CXD101 in Immunotherapy-related Liver Cancer

To move from bench to clinic, it is crucial to validate the above in HCC patients demonstrating resistance to ICI-based treatment. In this grant, the investigators propose a randomized phase II clinical trial in patients with HCC who developed progressive disease to prior regimen containing anti-PD(L)-1. The investigators have already secured support of study medications from two pharmaceuticals to provide class 1 HDAC inhibitor and anti-PD1, respectively. Patients were randomized 1:1 to two study arms: the experiment arm consists of CXD101 20mg twice daily Day 1-5 every 3 weeks and an anti-PD1, geptanolimab at 3mg/kg Day 1 every 2 weeks. The dose of CXD101 has already been confirmed to be safe to combine with anti-PD1 in phase I/II studies in cancer patients. The control arm consists of investigators' choice of lenvatinib or sorafenib which are both considered standard treatment after failure with first-line atezolizumab-bevacizumab or other anti-PD(L)-1-based treatment. The primary endpoint is progress-free survival. Along the clinical trial, tumor biopsy will also be conducted at baseline and 6-week post-treatment to explore potential predictive biomarkers. Results of the study not only act as proof-of-concept but also potentially develop a novel treatment combination to tackle resistance to anti-PD(L)-1 treatment in HCC.

Inclusion criteria

• Diagnosis of HCC according to the AASLD guideline20
• Prior treatment with systemic treatment consisting of immune checkpoint inhibitors (anti-PD1, anti-PDL1 or anti-CTLA4)
• The duration of previous ICI must be 6 weeks or longer to avoid chance of pseudo-progression
• Eastern Cooperative Oncology Group (ECOG) Performance status of 0-1
• Adequate hematological function:
• Absolute neutrophil count (ANC) ≥ 1.5 x109/L; Platelets ≥ 100 x 109/L and Hemoglobin ≥ 8g/dL
• Adequate renal function:
• Urine protein/creatinine ratio ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1g
• Serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40 mL/min (according to the Cockcroft-Gault equation)
• Adequate hepatic function parameters:
• Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L)
• Serum albumin ≥ 2.8 g/dL (≥ 28 g/L)
• Alanine aminotransferase (ALT) < 3.0 upper limit of normal (ULN)

Exclusion criteria

• Previous development of severe autoimmune complications from immune checkpoint inhibitors
• History of moderate to sever autoimmune disease requiring steroid use
• History of organ transplant
• Prior use of lenvatinib or sorafenib
• Disease involvement/thrombosis of major vessels (including main trunk of portal vein, inferior vena cava or pulmonary artery)
• More than two lines of systemic therapy (i.e., study treatment must be second-line or third-line treatment)
• Clinically significant bleeding events (eg.. esophageal varices) within 3 months
• Moderate or severe ascites
• Child-pugh B or C hepatic function
• Systolic blood pressure of 200mmHg or higher
• Pregnant or lactating females