abexinostat (CG-781) / Xynomic, AbbVie - LARVOL DELTA

Identifying Novel Drug Vulnerabilities in Specified Molecular Subsets of Chronic Lymphocytic Leukemia (ASH 2024) - "Supporting the clinical and biological relevance of our results, venetoclax and ibrutinib were highly effective across CLL, nutlin-3 was ineffective in p53 mutant CLL. Novel drugs with the greatest pan-CLL effects include abexinostat, navitoclax, cerdulatinib, gandotinib and nutlin-3...We found many such associations including high sensitivity of IGHV-mutated CLL (M-CLL) to nutlin-3, IGHV-unmutated CLL (U-CLL) to Onalespib (MWU test, q<0.1), the intermediate epigenetic subtype (i-CLL) to Rapamycin (ANOVA, q<0.1). RNA subtype EC-m4 (TNF- and IFN- high M-CLLs) was specifically sensitive to nutlin-3 and onalespib; and EC-m2 (trisomy 12 enriched M-CLLs) demonstrated resistance to venetoclax and sensitivity to abexinostat (MWU test, p<0.05). Response to lenalidomide was associated with trisomy 12 (MWU, p=0.002)...In summary, we present an experimental strategy to rapidly prioritize novel treatments for CLL patients and a computational framework to inform precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD5 • IGH • TP53

Three novel epigenetic-modifying compounds identified as HIV latency-reversing agents in Ghana (ASTMH 2024) - "The lead compounds were further screened in CD4+ T cells of four individuals living with HIV on suppressive ART.We identified five positive hits (MC1568, Abexinostat, Pracinostat, EPZ2015666, CXC6258-HCL) from the J.LAT 10.6 cell culture system with GFP-positive cells (20-91%). These compounds effectively reactivated latent HIV-1 in vitro and induced HIV expression ex vivo. Our findings suggest that these LRAs hold promise for reactivating latent HIV in individuals living with the virus."

Human Immunodeficiency Virus • Infectious Disease • CD4

A phase 1 trial of abexinostat with ibrutinib in relapsed/refractory mantle cell lymphoma and non-germinal center diffuse large B cell lymphoma. (PubMed, Leuk Lymphoma) - No abstract available

Journal • P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

The Bioequivalence of Abexinostat (CRA-024781) Tosylate Tablet (20 mg) in Chinese Healthy Subjects Under Fasting Conditions. (PubMed, Clin Pharmacol Drug Dev) - "The 90% confidence intervals (CIs) for the Cmax, AUC0-t, and AUC0-∞ of CRA-024781 and its 2 major metabolites (PCI-27789 and PCI-27887, both metabolites are pharmacologically inactive on HDAC1) fell within the acceptable range of 80%-125%. The results suggest that the CRA-024781 test preparation (Test [T1]) is bioequivalent to the reference preparation (Reference [T2]) in healthy Chinese subjects under fasting conditions."

Journal • HDAC1

A Study of Temodar With Abexinostat (PCI-24781) for Patients With Recurrent Glioma (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: University of Nebraska | Trial completion date: Jun 2027 ➔ Mar 2027 | Trial primary completion date: Feb 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Oligodendroglioma • Oncology • Sarcoma • Solid Tumor

Chromatin context-dependent effects of epigenetic drugs on CRISPR-Cas9 editing. (PubMed, Nucleic Acids Res) - "For example, we find a subset of histone deacetylase inhibitors that improve Cas9 editing efficiency throughout all types of heterochromatin (e.g. PCI-24781), while others were only effective in euchromatin and H3K27me3-marked regions (e.g. apicidin). In summary, this study reveals that most epigenetic drugs alter CRISPR editing in a chromatin-dependent manner, and provides a resource to improve Cas9 editing more selectively at the desired location."

Journal

A phase II multicenter study of abexinostat, an oral histone deacetylase inhibitor, in patients with relapsed/refractory follicular lymphoma. (ASCO 2024) - P2 | "Abx was well tolerated at dose of 80 mg BID as monotherapy, and demonstrated a significant response in pts with heavily pretreated R/R FL."

Clinical • Epigenetic controller • P2 data • Anemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukopenia • Lymphoma • Neutropenia • Oncology • Thrombocytopenia • CREBBP • EP300

Abexinostat and Ibrutinib in Diffuse Large B-cell Lymphoma and Mantle Cell Lymphoma (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: May 2024 ➔ May 2025 | Trial primary completion date: May 2024 ➔ May 2025

Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL6 • IRF4 • MME

Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies (clinicaltrials.gov) - P1 | N=35 | Completed | Sponsor: Rahul Aggarwal | Active, not recruiting ➔ Completed | Phase classification: P1b ➔ P1

Combination therapy • Metastases • Phase classification • Trial completion • Cutaneous Melanoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Squamous Cell Skin Cancer • Urothelial Cancer • MSI

Development of an UPLC-MS/MS method for quantitative analysis of abexinostat levels in rat plasma and application of pharmacokinetics. (PubMed, BMC Chem) - "The mobile phase we used was acetonitrile and 0.1% formic acid, and the internal standard (IS) was givinostat. In addition, the recovery and matrix effects of this method were within acceptable limits. Finally, the method presented in this paper enabled accurate and quick determination of abexinostat levels in rat plasma from the pharmacokinetic study following gavage at a dose of 8.0 mg/kg abexinostat."

