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出境医 / 临床实验 / Infusion of PD1/PDL1 Inhibitor Via Hepatic Arterial Versus Vein for Immunotherapy of Advanced Hepatocellular Carcinoma

Infusion of PD1/PDL1 Inhibitor Via Hepatic Arterial Versus Vein for Immunotherapy of Advanced Hepatocellular Carcinoma

Study Description
Brief Summary:
This trial was designed to investigate the survival outcomes, response rates, and safety of patients with Barcelona-Clinical Hepatocellular Carcinoma (BCLC)-C-stage liver cancer by hepatic artery versus vein infusion of PD1/PDL1 inhibitor.

Condition or disease Intervention/treatment Phase
Liver Cancer Drug: PD1/PDL1 inhibitor Phase 3

Detailed Description:

Liver cancer is the fifth most common malignancy worldwide, but the mortality rate ranks third. China has a large population base, with more than 400,000 new cases each year, and more than half of the world's new liver cancer and deaths. More than 70% of liver cancer patients in China are diagnosed at mid-to-late stage and have lost the chance of surgery. Only 10%-15% of newly diagnosed patients can undergo radical resection, and the recurrence rate after 5 years is as high as 50%-80%. So far, sorafenib is still the only standard treatment that can prolong the overall survival of advanced hepatocellular carcinoma. SHARP's latest research shows that sorafenib can only extend patients with advanced liver cancer for 2.8 months, and many adverse reactions; regofenib can be used in patients with advanced liver cancer after taking sorafenib resistance, but the overall efficiency is still low. It is difficult to be widely used in patients with advanced liver cancer, and more alternative therapies are urgently needed.

PD1/PDL1 inhibitor is widely used in treatment of various cancers in China now. The hepatic arterial chemotherapy infusion for advanced liver cancer, through the "first pass effect" of drug treatment, can significantly increase the local drug concentration of the tumor, improve the efficacy, reduce systemic adverse reactions, meanwhile Folfox regimen has been confirmed by the hepatic arterial chemotherapy infusion program. To the investigator's knowledge, no studies have been developed on the survival benefit of hepatic arterial infusion of immunotherapeutic agents in patients with advanced liver cancer. This phase III clinical trial was designed to compare the effects of PD1/PDL1 inhibitor via IA and IV on the survival benefit of patients with advanced liver cancer, including ORR, DCR, median survival time, and safety.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Randomized Trial of Comparison of Survival Benefit of Administration of PD1/PDL1 Inhibitor Via Hepatic Arterial Infusion Versus Vein for Immunotherapy of Advanced Liver Cancer
Actual Study Start Date : January 1, 2019
Estimated Primary Completion Date : January 1, 2022
Estimated Study Completion Date : January 2, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: PD1/PDL1 inhibitor hepatic artery infusion
Interventional technique to place microcatheter in hepatic artery to infuse PD1/PDL1 inhibitor in 30 minutes.
Drug: PD1/PDL1 inhibitor
Infusion of PD1/PDL1 inhibitor through peripheral vein or hepatic artery.
Other Name: Administration of PD1/PDL1 inhibitor through vein or interventional technique.

Experimental: PD1/PDL1 inhibitor vein infusion
Regular IV infusion of PD1/PDL1 inhibitor in 30 minutes.
Drug: PD1/PDL1 inhibitor
Infusion of PD1/PDL1 inhibitor through peripheral vein or hepatic artery.
Other Name: Administration of PD1/PDL1 inhibitor through vein or interventional technique.

Outcome Measures
Primary Outcome Measures :
  1. Overall survival [ Time Frame: 2 years ]
    Overall survival (OS) will be defined as the elapsed time from the enrollment to death from any cause. For surviving patients, follow-up will be censored at the date of last contact (or last date known to be alive). Follow-up for OS will occur every 12 weeks (±1 month) until death or withdrawal of consent from the study.


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 2 years ]
    Progression-free survival (PFS) will be defined as the elapsed time from the first date of study treatment until documented disease progression (as per mRECIST) or death from any cause, whichever is earlier. For patients who remain alive without progression, follow-up time will be censored at the date of last disease assessment.

  2. Adverse event rate [ Time Frame: 2 years ]
    Adverse event rate will be defined as the rate of patients who developed adverse event.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Cytohistological confirmation is required for diagnosis of HCC.、
  2. Signed informed consent before recruiting
  3. Age between 18 to 80 years with estimated survival over 3 months.
  4. Child-Pugh class A or B/Child score > 7; ECOG score < 2
  5. Tolerable coagulation function or reversible coagulation disorders
  6. Laboratory examination test within 7 days prior to procedure: WBC≥3.0×10E9/L; Hb≥90g/L; PLT ≥50×10E9/L;INR < 2.3 or PT < 6 seconds above control;Cr ≤ 145.5 umul/L;Albumin > 28 g/L;Total bilirubin < 51 μmol/L
  7. At least one tumor lesion meeting measurable disease criteria as determined by RECIST v1.1.
  8. Patients with advanced (unresectable and/or metastatic, stage C based on Barcelona-Clinic Liver Cancer [BCLC] staging classification) hepatocellular carcinoma which would not be suitable for treatment with loco-regional therapies or have progressed following locoregional therapy such as surgical resection, percutaneous hepatic arterial embolization, radiofrequency ablation, and percutaneous interventional therapy.
  9. Birth control.
  10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Exclusion Criteria:

