NCT05873244

Brief 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.

Trial Health

77
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
44

participants targeted

Target at P25-P50 for phase_2

Timeline
19mo left

Started Aug 2023

Typical duration for phase_2

Geographic Reach
1 country

2 active sites

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress63%
Aug 2023Dec 2027

First Submitted

Initial submission to the registry

May 3, 2023

Completed
21 days until next milestone

First Posted

Study publicly available on registry

May 24, 2023

Completed
3 months until next milestone

Study Start

First participant enrolled

August 21, 2023

Completed
3.4 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 30, 2026

Expected
1 year until next milestone

Study Completion

Last participant's last visit for all outcomes

December 30, 2027

Last Updated

March 21, 2025

Status Verified

March 1, 2025

Enrollment Period

3.4 years

First QC Date

May 3, 2023

Last Update Submit

March 19, 2025

Conditions

HCC

Outcome Measures

Primary Outcomes (1)

  • The progression-free survival in HCC patients treated with CXD101 plus Geptanolimab and control arm

    2 years

Secondary Outcomes (4)

  • The overall survival in HCC patients treated with CXD101 plus Geptanolimab and control arm

    2 years

  • The radiological response rate in HCC patients treated with CXD101 plus Geptanolimab and control arm

    2 years

  • The time-to-progression in HCC patients treated with CXD101 plus Geptanolimab and control arm

    2 years

  • Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

    2 years

Study Arms (2)

Experiment arm

EXPERIMENTAL

* Zabadinostat (CXD101) at 20mg twice daily per orally Day 1-5 every 3 weeks * Geptanolimab at 3mg/kg given intravenously every 2 weeks

Drug: Zabadinostat (CXD101) and Geptanolimab

Control arm

OTHER

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

Drug: Lenvatinib and Sorafenib

Interventions

Zabadinostat (CXD101) and GeptanolimabDRUG

* Zabadinostat (CXD101) at 20mg twice daily per orally Day 1-5 every 3 weeks * Geptanolimab at 3mg/kg given intravenously every 2 weeks

Experiment arm
Lenvatinib and SorafenibDRUG

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

Control arm

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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)

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Department of Clinical Oncology, Prince of Wales Hospital

Hong Kong, Hong Kong

RECRUITING

School of Biomedical Science, The Chinese University of Hong Kong

Hong Kong, Hong Kong

ACTIVE NOT RECRUITING

Related Publications (1)

  • Tu 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: 39486886DERIVED

MeSH Terms

Interventions

lenvatinibSorafenib

Intervention Hierarchy (Ancestors)

Phenylurea CompoundsUreaAmidesOrganic ChemicalsBenzene DerivativesHydrocarbons, AromaticHydrocarbons, CyclicHydrocarbonsNiacinamideNicotinic AcidsAcids, HeterocyclicHeterocyclic CompoundsPyridinesHeterocyclic Compounds, 1-Ring

Central Study Contacts

Stephen Chan, MD, FRCP

CONTACT

3505 2166chanlam_stephen@cuhk.edu.hk

Nicole Yim, RN

CONTACT

3505 1046nicole@clo.cuhk.edu.hk

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Professor

Study Record Dates

First Submitted

May 3, 2023

First Posted

May 24, 2023

Study Start

August 21, 2023

Primary Completion (Estimated)

December 30, 2026

Study Completion (Estimated)

December 30, 2027

Last Updated

March 21, 2025

Record last verified: 2025-03

Locations

HK(2)