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Hepatic Arterial Infusion combined with Apatinib and Camrelizumab

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.

Yang-kui Gu, Prof.

Tian-qi Zhang, Dr.

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.

A Trial of Hepatic Arterial Infusion Combined With Apatinib and Camrelizumab for C-staged Hepatocellular Carcinoma in BCLC Classification

A Prospective, Single-arm, Phase II Trial to Evaluate the Effectiveness and Safety of Hepatic Arterial Infusion Chemotherapy (HAIC) of Oxaliplatin, 5-fluorouracil and Leucovorin (mFOLFOX7) Combined With Apatinib-Mesylate Tablets and Camrelizumab for Injection for C-staged Hepatocellular Carcinoma in BCLC Classification.

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.

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.

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.

TTR was calculated as the time from treatment initiation to first documented response as assessed 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).

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.

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.

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.

The exploratory endpoint was the QoL, which was assessed using the European Organisation for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30).

Jiangsu HengRui Medicine Co., Ltd.

Sun Yat-sen University

Associate Professor

combination of hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX7) , targeted drugs (Apatinib 250mg), and anti-PD-1 immunotherapy (Camrelizumab 200mg)

combination of targeted drugs (Apatinib 250mg), and anti-PD-1 immunotherapy (Camrelizumab 200mg)

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 the 8th day 30minutes after meals, once a day, for continuous medication.

3. On the 22nd day of treatment, namely the second session of HAIC, intravenous infusion of Camrelizumab 200mg every 3 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.

Drug: Camrelizumab for injection and Apatinib-Mesylate Tablets Procedure: 1. Taking Apatinib-Mesylate Tablets (250 mg/tablet) orally 30minutes after meals, once a day, for continuous medication 2. Intravenous infusion of Camrelizumab 200mg every 2 weeks.

Apatinib combined with Camrelizumab

Meng-xuan Zuo, Dr.

Zhi-yu Xiao, Prof.

Jing-zhang Chen, Prof.

Nan Lin, Prof.

Liang-rong Shi, Prof.

This study was designed to evaluate the effectiveness and safety of hepatic arterial infusion chemotherapy combined with Apatinib and Camrelizumab (treatment group) versus Apatinib and Camrelizumab (control group) for C-staged Hepatocellular Carcinoma in BCLC classification.

The primary outcome measure is to evaluate the progression-free-survival (PFS) of treatment group and control group for C-staged Hepatocellular Carcinoma in BCLC classification.

The secondary Outcome measures include the overall survival (OS), time to progress (TTP), time-to-response (TTR), duration of response (DOR), objective response rate (ORR) and disease control rate (DCR) of treatment group and control group for C-staged Hepatocellular Carcinoma in BCLC classification.

Moreover, this study aims to assess the safety and tolerability of treatment group and control group 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? A phase-II study conducted by our team revealed that a combination of hepatic arterial infusion chemotherapy, targeted drugs (Apatinib), and anti-PD-1 immunotherapy (Camrelizumab) showed promising clinical benefits and acceptable safety for BCLC Stage C HCC, as the confirmed ORR was 61.54% per RECIST 1.1. However, there is no prospective randomized study to prove the efficacy and safety of HAIC combined with apatinib and camrelizumab. So this study was designed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy combined with Apatinib and Camrelizumab versus Apatinib and Camrelizumab to provide a more effective and toxic-tolerable treatment for patients in C-staged Hepatocellular Carcinoma in BCLC classification.

A Trial of Hepatic Arterial Infusion Combined With Apatinib and Camrelizumab Versus Apatinib and Camrelizumab for C-staged Hepatocellular Carcinoma in BCLC Classification

A Randomized Controlled, Open-label, Multicenter Phase III Clinical Trial to Evaluate the Effectiveness and Safety of Hepatic Arterial Infusion Chemotherapy (HAIC) of Oxaliplatin, 5-fluorouracil and Leucovorin (mFOLFOX7) Combined With Apatinib and Camrelizumab Versus Apatinib and Camrelizumab for C-staged Hepatocellular Carcinoma in BCLC Classification.

DOR is defined as the time from the first documentation of CR or PR to the date of first documentation of disease progression or death (whichever occurs first) as assessed by RECIST 1.1 and 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 RECIST 1.1 and mRECIST

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Trial of Hepatic Arterial Infusion Combined With Apatinib and Camrelizumab for C-staged Hepatocellular Carcinoma in BCLC Classification	NCT04191889	C-staged Hepato...	Hepatic Arteria...	18 Years - 70 Years	Sun Yat-sen University
A Trial of Hepatic Arterial Infusion Combined With Apatinib and Camrelizumab for C-staged Hepatocellular Carcinoma in BCLC Classification	NCT04191889	C-staged Hepato...	Hepatic Arteria...	18 Years - 70 Years	Sun Yat-sen University
A Trial of Hepatic Arterial Infusion Combined With Apatinib and Camrelizumab Versus Apatinib and Camrelizumab for C-staged Hepatocellular Carcinoma in BCLC Classification	NCT05313282	C-staged Hepato...	Hepatic Arteria... Apatinib combin...	18 Years -	Sun Yat-sen University
A Trial of Hepatic Arterial Infusion Combined With Apatinib and Camrelizumab for C-staged Hepatocellular Carcinoma in BCLC Classification	NCT04191889	C-staged Hepato...	Hepatic Arteria...	18 Years - 70 Years	Sun Yat-sen University

Spots Global Cancer Trial Database for hepatic arterial infusion combined with apatinib and camrelizumab