  1. Patients participated in clinical trials of equipment or drugs (signed informed consent) within 4 weeks;
  2. Patients accompany by ascites, hepatic encephalopathy and esophageal and gastric varices bleeding;
  3. Any serious accompanying disease, which is expected to have an unknown, impact on the prognosis, include heart disease, inadequately controlled diabetes and psychiatric disorders;
  4. Patients accompanied with other tumors or past medical history of malignancy;
  5. Pregnant or lactating patients, all patients participating in this trial must adopt appropriate birth control measures during treatment;
  6. Patients have poor compliance.

    Any contraindications for hepatic arterial infusion procedure:

    A.Impaired clotting test (platelet count < 60000/mm3, prothrombin activity < 50%).

    B.Renal failure / insufficiency requiring hemo-or peritoneal dialysis. C.Known severe atheromatosis. D.Known uncontrolled blood hypertension (> 160/100 mm/Hg).

  7. Patients have the past history of liver cancer treatment, such as transplantation, resection, radiotherapy, chemotherapy and so on;
  8. Allergic to adriamycin chemotherapy drugs,contrast agent and lipiodol;
  9. Any agents which could affect the absorption or pharmacokinetics of the study drugs
  10. Subjects unable to suffer the discomfort of the HAI procedure
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Hui Lian, MD 02034153532 lian-hui-2008@163.com
Contact: Zhenfeng Zhang, MD, PhD +862039195966 zhangzhf@gzhmu.edu.cn

Locations
Layout table for location information
China, Guangdong
The Second Affiliated Hospital of Guangzhou Medical University Recruiting
Guanzhou, Guangdong, China, 51260
Contact: Hui Lian, MD    02034153532    lian-hui-2008@163.com   
Contact: Zhenfeng Zhang, MD, PhD    +862039195966    zhangzhf@gzhmu.edu.cn   
Principal Investigator: Hui Lian, MD         
Sub-Investigator: Zhenfeng Zhang, MD, PHD         
Sponsors and Collaborators
Second Affiliated Hospital of Guangzhou Medical University
Investigators
Layout table for investigator information
Principal Investigator: Hui Lian, MD Second Affiliated Hospital of Guangzhou Medical University
Principal Investigator: Zhenfeng Zhang, MD, PhD Second Affiliated Hospital of Guangzhou Medical University
Tracking Information
First Submitted Date  ICMJE May 13, 2019
First Posted Date  ICMJE May 14, 2019
Last Update Posted Date April 6, 2021
Actual Study Start Date  ICMJE January 1, 2019
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 13, 2019)
Overall survival [ Time Frame: 2 years ]
Overall survival (OS) will be defined as the elapsed time from the enrollment to death from any cause. For surviving patients, follow-up will be censored at the date of last contact (or last date known to be alive). Follow-up for OS will occur every 12 weeks (±1 month) until death or withdrawal of consent from the study.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 13, 2019)
  • Progression-free survival [ Time Frame: 2 years ]
    Progression-free survival (PFS) will be defined as the elapsed time from the first date of study treatment until documented disease progression (as per mRECIST) or death from any cause, whichever is earlier. For patients who remain alive without progression, follow-up time will be censored at the date of last disease assessment.
  • Adverse event rate [ Time Frame: 2 years ]
    Adverse event rate will be defined as the rate of patients who developed adverse event.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Infusion of PD1/PDL1 Inhibitor Via Hepatic Arterial Versus Vein for Immunotherapy of Advanced Hepatocellular Carcinoma
Official Title  ICMJE A Phase III Randomized Trial of Comparison of Survival Benefit of Administration of PD1/PDL1 Inhibitor Via Hepatic Arterial Infusion Versus Vein for Immunotherapy of Advanced Liver Cancer
Brief Summary This trial was designed to investigate the survival outcomes, response rates, and safety of patients with Barcelona-Clinical Hepatocellular Carcinoma (BCLC)-C-stage liver cancer by hepatic artery versus vein infusion of PD1/PDL1 inhibitor.
Detailed Description

Liver cancer is the fifth most common malignancy worldwide, but the mortality rate ranks third. China has a large population base, with more than 400,000 new cases each year, and more than half of the world's new liver cancer and deaths. More than 70% of liver cancer patients in China are diagnosed at mid-to-late stage and have lost the chance of surgery. Only 10%-15% of newly diagnosed patients can undergo radical resection, and the recurrence rate after 5 years is as high as 50%-80%. So far, sorafenib is still the only standard treatment that can prolong the overall survival of advanced hepatocellular carcinoma. SHARP's latest research shows that sorafenib can only extend patients with advanced liver cancer for 2.8 months, and many adverse reactions; regofenib can be used in patients with advanced liver cancer after taking sorafenib resistance, but the overall efficiency is still low. It is difficult to be widely used in patients with advanced liver cancer, and more alternative therapies are urgently needed.

