At a glance
ClinicalIndex Comparison Record- ✓Diagnosis of HCC according to AASLD guideline
- ✓Prior systemic treatment with immune checkpoint inhibitors (anti-PD1, anti-PDL1 or anti-CTLA4)
- ✓Previous ICI duration of 6 weeks or longer
- ✕Previous severe autoimmune complications from immune checkpoint inhibitors
- ✕History of moderate to severe autoimmune disease requiring steroid use
- ✕History of organ transplant
- ✕Prior use of lenvatinib or sorafenib
Standardized by ClinicalIndex from the ClinicalTrials.gov record · verify against the source.
Epigenetic Therapeutics to Overcome Resistance Against Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: A Proof-of-concept Clinical Trial
In Brief
A Phase 2 clinical trial evaluating Zabadinostat (CXD101) and Geptanolimab and Lenvatinib and Sorafenib for HCC. Active but no longer recruiting, targeting 26 participants across 2 sites.
Detailed Summary
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.
Study Details
Timeline
Arms & Interventions
* Zabadinostat (CXD101) at 20mg twice daily per orally Day 1-5 every 3 weeks * Geptanolimab at 3mg/kg given intravenously every 2 weeks
Clinicians' choice of TKI at corresponding recommended dosage: * Lenvatinib at 8mg daily for patients with body weight \<60kg or 12mg daily with body weight ≥ 60kg * Sorafenib at 400mg twice daily
Interventions
* Zabadinostat (CXD101) at 20mg twice daily per orally Day 1-5 every 3 weeks * Geptanolimab at 3mg/kg given intravenously every 2 weeks
Clinicians' choice of TKI at corresponding recommended dosage: * Lenvatinib at 8mg daily for patients with body weight \<60kg or 12mg daily with body weight ≥ 60kg * Sorafenib at 400mg twice daily