A Trial of Hepatic Arterial Infusion Combined With Bevacizumab and Sintilimab for Unresectable A-staged Hepatocellular Carcinoma in BCLC Classification (D-TRIPLET)

A Prospective, Single-arm, Multicenter, Phase II Trial to Evaluate the Effectiveness and Safety of Hepatic Arterial Infusion Chemotherapy (HAIC) of Oxaliplatin, 5-fluorouracil and Leucovorin (mFOLFOX7) Combined With Bevacizumab and Sintilimab for Unresectable A-staged Hepatocellular Carcinoma in BCLC Classification

This study was designed to evaluate the effectiveness and safety of hepatic arterial infusion chemotherapy combined with Bevacizumab and Sintilimab (Triplet-combined Therapy) for Unresectable A-staged Hepatocellular Carcinoma in BCLC classification.

The primary outcome measure is to evaluate the objective response rate (ORR RECIST 1.1) of Triplet-combined Therapy for Unresectable A-staged Hepatocellular Carcinoma in BCLC classification.

The secondary Outcome measures include the objective response rate (ORR mRECIST 1.1), duration of response (DOR), disease control rate (DCR), progression-free survival rate (PFSR) [ Time Frame: 6- and 12-month], overall survival rate (OSR) [ Time Frame: 6- and 12-month], the median progression-free survival time (mPFS) and median overall survival time (mOS) of Triplet-combined Therapy for Unresectable A-staged Hepatocellular Carcinoma in BCLC classification.

Moreover, this study aims to assess the safety and tolerability of Triplet-combined Therapy for Unresectable A-staged Hepatocellular Carcinoma in BCLC classification.

Primary liver cancer is a common malignant tumor of the digestive system in the world. There are about 854,000 new incidences and 810,000 mortality each year. In China, there is a high incidence of liver cancer, with about 466,000 new cases and 422,000 mortality each year. Hepatocellular carcinoma (HCC) accounted for about 90% of primary liver cancer in pathological type. Most patients have reached advanced stage or are unresectable when diagnosed and the natural median survival time is only 3 to 4 months. Then only systemic therapy is recommended for patients in advanced HCC in many global guidelines. Hepatic arterial infusion chemotherapy (HAIC) of mFOLFOX7, anti-angiogenic targeting drugs, and antibody immunotherapy against programmed death molecule-1 (PD-1) immunological checkpoints are effective treatment options for advanced hepatocellular carcinoma. Many clinical studies have shown that the two-two combination of the above three treatment options can improve the anti-tumor overall response rate, the survival rate and even achieve clinical complete remission of patients with unresectable HCC. Shi Ming et al reported HAIC combined with systemic targeted therapy has a better survival outcome compared to systemic targeted therapy monotherapy [OS 13.37 vs 7.13 months, PFS 7.03 vs 2.6 months] in JAMA Oncology. In summary, for patients of unresectable Hepatocellular Carcinoma, HAIC, antiangiogenic targeted therapy, and anti-PD-1 immunotherapy have their important status, and the combination of any two treatments brings about synergy effect. Then, could the combination of the three treatment methods further improve the outcome of unresectable hepatocellular carcinoma? This study was designed to evaluate the efficacy and safety of a combination of hepatic arterial infusion chemotherapy, targeted drugs (Apatinib), and anti-PD-1 immunotherapy (Camrelizumab) to provide a more effective and toxic-tolerable treatment for patients in unresectable A-staged Hepatocellular Carcinoma in BCLC classification. This is a single-arm phase II study, and 30 patiented will be enrolled. The patients will receive Hepatic Arterial Infusion(mFOLFOX7) on the first day, and intravenous infusion of Bevacizumab on the 4th day, and intravenous infusion of Sintilimab on the 25th day. The intervention is repeated every 3 weeks. The primary outcome measure is ORR by RECIST 1.1.

Inclusion Criteria:

• The patient voluntarily joins the study and signs an informed consent;

• Age≥18 years old, ≤70 years old, both men and women;

• Clinical or pathologically confirmed unresectable BCLC A-stage hepatocellular carcinoma, no further anti-tumor treatment;

• Child-Pugh score small or equal to 6 points (Child-Pugh A-B);

• ECOG score: 0 to 1 (according to the ECOG score classification);

• The expected survival is longer than 12 weeks;

• The laboratory parameters meets the following requirements (no blood components and cell growth factors are allowed within 14 days before the first dose):