PD1/PDL1 inhibitor is widely used in treatment of various cancers in China now. The hepatic arterial chemotherapy infusion for advanced liver cancer, through the "first pass effect" of drug treatment, can significantly increase the local drug concentration of the tumor, improve the efficacy, reduce systemic adverse reactions, meanwhile Folfox regimen has been confirmed by the hepatic arterial chemotherapy infusion program. To the investigator's knowledge, no studies have been developed on the survival benefit of hepatic arterial infusion of immunotherapeutic agents in patients with advanced liver cancer. This phase III clinical trial was designed to compare the effects of PD1/PDL1 inhibitor via IA and IV on the survival benefit of patients with advanced liver cancer, including ORR, DCR, median survival time, and safety.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Liver Cancer
Intervention  ICMJE Drug: PD1/PDL1 inhibitor
Infusion of PD1/PDL1 inhibitor through peripheral vein or hepatic artery.
Other Name: Administration of PD1/PDL1 inhibitor through vein or interventional technique.
Study Arms  ICMJE
  • Experimental: PD1/PDL1 inhibitor hepatic artery infusion
    Interventional technique to place microcatheter in hepatic artery to infuse PD1/PDL1 inhibitor in 30 minutes.
    Intervention: Drug: PD1/PDL1 inhibitor
  • Experimental: PD1/PDL1 inhibitor vein infusion
    Regular IV infusion of PD1/PDL1 inhibitor in 30 minutes.
    Intervention: Drug: PD1/PDL1 inhibitor
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 13, 2019)
200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2, 2022
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Cytohistological confirmation is required for diagnosis of HCC.、
  2. Signed informed consent before recruiting
  3. Age between 18 to 80 years with estimated survival over 3 months.
  4. Child-Pugh class A or B/Child score > 7; ECOG score < 2
  5. Tolerable coagulation function or reversible coagulation disorders
  6. Laboratory examination test within 7 days prior to procedure: WBC≥3.0×10E9/L; Hb≥90g/L; PLT ≥50×10E9/L;INR < 2.3 or PT < 6 seconds above control;Cr ≤ 145.5 umul/L;Albumin > 28 g/L;Total bilirubin < 51 μmol/L
  7. At least one tumor lesion meeting measurable disease criteria as determined by RECIST v1.1.
  8. Patients with advanced (unresectable and/or metastatic, stage C based on Barcelona-Clinic Liver Cancer [BCLC] staging classification) hepatocellular carcinoma which would not be suitable for treatment with loco-regional therapies or have progressed following locoregional therapy such as surgical resection, percutaneous hepatic arterial embolization, radiofrequency ablation, and percutaneous interventional therapy.
  9. Birth control.
  10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Exclusion Criteria:

  1. Patients participated in clinical trials of equipment or drugs (signed informed consent) within 4 weeks;
  2. Patients accompany by ascites, hepatic encephalopathy and esophageal and gastric varices bleeding;
  3. Any serious accompanying disease, which is expected to have an unknown, impact on the prognosis, include heart disease, inadequately controlled diabetes and psychiatric disorders;
  4. Patients accompanied with other tumors or past medical history of malignancy;
  5. Pregnant or lactating patients, all patients participating in this trial must adopt appropriate birth control measures during treatment;
  6. Patients have poor compliance.

    Any contraindications for hepatic arterial infusion procedure:

    A.Impaired clotting test (platelet count < 60000/mm3, prothrombin activity < 50%).

    B.Renal failure / insufficiency requiring hemo-or peritoneal dialysis. C.Known severe atheromatosis. D.Known uncontrolled blood hypertension (> 160/100 mm/Hg).

  7. Patients have the past history of liver cancer treatment, such as transplantation, resection, radiotherapy, chemotherapy and so on;
  8. Allergic to adriamycin chemotherapy drugs,contrast agent and lipiodol;
  9. Any agents which could affect the absorption or pharmacokinetics of the study drugs
  10. Subjects unable to suffer the discomfort of the HAI procedure
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Hui Lian, MD 02034153532 lian-hui-2008@163.com
Contact: Zhenfeng Zhang, MD, PhD +862039195966 zhangzhf@gzhmu.edu.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03949231
Other Study ID Numbers  ICMJE Artery PD1/PDL1 agent for HCC
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Second Affiliated Hospital of Guangzhou Medical University
Study Sponsor  ICMJE Second Affiliated Hospital of Guangzhou Medical University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Hui Lian, MD Second Affiliated Hospital of Guangzhou Medical University
Principal Investigator: Zhenfeng Zhang, MD, PhD Second Affiliated Hospital of Guangzhou Medical University
PRS Account Second Affiliated Hospital of Guangzhou Medical University
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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