zabinostat (CXD101) / IngenOx Therap, Nuance Biotech - LARVOL DELTA

HDAC and CDK inhibitor combinations suppress neutrophil activation in myeloma (ASH 2025) - "To overcome translational barriers associated with dinaciclib and entinostat, we evaluated next-generation agents: KB0742, a selective and orally bioavailable CDK9 inhibitor, in combination with quisinostat or zabadinostat , two potent HDAC inhibitors with more favorable pharmacokinetic and safety profiles. These transcriptional changes, accompanied by increased re-expression of tumor suppressors (e.g.,p16) and TGFβ/SMAD signaling components, would predict reprogramming of an anti-inflammatory microenvironment by these combination treatments in myeloma. These findings point to a promising but underdeveloped therapeutic avenue whereby suppressing neutrophil-driven inflammation enhances anti-myeloma immunity."

Hematological Malignancies • Multiple Myeloma • Smoldering Multiple Myeloma • BCL2L1 • CXCL1 • CXCL8 • IL1A • IL23A • ITGAM • NRAS • SDC1

HDAC and CDK Inhibitor Combinations Synergize in Limiting Myeloma (IMS 2025) - "Further investigation into a combined genetic signature will aid in discovering mechanisms of drug synergy and provide biomarkers for a combined response that may translate to the clinic."

Late-breaking abstract • Hematological Malignancies • Multiple Myeloma • ANXA5 • BCL2L1 • CDK1 • HDAC1 • MYC • SDC1

Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma. (PubMed, Gut) - P2 | "Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance (NCT05873244)."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD8 • GSDME • GZMB • HDAC1 • IFNG • STAT1

Epigenetic activation of tumoral IFNγresponse and pyroptosis overcomes immunotherapy resistance in hepatocellular carcinoma (AACR 2024) - "Our findings suggest that corruption of tumor intrinsic IFNγ signaling may confer ICB resistance upon ICB therapy, which can be rectified by class I HDAC inhibitor mediated IFNγ response and tumor cell pyroptosis. Based on these findings, we have commenced a Phase II clinical study of a new epigenetic immunotherapy (CXD101 plus anti-PD-1) for HCC patients resisting anti-PD-(L)1 alone."

Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • IFNG

CXD101 in Immunotherapy-related Liver Cancer (clinicaltrials.gov) - P2 | N=44 | Recruiting | Sponsor: Stephen Chan Lam | Not yet recruiting ➔ Recruiting

Checkpoint inhibition • Enrollment open • Gastrointestinal Cancer • Gene Therapies • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

CXD101 in Immunotherapy-related Liver Cancer (clinicaltrials.gov) - P2 | N=44 | Not yet recruiting | Sponsor: Stephen Chan Lam

Checkpoint inhibition • New P2 trial • Gastrointestinal Cancer • Gene Therapies • Hepatocellular Cancer • Hepatology • Immune Modulation • Liver Cancer • Oncology • Solid Tumor

Epigenetic activation of tumoral INFγ response and pyroptosis overcomes immunotherapy resistance in hepatocellular carcinoma (IDDF 2023) - "Based on these findings, industrial support for the Phase II clinical study of CXD101 plus anti-PD-1 has been secured to provide new epigenetic immunotherapy for ICB-resistant patients. This project is supported by the CRF (C4045-18W), GRF (14115820), TRS (T11-706/18-N), Li Ka Shing Foundation, CUHK Strategic Seed Funding for Collaborative Research Scheme."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Oncology • Solid Tumor • GSDME • IFNG • STAT1

A phase Ib/ II trial to assess the safety and efficacy of CXD101 in combination with the PD-1 inhibitor nivolumab in patients with metastatic, previously-treated, microsatellite-stable (MSS) colorectal carcinoma (short title CAROSELL) (ESMO 2019) - "Legal entity responsible for the study: Celleron Therapeutics Ltd. Funding: Celleron Therapeutics Ltd."

Clinical • Combination therapy • IO biomarker • P1/2 data • PD(L)-1 Biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity. (PubMed, Commun Biol) - "We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response...The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • CD4 • CD8

CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): a multicentre, open-label, single-arm, phase II trial. (PubMed, ESMO Open) - "The primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious."

Journal • P2 data • Colorectal Cancer • Endocrine Disorders • Gastrointestinal Cancer • Hematological Disorders • Immune Modulation • Immunology • Inflammation • Neutropenia • Oncology • Pneumonia • Solid Tumor

Phase 1 Trial of CXD101 in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=51 | Completed | Sponsor: Oxford University Hospitals NHS Trust | Active, not recruiting ➔ Completed

Biomarker • Trial completion • Oncology • Solid Tumor

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma. (PubMed, BMC Cancer) - P1 | "CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted."