  1. Absolute neutrophil count≥3.0×109 / L;
  2. Platelets≥80×109 / L;
  3. Hemoglobin≥90 g / L;
  4. serum albumin≥28 g / L;
  5. Thyroid stimulating hormone (TSH)≤1×ULN (if abnormalities should be considered at the same time FT3, FT4 levels, patients with FT3 and FT4 levels in normal range can also be enrolled);
  6. bilirubin≤1.5×ULN (within 7 days prior to the first dose);
  7. ALT≤3 x ULN and AST≤3 x ULN (within 7 days prior to the first dose);
  8. AKP≤2.5×ULN; serum creatinine≤1.5×ULN;

• For female that non-surgical sterilization or in childbearing age need to use a medically approved contraceptive (such as an intrauterine device, contraceptive or condom) during the study period and within 3 months after the end of the study treatment period; For female that non-surgical sterilization or in childbearing age must have a negative serum or urine HCG test within 72 hours prior to study enrollment; and must be nonlactating; for male patients whose partner in a childbearing age, effective methods of contraception should be given during the trial and at the end of Sintilimab injection.

Exclusion Criteria:

• The patient has any active auto-immune disease or a history of autoimmune disease (such as the following, but not limited to: auto-immune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, thyroid hyperfunction; patients with vitiligo. For patient with history of asthma, complete remission of asthma in childhood without any intervention after adulthood can be included, while those asthma patients who require bronchodilators for medical intervention cannot be included.);
• The patient is using immunosuppressive agents or systemic hormonal therapy for immunosuppression purposes (dose > 10 mg/day of prednisone or other therapeutic hormones) and continues to be used within 2 weeks prior to enrollment;
• Severe allergic reactions to other monoclonal antibodies;
• Known for a history of central nervous system metastasis or hepatic encephalopathy;
• Having a history of organ transplantation;
• Patients with clinically symptomatic ascites who require puncture, drainage, or ascites drainage within 3 months, except for those who have a small amount of ascites but no clinical symptoms;
• Suffering from hypertension, and cannot be well controlled by antihypertensive drugs (systolic blood pressure≥140mmHg or diastolic blood pressure≥90 mmHg);
• Suffering heart diseases with clinical symptoms or those not well controlled, such as: (1) heart failure in NYHA class 2 or higher; (2) unstable angina; (3) myocardial infarction occurred within 1 year; (4) clinically symptomatic supraventricular or ventricular arrhythmia requiring treatment or intervention; (5) Tc > 450ms (male); Tc > 470ms (female);
• Coagulation dysfunction (INR>2.0, PT>16s), bleeding tendency or receiving thrombolysis or anticoagulant therapy, allowing prophylactic use of low-dose aspirin or low molecular heparin;
• There are significant clinically significant bleeding symptoms or clear bleeding tendency within 3 months before enrollment, such as hemoptysis of 2.5ml or more per day, gastrointestinal bleeding, esophageal varices with bleeding risk, hemorrhagic gastric ulcer or vasculitis, etc. If the fecal occult blood is positive in the baseline period, it can be watched, then gastroscope is needed for those fecal occult blood is still positive. If the gastroscope indicates severe esophageal varices, it cannot be enrolled, except for those who have undergone gastroscopy within a month or less to exclude such cases);
• Events of arterial/venous thrombosis occurring within the first 6 months of enrollment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
• There are known hereditary or acquired bleeding and thrombophilia (such as hemophilia patients, coagulopathy, thrombocytopenia, etc.);
• Urine routine indicates that urine protein≥++ and 24-hour urine protein amount > 1.0g was confirmed;
• The patient has active infection, unexplained fever (≥38.5°C) within 3 days before administration, or baseline white blood cell count>15×109/L;15 Patients with congenital or acquired immunodeficiency (such as HIVinfected patients);
• HBV-DNA>2000 IU/ml (or 104 copies/ml); or HCV-RNA>103 copies/ml; or HBsAg+ and anti-HCV antibody positive patients;
• The patient has had other malignant tumors in the past 3 years or at the same time (except for cured skin basal cell carcinoma and cervical carcinoma in situ);
• Patients with bone metastases who had received palliative radiotherapy >4% of the bone marrow area within 4 weeks prior to participation in the study;
• Patients have previously received other anti-PD-1 antibody therapy or other immunotherapy against PD-1/PD-L1, or have received apatinib before;
• Inoculation of a live vaccine within less than 4 weeks prior to study or possibly during the study period;
• Pregnant or lactating women, or women of childbearing age who are unwilling to take contraceptive measures;
• According to the investigators, the patient has other factors that may affect the results of the study or lead to the termination of the study, such as alcohol abuse, drug abuse, other serious diseases (including mental illness) requiring combined treatment, and serious laboratory tests, abnormalities, accompanied by factors such as family or society, which may affect the safety of enrolled patients.