Tislelizumab Monotherapy or Combined With Lenvatinib as Neoadjuvant Therapy for Resectable Hepatocellular Carcinoma.

Study Overview
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Brief Summary
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This is a phase II prospective study to evaluate the safety and efficacy of Tislelizumab monotherapy or combined with lenvatinib as neoadjuvant therapy for resectable hepatocellular carcinoma.

Official Title
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A Phase II Prospective Study to Evaluate the Safety and Efficacy of Tislelizumab Monotherapy or Combined With Lenvatinib as Neoadjuvant Therapy for Resectable Hepatocellular Carcinoma.

Conditions
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Resectable Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Tislelizumab
* Drug: Tislelizumab, Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a known diagnosis of HCC as defined in the protocol Patients must be evaluated by the Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Hospital to determine whether they can complete surgical treatment. Patients can be resectable in both oncology and surgery. At least ≥1 measurable lesion (RECIST 1.1) Age 18-75, male or female ECOG PS 0-1 Child-pugh A The function of vital organs meets the following requirements (excluding the use of any blood component and cell growth factor within 14 days) Blood routine: Neutrophils ≥1.5×109//L Platelet count ≥100×109/L Hemoglobin ≥90g/L Liver and kidney function: Serum creatinine (SCr) ≤ 1.5 times upper limit of normal value (ULN) or creatinine clearance ≥50 ml/min (Cockcroft-Gault formula) Total bilirubin (TBIL)≤ 1.5 times the upper limit of normal value (ULN) AST or ALT levels ≤ 3 times the upper limit of normal value (ULN) Normal coagulation function, International standardized ratio INR≤1.5×ULN or Prothrombin time PT≤1.5ULN Normal thyroid function is defined as thyroid stimulating hormone (TSH) within the normal range. Subjects whose baseline TSH is outside the normal range may be enrolled if total T3 (or FT3) and FT4 are within the normal range. Myocardial enzyme profiles were within the normal range (simple laboratory abnormalities that were not clinically significant were also allowed to be included) Patients who have progressed to PD or increased SD after 2 cycles of tislelizumab monotherapy must be willing to continue 2 cycles of tislelizumab and Lenvatinib combination therapy and be evaluated. Exclusion Criteria: Have received any systemic anticancer therapy or radiotherapy for their current tumor or other primary tumor in the 6 months prior to study entry. Tumor load or tumor growth rate was considered by the investigator to be insufficient to delay surgery. Had major surgery within 14 days prior to neoadjuvant therapy. Uncontrolled co-morbidities defined in the protocol and identified by the investigator. Receiving systemic steroid therapy or any other immunosuppressive therapy within 7 days prior to administration of the first dose of study therapy. Have had an active autoimmune disease requiring systemic treatment within the past 1 year. Have other malignancies that are known, developing and/or require aggressive treatment. Informed consent to encephalitis, meningitis, or uncontrolled seizures in the previous year. A history of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, systemic pneumonia) or active non-infectious pneumonia requires immunosuppressive doses of glucocorticoids to assist in treatment. Bleeding from esophageal or fundus varices caused by portal hypertension in the past 6 months; Severe (G3) varicose veins were known on endoscopy within 3 months prior to initial administration; Patients with evidence of portal hypertension (including imaging findings of a large spleen diameter of more than 10cm and platelets of less than 100) were at high risk of bleeding as assessed by the investigators. History of arteriovenous thromboembolism events within the past 6 months, including myocardial infarction, unstable angina pectoris, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or any other severe thromboembolism. Implantable venous port or catheter-derived thrombosis, or superficial venous thrombosis, except in patients with stable thrombus after conventional anticoagulant therapy. Severe bleeding tendency or coagulopathy, or receiving thrombolytic therapy. Prophylactic use of low-dose, low-molecular heparin (e.g., enoxaparin 40 mg/ day) is permitted, except for vitamin K antagonists (e.g., warfarin). Long-term use of drugs that inhibit platelet function such as aspirin, dipyridamole or clopidogrel is required. Uncontrolled hypertension, systolic blood pressure > 140mmHg or diastolic blood pressure > 90 mmHg after optimal medical treatment, history of hypertensive crisis or hypertensive encephalopathy. Symptomatic congestive heart failure (New York Cardiological Association Grade II-IV), symptomatic or poorly controlled arrhythmias, history of congenital long QT syndrome or adjusted QTc > 500ms at screening (calculated using the Fridericia method). A previous history of gastrointestinal perforation and/or fistula within the past 6 months, a history of intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive enterectomy (partial resection of the colon or extensive resection of the small intestine with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: tislelizumab<br>Received tislelizumab for 2 cycles, 200mg, iv, d1,Q3W. Patients achieved PR or reduced SD were enrolled in arm 1 and accepted surgery. After surgery, patients in arm 1 would receive tislelizumab as adjuvant therapy for 3-6 months. | Drug: Tislelizumab<br>* Tislelizumab 200mg, iv, d1, Q3W<br>|
| Experimental: tislelizumab+lenvatinib<br>Received tislelizumab for 2 cycles, 200mg, iv, d1,Q3W. Patients achieved PD or increased SD were enrolled in arm 2 and continued to accept treatment with tislelizumab and lenvatinib for 2 cycles. After 2 cycles, patients would receive surgery according to their physical conditions. After surgery, patients in arm 2 would receive tislelizumab and lenvatinib as adjuvant therapy for 3-6 months. | Drug: Tislelizumab<br>* Tislelizumab 200mg, iv, d1, Q3W<br>Drug: Tislelizumab, Lenvatinib<br>* Tislelizumab combined with lenvatinib: Tislelizumab 200mg, iv, d1, Q3W Lenvatinib 8mg，po，qd.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MPR rate | tumor necrosis rate ≥ 70% | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-year and 2-years DFS% | 1-year and 2-years disease-free survival rate | 36 months | 
| ORR | objective response rate | 3 months | 
| Surgery delay rate | Surgery was performed more than 28 days after the last cycle of neoadjuvant therapy | 3 months | 
| MiVI rate | Incidence of microvascular invasion | 3 months | 
| mOS | Median Overall survival | 5 years | 
| AE and SAE | adverse reactions | 1 year |