Clinical • Journal • P2a data • Fatigue • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Neutropenia • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia

Phase 1 Trial of CXD101 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=51; Active, not recruiting; Sponsor: Oxford University Hospitals NHS Trust; Trial completion date: Dec 2021 ➔ Dec 2022

Biomarker • Clinical • Trial completion date • Oncology

Phase 1 Trial of CXD101 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=51; Active, not recruiting; Sponsor: Oxford University Hospitals NHS Trust; Trial completion date: Oct 2021 ➔ Dec 2021

Biomarker • Clinical • Trial completion date • Oncology

PLACARD: A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1/2; N=0; Withdrawn; Sponsor: University College, London; N=45 ➔ 0; Trial completion date: Oct 2027 ➔ Apr 2025; Not yet recruiting ➔ Withdrawn; Trial primary completion date: Oct 2026 ➔ Apr 2024

Combination therapy • Enrollment change • Epigenetic controller • Trial completion date • Trial primary completion date • Trial withdrawal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6

PLACARD: A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1/2; N=45; Not yet recruiting; Sponsor: University College, London

Combination therapy • Epigenetic controller • New P1/2 trial • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6

PLACARD: A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1/2; N=45; Not yet recruiting; Sponsor: University College, London; Trial completion date: Jan 2026 ➔ Oct 2027; Trial primary completion date: Jan 2025 ➔ Oct 2026

Combination therapy • Epigenetic controller • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6

PLACARD: A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1/2; N=45; Not yet recruiting; Sponsor: University College, London; Trial completion date: Apr 2025 ➔ Jan 2026; Trial primary completion date: Apr 2024 ➔ Jan 2025

Combination therapy • Epigenetic controller • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6

Immune modulation underpins the anti-cancer activity of HDAC inhibitors. (PubMed, Mol Oncol) - "The altered TME reflected enhanced anti-tumour activity when CXD101 was combined with immune checkpoint inhibitors (ICIs), such as anti-PD1 and anti-CTLA4. The ability of CXD101 to re-instate immune-relevant gene expression in the TME and act together with ICIs provides a powerful rationale for exploring the combination therapy in human cancers."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Immunology • Inflammation • Oncology • Solid Tumor • CD4 • CD8

Phase 1 Trial of CXD101 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=51; Active, not recruiting; Sponsor: Oxford University Hospitals NHS Trust; Recruiting ➔ Active, not recruiting; Trial completion date: Nov 2019 ➔ Oct 2021

Biomarker • Clinical • Enrollment closed • Trial completion date • Oncology

Celleron picks up discarded cancer drug from Roche (PharmaTimes) - "Oxford, UK-based Celleron Therapeutics has signed a licensing agreement with Roche for exclusive rights to emactuzumab, a monoclonal antibody and tumour microenvironment modulator....The UK biopharma company also has a global license partnership with AstraZeneca for CXD101, a HDAC inhibitor that has demonstrated clinically important tumour remissions in a Phase I trial."

Licensing / partnership • Oncology • Solid Tumor

A phase I trial to assess the safety, PK and PD of CXD101 in advanced cancer expressing the biomarker HR23B (ESMO 2016) - P1; "Disease activity was seen in T cell lymphoma, Follicular lymphoma and Hodgkin lymphoma. Further analysis of HR23B correlated tumour response and durability is ongoing and will be presented alongside PK and PD data."

Biomarker • Clinical • Biosimilar • Hematological Malignancies • Hodgkin Lymphoma • Immunology • Indolent Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A phase I study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer. (PubMed, Cancer) - "The MTD in the current study was found to be 20 mg twice daily. Encouraging and durable activity was observed in patients with Hodgkin lymphoma, T-cell lymphoma, and follicular lymphoma."

Clinical • Journal • P1 data • PK/PD data

CAROSELL: A Trial of CXD101 in Combination With Nivolumab in Patients With Metastatic Microsatellite-Stable Colorectal Cancer (clinicaltrials.gov) - P1/2; N=55; Active, not recruiting; Sponsor: Celleron Therapeutics Ltd.

Clinical • Combination therapy • New P1/2 trial

Phase 1 Trial of CXD101 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=40; Recruiting; Sponsor: Oxford University Hospitals NHS Trust; Trial completion date: Dec 2017 ➔ Nov 2019; Trial primary completion date: Jun 2017 ➔ Nov 2019

Biomarker • Clinical • Trial completion date • Trial primary completion date