KN046 Combined With Ningatinib in the Treatment of Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This study is an open, multi-center clinical trial, the purpose is to study the safety and preliminary efficacy of KN046 combined with Ningatinib in subjects with advanced hepatocellular carcinoma.

Detailed Description
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The study consists of dose escalation and dose expansion, the mTPI-2 (Modified Toxicity Probability Interval) will be used for dose exploration. The preset dose of KN046 is 5 mg/kg Q3W and the preset dose of ningatinib is 10 mg (rapid titration), 20 mg QD, 30 mg QD, and 40 mg QD.Dose expansion will be divided into two cohorts, cohort 1 will enroll subjects who have not received system therapy and cohort 2 will enroll subjects who have previously received at least first-line system therapy.

Official Title
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An Open, Multi-center, Ib/II Clinical Trial of KN046 Combined With Ningatinib in the Treatment of Advanced Hepatocellular Carcinoma

Conditions
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Advanced HCC

Intervention / Treatment
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* Drug: KN046 （PD-L1/CTLA4 BsAb）
* Drug: Ningetinib Tosylate（multi-target TKI）


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of hepatocellular carcinoma confirmed by histology or cytology； Barcelona Clinic Liver Cancer (BCLC) Stage B or C； ECOG performance status: 0-1； Child Pugh score≤7； Enough organ function； Has at least one measurable lesion based on RECIST 1.1； Life expectancy ≥3 months； Patients must be able to understand and willing to sign a written informed consent document； Exclusion Criteria: Fibrous lamina hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, cholangiocarcinoma etc; Past or present hepatic encephalopathy; or Budd-Chiari syndrome; or Tumor thrombus invasion at the main portal vein (Vp4), inferior vena cava or heart involvement; Subjects who have previously received immune checkpoint inhibitors (such as anti-PD-1/L1, CTLA-4, etc.); or have a history of ≥ grade 3 immune-related adverse reactions; or hyperprogressive after immunotherapy previously； Subjects who have received liver local treatment (transcatheter chemoembolization, transcatheter embolization, hepatic artery perfusion, radiotherapy, radioembolization or ablation) within 4 weeks before administration; Subjects who need corticosteroids or immunosuppressive agents for systemic therapy; Any previous or current active autoimmune disease or history of autoimmune disease; History of liver transplantation; History of interstitial lung disease or non-infectious pneumonia; History of allergic reactions to related drugs; LVEF< 50% or LLN Clinically obvious gastrointestinal abnormalities, which may affect the intake, transport or absorption of drugs (such as inability to swallow, chronic diarrhea, intestinal obstruction, etc.), or patients undergoing total gastrectomy; With serious systemic diseases such as heart disease and cerebrovascular disease, and the condition is unstable or uncontrollable; Subjects with clinically significant gastrointestinal bleeding or thrombosis or embolic events within 6 months; Untreated hepatitis infection: HBV DNA>2000IU/ml or10000 copies/ml, HCV RNA> 1000copy/ml, both HbsAg and anti-HCV body are positive; Evidence of active pulmonary tuberculosis (TB); Positive test of immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS); Pleural effusion, ascites and pericardial effusion with clinical symptoms or needing drainage;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects who have not received first-line system treatment previously; | Drug: KN046 （PD-L1/CTLA4 BsAb）<br>* KN046 5mg/kg Q3W<br>Drug: Ningetinib Tosylate（multi-target TKI）<br>* ningtinib QD, dose will be decided by investigator<br>|
| Experimental: Cohort 2<br>Subjects who have received at least first-line system treatment | Drug: KN046 （PD-L1/CTLA4 BsAb）<br>* KN046 5mg/kg Q3W<br>Drug: Ningetinib Tosylate（multi-target TKI）<br>* ningtinib QD, dose will be decided by investigator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Dose limit toxicity | 1 months | 
| ORR | objective response rate (ORR) based on the RECIST 1.1 by investigator | 1 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | progression free survival | 1.5 years | 
| OS | overall survival | 3 years |