A Phase 2 Study on Immune Checkpoint Inhibitors and Radioembolisation for Previously Untreated Metastatic Hepatocellular Carcinoma
Hepatocellular carcinoma is one of the most intractable primary malignancies in the hepatobiliary and pancreatic tract with a poor overall survival worldwide. Unfortunately, the vast majority of hepatocellular carcinoma patients suffer from advanced unresectable or metastatic disease at diagnosis. Currently targeted therapy alone, or in combination with anti-vascular endothelial growth factor antagonist, is the standard first-line treatment for metastatic hepatocellular carcinoma. On the other hand, there is growing evidence suggesting that radiation therapy (external or internal) with or without immune checkpoint inhibitors can produce or even augment abscopal effect in which the tumours away from the radiation field also show significant tumour shrinkage. The underlying mechanism of eliciting abscopal effect includes the increased antigen presentation by the myeloid cells within the tumour stroma leading to enhanced tumour cell killing. Previous case reports showed that radiation therapy alone can induce abscopal effect in mice and human models. However, a robust and concrete evidence of abscopal effect with combinational immune checkpoint inhibitors and radioembolisation or external radiation therapy in hepatocellular carcinoma is still lacking. This study investigates the efficacy and safety of immune checkpoint inhibitors and radioembolisation as first-line treatment for previously untreated metastatic hepatocellular carcinoma.
• Metastatic hepatocellular carcinoma (HCC) confirmed by radiological findings with contrast-enhanced triphasic CT scan of the liver and/or MRI scan of the abdomen, without or without histological/cytological confirmation or elevation of serum alpha-feto protein.
• Must be of age 18 years or above.
• Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry.
• Must be eligible to receive immune checkpoint inhibitor and yttrium-90 microsphere injection.
• Must have baseline efficacy images with CT or MRI and measurable target lesions in the liver according to RECIST 1.1 and mRECIST, taken within 28 days prior to the start of immune checkpoint inhibitor.
• Must be able to provide written informed consent.
• Adequate serum hematological functions defined as:
⁃ Absolute neutrophil count (ANC) ≥1.0 x 10\^9/l Platelet ≥75 x 10\^9/l Haemoglobin ≥9 g/dL
• Adequate serum biochemistry functions defined as:
⁃ Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). \<\<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.\>\> Serum aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤2.5 times of institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5 times of ULN
⁃ Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
⁃ Males:
⁃ Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
⁃ Females:
⁃ Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)