Lenvatinib Combined Toripalimab in Advanced Hepatocellular Carcinoma: a Single-center, Single-arm, Non-randomized Clinical Study

JS-2295

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.

2020-07-11

2024-04-01

2025-04-01

Recruiting

Early phase I

76

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.

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2023-03-29