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Lenvatinib Combined Toripalimab in Advanced Hepatocellular Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04368078
Recruitment Status : Recruiting
First Posted : April 29, 2020
Last Update Posted : October 14, 2020
Shanghai Junshi Biosciences Co., LTD
Information provided by (Responsible Party):
Peking Union Medical College Hospital

Brief Summary:
The investigators design a phase IIB clinical study to explore the efficacy and safety of Lenvatinib plus Toripalimab in patients with advanced hepatocellular carcinoma and to analyze potential biomarkers of therapeutic response.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: Toripalimab plus Lenvatinib Phase 2

Detailed Description:

This trial is a single-arm, non-randomized and single-center clinical study of targeted therapy combined immunotherapy in patients with hepatocellular carcinoma.

It is estimated that 76 patients who met the study criteria will be enrolled in Peking Union Medical College Hospital(PUMCH) and treated with Lenvatinib and Toripalimab. The investigators will follow up and collect subjects' data monthly to evaluate the efficacy and safety of treatment, including overall survival and time to progression. Multi-omics data analysis will be used to find potential biomarkers of treatment response.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Lenvatinib Combined Toripalimab in Advanced Hepatocellular Carcinoma: a Single-center, Single-arm, Non-randomized Clinical Study
Estimated Study Start Date : October 11, 2020
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Lenvatinib

Arm Intervention/treatment
Experimental: Toripalimab plus Lenvatinib

Lenvatinib is a novel angiogenesis inhibitor which targets vascular endothelial growth factor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor β, RET and KIT.

Toripalimab is a recombinant anti-human PD-1 monoclonal antibody.

Drug: Toripalimab plus Lenvatinib

Toripalimab 240mg, every 3 weeks, intravenous infused, day 1, 6 weeks a cycle. Lenvatinib 8mg (weight<60kg) or 12mg (weight≥60kg), once a day, oral at least 38 days of each 6 weeks cycle, day 2.

Number of cycle: until progression or unacceptable toxicity events develop

Other Name: JS001 plus E7080

Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: Up to 1 year ]
    Proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response and partial response patients.

Secondary Outcome Measures :
  1. Disease Control Rate (DCR) [ Time Frame: Up to 1 year ]
    Proportion of patients whose tumor volume control (reduced or enlarged) reaches a predetermined value and can maintain a minimum time limit.

  2. Progression-free Survival (PFS) [ Time Frame: Up to 1 years ]
    A duration from the date of initial treatment with lenvatinib plus pembrolizumab to disease progression (defined by RECIST 1.1) or death of any cause.

  3. 3-months and 6-month Progression free survival rate [ Time Frame: Up to 6 months ]
    Portion of patients who do not experience disease progression (defined by RECIST 1.1) or death of any cause after treated with toripalimab plus lenvatinib for 3 months and 6 months, respectively.

  4. 6-months and 1-year mortality rate [ Time Frame: Up to 1 years ]
    Portion of patients who die of any cause after treated with toripalimab plus lenvatinib at 6 months and 1 year, respectively.

  5. Duration of Response (DOR) [ Time Frame: Up to 1 years ]
    Duration from the first time reported partial response or complete response to the first time of disease progression or death.

  6. Overall Survival (OS) [ Time Frame: Up to 2 years ]
    Duration from the date of initial treatment with lenvatinib plus pembrolizumab to the date of death due to any cause.

  7. clinical benefit rate (CBR) [ Time Frame: up to 2 years ]
    Proportion of patients achieved complete response and partial response for more than 6 months.

  8. Adverse events (AE) [ Time Frame: up to 2 years ]
    Any adverse events related with treatment drugs and details include adverse events type, frequency and severity.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Subjects volunteer to participate in the study and agree to sign the informed consent with good compliance and follow-up.
  • Subjects are 18 years old or older when signing the informed consent and gender is not limited.
  • Imaging (by AASLD or Standard for the diagnosis and treatment of primary liver cancer 2017 in China) or histopathologically or cytologically confirmed advanced Hepatocellular carcinoma.
  • BCLC stage B or C. The disease is not suitable for radical surgery and/or topical treatment, or disease progression occurs after surgery and/or local treatment.
  • Subjects who have received first-line systemic treatment (targeted therapies other than Lenvatinib, chemotherapy, biological immunotherapy, etc.) except Toripalimab and Lenvatinib could be involved.
  • At least one measurable lesion (according to RECIST version 1.1): the measurable lesion has a long diameter ≥ 10 mm or lymphadenpathy has a short diameter ≥ 15 mm in spiral CT scan.
  • The ECOG score is 0-1 within 1 week before enrollment.
  • Liver function assessment: Child-Pugh Grade A (5-6 points).
  • Estimated survival time ≥ 3 months.
  • 10. Subjects with HBV infection: HBV DNA<2000 IU/ml or <10^4 copy/mL, and have received anti-HBV therapy for at least 14 days prior to enrollment in the study, subjects with HCV-RNA(+) must receive antiviral therapy;
  • Hematology and organ function are sufficient based on the following laboratory results within 14 days prior to the treatment of this study:
  • Whole blood cell examination (no blood transfusion within 14 days, no G-CSF use and no drugs use): WBC≥3.0×10^9/L, Hb≥85g/L, ANC≥1.5×10^9/L, PLT≥75×10^9/L.
  • Biochemical examination (no ALB infused within 14 days): ALB≥29 g/L, ALP and ALT and AST<5×ULN, TBIL≤3×ULN, creatinine≤1.5×ULN or CCr >50mL/min (standard Cockcroft-Gault formula): Female: CrCl=((140-age) × body weight (kg) × 0.85) / 72 × Serum creatinine (mg/dL); Male: CrCl=((140- age) × body weight (kg) × 1.00) / 72 × Serum creatinine (mg/dL)
  • Agree to abstain from sex (avoid heterosexual intercourse) or use contraceptive methods with an annual contraceptive failure rate of less than 1% during treatment and for at least 6 months after the last administration.

