Lenvatinib Combined Toripalimab in Advanced Hepatocellular Carcinoma

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.

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.

Eligibility Criteria:
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.