This study was designed to evaluate the effectiveness and safety of hepatic arterial infusion chemotherapy combined with Apatinib and Camrelizumab (Triplet-combined Therapy) for C-staged Hepatocellular Carcinoma in BCLC classification. The primary outcome measure is to evaluate the objective response rate (ORR) of Triplet-combined Therapy for C-staged Hepatocellular Carcinoma in BCLC classification. The secondary Outcome measures include the 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 C-staged Hepatocellular Carcinoma in BCLC classification. Moreover, this study aims to assess the safety and tolerability of Triplet-combined Therapy for C-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 with distant metastasis 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 advanced HCC. Shi Ming et al reported HAIC combined with systemic targeted therapy has a better survival outcome compared to systemic targeted therapy mono-therapy \[OS 13.37 vs 7.13 months, PFS 7.03 vs 2.6 months\] in JAMA Oncology. Although the toxicity of combination therapy is slightly higher than that of sorafenib monotherapy, these adverse effects are tolerable. In addition, in a phase Ib study of Camrelizumab combined with apatinib in the treatment of advanced liver cancer, gastric cancer or gastroesophageal junction cancer showed that in 16 patients with HCC, the ORR was 50.0% and the DCR was 93.8%. When the dose of apatinib was 250 mg, the median PFS was 7.2 months. Camrelizumab combined with low dose apatinib can effectively reduce the incidence of adverse reactions, ≥10% of patients have treatment-related adverse reactions (all levels), no treatment-related adverse reactions leading to death. Therefore, low-dose anti-angiogenic drugs can inhibit tumor angiogenesis on the one hand, reduce immunosuppression by inducing normalization of blood vessels, enhance effector immune cell infiltration, and enhance anti-tumor immunity. In summary, for patients of C-staged Hepatocellular Carcinoma, HAIC, anti-angiogenic 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 advanced 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 C-staged Hepatocellular Carcinoma in BCLC classification.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
47
Drug: FOLFOX Protocol (Oxaliplatin, fluorouracil, and leucovorin); Camrelizumab for injection and Apatinib-Mesylate Tablets Procedure: 1. On the first day of treatment, HAIC was conducted through a catheter intubated into the tumor feeding artery under DSA guidance with the following chemotherapeutic drugs (mFOLFOX7, oxaliplatin 85 mg/m2 2 hours, folinic acid 400 mg/m2, 5-FU 2500 mg/m2 46 hours) pumped into the tumor artery. The HAIC is repeated every 3 weeks. The cumulative maximum sessions of HAIC is up to 6 times. 2. Taking Apatinib-Mesylate Tablets (250 mg/tablet) orally on day 8 in the first HAIC cycle, once a day, for continuous medication. 3. The first dose of Camrelizumab was administered on day 4 of the second HAIC cycle, at a dose of 200 mg intravenously, every three weeks. 4. The cumulative maximum drug use period is up to 2 years. The patient is concurrent on medication until the treatment discontinuation criteria specified in the protocol appear.
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, China
RECRUITINGObjective response rate (ORR) by RECIST 1.1
ORR is defined as the percentage of participants who have best overall response (BOR) of complete response (CR) or partial response (PR) at the time of data cutoff as assessed by RECIST 1.1.
Time frame: From date of first dose of study drug until disease progression (up to approximately 3 years)
Objective response rate (ORR) by mRECIST
ORR is defined as the percentage of participants who have best overall response (BOR) of complete response (CR) or partial response (PR) at the time of data cutoff as assessed by mRECIST.
Time frame: From date of first dose of study drug until disease progression (up to approximately 3 years)
The disease control rate (DCR)
DCR is defined as the percentage of participants who have best overall response (BOR) of complete response (CR) or partial response (PR) or stable disease (SD) at the time of data cutoff as assessed by RECIST 1.1 and mRECIST.
Time frame: From date of first dose of study drug until disease progression, stable disease (up to approximately 3 years)
The time to response (TTR)
TTR was calculated as the time from treatment initiation to first documented response as assessed by RECIST 1.1 and mRECIST.
Time frame: From date of first dose of study drug to the date of first documentation of CR or PR (up to approximately 3 years)
Duration of response (DOR) by RECIST 1.1 and mRECIST
DOR is defined as the time from the first documentation of CR or PR to the date of first documentation of disease progression as assessed by RECIST 1.1 and mRECIST or death (whichever occurs first).
Time frame: From the first documentation of CR or PR to the first date of documentation of disease progression or death whichever occurs first (up to approximately 3 years)
The progression-free survival time (PFS)
The progression-free survival time (PFS) defined as the time from the first study dose date to the date of first documentation of disease progression as assessed by RECIST 1.1 and mRECIST or death, whichever comes earlier.
Time frame: From date of first dose of study drug to the date of first documentation of disease progression or death (up to approximately 3 years)
The liver-specific progression-free survival time (liver-specific PFS)
The liver-specific PFS was defined as the time from treatment initiation to disease progression within the liver as assessed by RECIST 1.1 and mRECIST or death, whichever comes earlier.
Time frame: From date of first dose of study drug to the date of first documentation of disease progression within the liver or death (up to approximately 3 years)
The median overall survival time (OS)
OS is measured from the start date of the Treatment Phase (date of first study dose) until date of death from any cause. Participants who are lost to follow-up and the participants who are alive at the date of data cutoff will be censored at the date the participant was last known alive or the cut-off date.
Time frame: From the start date of the Treatment Phase until date of death from any cause (up to approximately 3 years)
The progression-free survival rate (PFSR) by RECIST 1.1 and mRECIST
Time frame: From date of first dose of study drug to the date of first documentation of disease progression or death, whichever occurs first (up to approximately 3 years)
The overall survival rate (OSR)
Time frame: From date of first dose of study drug to the date of documentation of death from any cause (up to approximately 3 years)
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: From the start date of the Treatment Phase until date of death from any cause (up to approximately 3 years)
Exploratory outcome measure: The quality of life (QoL)
The exploratory endpoint was the QoL, which was assessed using the European Organisation for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30).
Time frame: From date of first dose of study drug to the date of first documentation of disease progression within the liver or death (up to approximately 3 years)
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