Exclusion Criteria:

  • Hepatocellular carcinoma patients with any of the following: Suitable for radical surgery; or without an assessment lesion after radical surgery; or liver transplantation history or ready for liver transplantation;
  • ECOG score ≥ 2 points.
  • Previously received Lenvatinib or Toripalimab treatment.
  • History of hepatic encephalopathy.
  • Histopathological result show hepatobiliary carcinoma, sarcomatoid liver cancer, mixed cell carcinoma and layered cell carcinoma.
  • Already known to be allergic or intolerant to recombinant humanized PD-1 monoclonal antibody drugs (or components) or Lenvatinib.
  • Pregnant (positive pregnancy test before taking medicine) or lactating women.
  • Received any topical treatment within 4 weeks prior to the study, including but not limited to surgery, radiotherapy, hepatic artery embolization, TACE, hepatic artery perfusion, radiofrequency ablation, cryoablation or percutaneous ethanol injection.
  • Previous or existing grade 3 (CTCAE5.0 ) and above gastrointestinal fistula or non-gastrointestinal fistula (such as skin).
  • Factors affect Lenvatinib use, such as inability to swallow, chronic diarrhea, intestinal obstruction, or other conditions that significantly affect drug intake and absorption.
  • Ascites with clinical symptoms which requires abdominal puncture or drainage therapy, or Child-Pugh score >2.
  • Surgery performed within 4 weeks or minor surgery (simple resection or biopsy) within 7 days prior to the trial and patients must be evaluated before the first medication.
  • Severe cardiovascular and cerebrovascular diseases, including but not limited to acute myocardial infarction, severe/unstable angina pectoris, cerebrovascular accident or transient ischemic attack, congestive heart failure and arrhythmias within 6 months before enrollment.
  • Hepatic and renal dysfunction evidence: jaundice, ascites, and/or bilirubin ≥ 3× ULN, and/or ≥ 3 grade (CTC-AE 5.0) proteinuria (> 3.5g /24 hours), or renal failure requiring blood dialysis or peritoneal dialysis, and / or urine examination shows urinary protein ≥ ++ or 24 hours urine protein >1.0g.
  • Persistent >2 grade (CTCAE 5.0) infection.
  • Thromboembolism (including stroke and / or transient ischemic attack) within 12 months.
  • Hypertension that cannot be controlled well with antihypertensive drugs (systolic blood pressure> 160mmHg, diastolic blood pressure> 100mmHg).
  • Already known active central nervous system metastasis and/or cancerous meningitis.
  • Active autoimmune disease or autoimmune disease within two years.
  • Known central nervous system metastasis and/or cancerous meningitis.
  • Prepared or previously received an organ or allogeneic bone marrow transplant
  • History of active tuberculosis, such as mycobacterium tuberculosis.
  • Gastrointestinal bleeding history in the past 6 months or tendency to gastrointestinal bleeding, such as esophageal varices, local active ulceration lesions, fecal occult blood ≥ (++) (gastroscopy is required when fecal occult blood is (+)).
  • History of human immunodeficiency virus infection.
  • History of hepatitis B virus or hepatitis C virus infection, and not receive regular treatment.
  • Severe non-healing wounds, ulcers or fractures.
  • With other malignant tumors within 5 years.
  • Previous and current evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-associated pneumonia and severe impairment of lung function.
  • Received a potent CYP3A4 inhibitor treatment within 7 days prior to the study or received a potent CYP3A4 inducer within 12 days prior to the study.
  • With other active malignant tumor except Hepatocellular carcinoma within 5 years or simultaneously.
  • Patients are unsuitable for participation in this research after comprehensive assessment by the researchers.
  • Patients participate in another clinical study at the same time.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04368078

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Contact: Xiaobo Yang, doctor 8613811675126
Contact: Xu Yang, doctor 8615810667683

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China, Beijing
Chinese Academy of Medical Sciences & Peking Union Medical College Hospital Recruiting
Beijing, Beijing, China, 100730
Contact: Xu Yang    +86 15810667683 ext 010-69156043   
Contact: Haitao Zhao, MD   
Sponsors and Collaborators
Peking Union Medical College Hospital
Shanghai Junshi Biosciences Co., LTD
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Principal Investigator: Haitao Zhao, MD Peking Union Medical College Hospital

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Responsible Party: Peking Union Medical College Hospital Identifier: NCT04368078    
Other Study ID Numbers: JS-2295
First Posted: April 29, 2020    Key Record Dates
Last Update Posted: October 14, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Peking Union Medical College Hospital:
Hepatocellular carcinoma
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action