CXD101 in Immunotherapy-related Liver Cancer

For hepatocellular carcinoma (HCC), durable responses and improved survivals have been reported in clinical trials on immune checkpoint inhibitor (ICI)-based treatment. However, resistance to ICI is increasingly encountered in clinical practice in HCC patients. Various approaches are currently evaluated in clinical setting to tackle acquired resistance during treatment of ICIs in HCC. Our group has a track record of studying the role of histone deacetylases (HDACs) in mediating resistance to ICI in HCC. First, based on single-cell sequencing data of serial biopsy of tumor in our phase II clinical trial on pembrolizumab in HCC (NCT03419481), the investigators reveal an upregulation of class 1 HDAC in patients with acquired resistance to pembrolizumab, which was associated with reduced lymphoid/myeloid cellular ratio in the tumor. Further, the investigators showed that HDAC8, a class 1 HDAC, could diminish the efficacy of anti-programmed cell death (ligand)-1 (PD\[L\]-1) by the mechanism of T-cell exclusion from the tumor environment (SciTranl Med. 2021;13:online). Finally, the investigators combine CXD101, a potent selective class I HDAC inhibitor, with anti-PD(L)-1 in orthotopic immunocompetent HCC mouse model with resistance to anti-PD(L)-1 treatment and find that the combination regimen could reverse the resistance phenotype and significantly improve survivals of mice than either CXD101 or anti-PD(L)-1 alone.

Sex

All

Minimum age

18 Years

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

• DERIVEDTu Y, Wu H, Zhong C, Liu Y, Xiong Z, Chen S, Wang J, Wong PP, Yang W, Liang Z, Lu J, Chen S, Zhang L, Feng Y, Si-Tou WW, Yin B, Lin Y, Liang J, Liang L, Vong JSL, Ren W, Kwong TT, Leung H, To KF, Ma S, Tong M, Sun H, Xia Q, Zhou J, Kerr D, La Thangue N, Sung JJY, Chan SL, Cheng AS. Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma. Gut. 2025 Mar 6;74(4):613-627. doi: 10.1136/gutjnl-2024-332281. PMID 39486886