiliary cancers (incidence of genetic alteration, association with treatment response and survival duration)

Multi-omics analysis to further subtype and find therapeutic targets of HCC

Molecular biomarker associated with overall survival, progression-free survival and objective response rate in patients who receive atezolizumab plus bevacizumab

Assistant professor, Department of Medical Oncology

Leucovorin

Fluorouracil

Oxaliplatin

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries, Q3W

HAIC with FOLFOX

Atezolizumab plus bevacizumab is the first-line treatment for patients with advanced hepatocellular carcinoma. However, the prognosis for high-risk hepatocellular carcinoma is still poor, with a median overall survival of 7.6 months. Hepatic arterial infusion chemotherapy of oxaliplatin, 5-fluorouracil and leucovorin is effective in large hepatocellular carcinoma or hepatocellular carcinoma with major portal vein tumor thrombus. Our previous showed that hepatic arterial infusion chemotherapy plus lenvatinib and toripalimab (programmed cell death protein-1 antibody) had a powerful anti-tumor effect for high-risk hepatocellular carcinoma, with a median overall survival of 18 months. Thus, the purpose of this study is to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy of oxaliplatin, 5-fluorouracil and leucovorin plus atezolizumab plus bevacizumab for patients with high-risk hepatocellular carcinoma.

HAIC Plus A+T for Patients With High-risk HCC: a Single-arm Phase 2 Trial

Hepatic Arterial Infusion Chemotherapy With FOLFOX Plus Atezolizumab and Bevacizumab for Patients With High-risk Hepatocellular Carcinoma: a Single-arm Phase 2 Trial

Progression was defined as progressive disease by independent radiologic review according to RECIST 1.1 or death from any cause

ORR, as determined based on tumor response according to RECIST 1.1, is defined as the proportion of all randomized subjects whose best overall response (BOR) is either a CR or PR.

Professor

Atezolizumab+Bevacizumab, combined EBRT to vascular invasion

* Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.
* Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.
* The external beam radiotherapy will commence after day 2 of the first cycle of A+B, and will be delivered in accordance with institutional protocol.

* Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.
* Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.

The external beam radiotherapy will commence after day 2 of the first cycle of atezolizumab+bevacizumab, and will be delivered in accordance with institutional protocol.

3D-conformal radiotherapy technique is used to determine target volumes, radiation ports, and dose prescriptions by using a 3D radiotherapy planning system.

The gross tumor volume (GTV) includes vascular invasion and a 2-cm margin into the contiguous HCC. The GTV can consist of the entire HCC and vascular invasion at the discretion of the investigator.

The target dose is 45 Gy, however, the total dose can be reduced as low as 30 Gy according to the liver function, liver volumes, or the maximum dose to the stomach/duodenum during the planning process according to the judgment of the radiation oncologist of each participating sites.

Atezolizumab plus bevacizumab, combined EBRT to vascular invasion

Jihyun An

Ju Hyun Shim

The recent global IMbrave150 study evaluated the combination of atezolizumab and bevacizumab versus sorafenib in 501 patients with advanced or metastatic Hepatocellular Carcinoma (HCC). The median overall survival (OS) was notably better in the atezolizumab/bevacizumab group. However, for HCC patients with intrahepatic macrovascular invasion (MVI), the prognosis remains poor, indicating a significant unmet need in this group.

External Beam Radiotherapy (EBRT) has shown promising results in treating HCC with MVI, especially when used in combination with trans-arterial chemoembolization (TACE). It has been reported that radiotherapy may make tumor cells more susceptible to immune-mediated therapy, potentially enhancing the effects of atezolizumab and bevacizumab.

Thus, this study aims to investigate the efficacy and safety of atezolizumab/bevacizumab alone versus atezolizumab/bevacizumab in combination with EBRT in HCC patients with macrovascular invasion.

A total of 138 subjects are randomly assigned to one of two treatment groups (69 patients in the atezolizumab+bevacizumab group and 69 patients in the Atezolizumab plus Bevacizumab combined EBRT group).

* Radiotherapy combination:

  * Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.
  * Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.
  * The external beam radiotherapy will commence after day 2 of the first cycle of Atezolizumab+Bevacizumab, and will be delivered in accordance with institutional protocol.
* Atezolizumab+Bevacizumab:

  * Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.
  * Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.

Additional study identifiers: This study was also registered on the WHO's International Clinical Trials Registry Platform, CRIS, before the first participant was enrolled (ID: KCT0007365, Date of registration: 2022-06-08).

randomized, multicenter, open-label study

Atezolizumab Plus Bevacizumab Alone or Combined With External Beam Radiotherapy for HCC With Macrovascular Invasion

A Randomized, Multicenter, Open-Label, Phase II Trial of Atezolizumab Plus Bevacizumab Alone or Combined With External Beam RadioTherapy for HepatoCellular Carcinoma With Macrovascular Invasion (ALERT-HCC)

Randomization to the first occurrence of disease progression or death from any cause, whichever occurs first

Randomization to death from any cause, through the end of study

complete response or partial response as determined by the Investigator according to RECIST V1.1

Adverse reaction rate assessed by CTCAE version 5

The time from randomization to first deterioration (decrease from baseline of ≥10 points) in the patient-reported global health status (GHS) / Quality of life (QoL), physical function, or role function scales of the EORTC QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks

the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression or death is documented, whichever occurs first. DOR will be assessed in patients who had an objective response.

The decrease of \>20% in serum concentration of each marker from baseline across all time points during study period.

Seoul National University Hospital

Hanyang University

Soon Chun Hyang University

Asan Medical Center

Principal Investigator

The goal of this observational study is to learn about in patients with advanced hepatocellular carcinoma treated with atezoliozumab and bevacizumab.

In this clinical study, we intend to analyze the multiomics data by analyzing the peripheral blood and tumor tissue before and after treatment of patients with advanced liver cancer receiving systemic drug treatment, and analyzing the correlation with the treatment. This is an exploratory study that aims to discover biomarkers that are highly correlated with treatment response.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, and HCC is more frequently observed in Asia, including South Korea. As HCC is often accompanied by chronic hepatitis B or C virus and liver cirrhosis, treatment of HCC consider not only the tumor but also various factors such as liver function and the patient's performance status. Local treatment and surgery are possible in the early stages of HCC. However, it has a high recurrence rate even after curative surgeries due to underlying cirrhosis and the tumor microenvironment.

Although several studies have investigated gene mutations and differences in treatment response in advanced HCC through next-generation sequencing (NGS), studies on transcriptome analysis of advanced HCC through RNA-sequencing are hard to find, with a need for future research into precise classification and clinical significance of HCC based on multi-omics data to establish multi-omics data and discover biomarkers highly associated with treatment response in HCC patients who received atezolizumab and bevacizumab combination.

Predictive Biomarkers in Patients With Advanced Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab

Investigation of Predictive Biomarkers in Patients With Advanced Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab

tumor samples from patients with hepatocellular carcinoma (incidence of analysis of the expression patterns of various immune response-related proteins through H\&E staining, immunochemical staining, and immunofluorescent staining methods, association with treatment response and survival duration)

blood samples from patients with hepatocellular carcinoma (incidence of Flow cytometry, ELISA analysis, single cell RNA sequencing, association with treatment response and survival duration

Multi-omics analysis to further subtype and find therapeutic targets of HCC Multi-omics analysis is a total and integrated analysis of various molecular levels such as dielectric and protein.

Molecular biomarker associated with overall survival, progression-free survival and objective response rate in patients who receive atezolizumab plus bevacizumab A gene-based biomarker that predicts the therapeutic response of patients administered with Atezolizumab and Bevacizumab.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Organ-specific Responses to Atezolizumab Plus Bevacizumab in Advanced HCC	NCT04862949	Advanced Hepato...	Atezolizumab pl...	19 Years -	CHA University
Candonilimab Plus Bevacizumab for Patients With Advanced HCC Who Progressed on A+T	NCT05760599	Hepatocellular ...	Candonilimab Bevacizumab	18 Years - 75 Years	Sun Yat-sen University
Candonilimab Plus Bevacizumab for Patients With Advanced HCC Who Progressed on A+T	NCT05886257	Hepatocellular ...	Candonilimab Bevacizumab	18 Years - 75 Years	Sun Yat-sen University
TACE Plus Atezolizumab/Bevacizumab and I-125 Seeds Brachytherapy for HCC With Branch PVTT	NCT05984511	Hepatocellular ... Hepatic Portal ... Tumor Thrombus	I-125 Seeds Bra... Transcatheter a... Atezolizumab pl...	18 Years - 75 Years	Third Affiliated Hospital, Sun Yat-Sen University
Predictive Biomarkers in Patients With Advanced Hepatocellular Carcinoma Treated With Systemic Therapy	NCT05197504	Hepatocellular ...	atezolizumab pl...	19 Years -	CHA University
HAIC Plus A+T for Patients With High-risk HCC: a Single-arm Phase 2 Trial	NCT05886465	Hepatocellular ...	Atezolizumab Bevacizumab HAIC with FOLFO...	18 Years - 75 Years	Sun Yat-sen University
Atezolizumab Plus Bevacizumab Alone or Combined With External Beam Radiotherapy for HCC With Macrovascular Invasion	NCT05992220	Hepatocellular ... Hepatocellular ... Hepatocellular ... Hepatocellular ... Liver Cancer	Atezolizumab pl... Atezolizumab pl...	20 Years - 79 Years	Asan Medical Center
Predictive Biomarkers in Patients With Advanced Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab	NCT05173298	Advanced Hepato...	atezolizumab pl...	19 Years -	CHA University
Organ-specific Responses to Atezolizumab Plus Bevacizumab in Advanced HCC	NCT04862949	Advanced Hepato...	Atezolizumab pl...	19 Years -	CHA University
Predictive Biomarkers in Patients With Advanced Hepatocellular Carcinoma Treated With Systemic Therapy	NCT05197504	Hepatocellular ...	atezolizumab pl...	19 Years -	CHA University
Predictive Biomarkers in Patients With Advanced Hepatocellular Carcinoma Treated With Systemic Therapy	NCT05197504	Hepatocellular ...	atezolizumab pl...	19 Years -	CHA University

Spots Global Cancer Trial Database for atezolizumab plus bevacizumab