Journal • PK/PD data • Preclinical • Oncology

A Study of Pazopanib With or Without Abexinostat in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma (RENAVIV) (clinicaltrials.gov) - P3 | N=413 | Recruiting | Sponsor: Xynomic Pharmaceuticals, Inc. | Trial completion date: Jun 2023 ➔ Jun 2025 | Trial primary completion date: Jun 2023 ➔ Dec 2024

Metastases • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

A Clinical Study to Evaluate Pharmacokinetics, Safety, and Tolerability of Abexinostat in Chinese Patients (clinicaltrials.gov) - P1/2 | N=12 | Active, not recruiting | Sponsor: Xynomic Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting | N=25 ➔ 12 | Trial completion date: Dec 2023 ➔ Jun 2024

Enrollment change • Enrollment closed • Monotherapy • Trial completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

FORERUNNER: Study of Abexinostat in Patients With Relapsed or Refractory Follicular Lymphoma (clinicaltrials.gov) - P2 | N=139 | Active, not recruiting | Sponsor: Xynomic Pharmaceuticals, Inc. | Trial completion date: Dec 2023 ➔ Dec 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Study to Evaluate Efficacy and Safety of Oral Abexinostat in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL) (clinicaltrials.gov) - P2 | N=170 | Recruiting | Sponsor: Xynomic Pharmaceuticals, Inc. | Trial completion date: May 2024 ➔ May 2025 | Trial primary completion date: May 2024 ➔ Dec 2024

Monotherapy • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Multi-Center Phase 2 Study to Evaluate Efficacy and Safety of Oral Abexinostat as Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma (clinicaltrials.gov) - P2 | N=96 | Recruiting | Sponsor: Xynomic Pharmaceuticals, Inc. | Trial completion date: Jun 2023 ➔ Sep 2024 | Trial primary completion date: Jun 2023 ➔ Feb 2024

Epigenetic controller • Monotherapy • Trial completion date • Trial primary completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Pazopanib in Combination With PCI-24781 in Patients With Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=90 | Active, not recruiting | Sponsor: Pamela Munster | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Thyroid Gland Carcinoma

A Study of Temodar With Abexinostat (PCI-24781) for Patients With Recurrent Glioma (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: University of Nebraska | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Feb 2024 ➔ Feb 2025

Trial completion date • Trial primary completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Oligodendroglioma • Oncology • Sarcoma • Solid Tumor

A Study of Temodar With PCI-24781 for Patients With Recurrent Glioma (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: University of Nebraska | Not yet recruiting ➔ Recruiting | Trial completion date: Sep 2026 ➔ Jun 2026 | Trial primary completion date: May 2024 ➔ Feb 2024

Enrollment open • Trial completion date • Trial primary completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Oligodendroglioma • Oncology • Sarcoma • Solid Tumor

Study to Evaluate Efficacy and Safety of Oral Abexinostat in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL) (clinicaltrials.gov) - P2 | N=170 | Recruiting | Sponsor: Xynomic Pharmaceuticals, Inc. | Trial completion date: May 2023 ➔ May 2024 | Trial primary completion date: May 2023 ➔ May 2024

Monotherapy • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Abexinostat and Ibrutinib in Diffuse Large B-cell Lymphoma and Mantle Cell Lymphoma (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Phase classification: P1/2 ➔ P1

Phase classification • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL6 • IRF4 • MME

INTEGRATED ATAC-SEQ AND SINGLE-CELL SYNERGISTIC CHEMOSENSITIVITY PROFILING IDENTIFIES RATIONAL DRUG COMBINATIONS IN IBRUTINIB-TREATED CLL PATIENTS (EHA 2018) - P=N/A; "...Recent studies have explored combined use of ibrutinib with inhibitors for the proteasome (carfilzomib), BCL2i (venetoclax), and HDAC (abexinostat) in preclinical models, which has shown promising initial results...Results ATACseqidentified increases in chromatin accessibility and chemosensitivity in proteasome, inflammatory NF-B/TNF signaling, CoA biosynthesis, PI3K/Akt, pathways, along with changes affecting genes such as FOXO3 and IBa, and both the ex vivo drug testing of samples from patients after clinical ibrutinb and ex vivo synergy screeningrevealed that ibrutinib treatment in vivo and in vitro sensitizes CLL cells to compounds such as the proteasome inhibitor bortezomib, the JAK inhibitor ruxolitinib, the bisphosphate zoledronate, and the aurora kinaseinhibitor ZM447439... Our results show that synergistic combination and informatics-integration of chromatin profiling with functional drug screening is a powerful tool to identify targetable path

Clinical • Chronic Lymphocytic Leukemia • Indolent Lymphoma

Integrated ATAC-Seq and Chemosensitivity Profiling Identifies Rational Drug Combinations in Ibrutinib-Treated CLL Patients (ASH 2017) - P=N/A; "...Recent studies have explored the combined use of ibrutinib with the proteasome inhibitor carfilzomib, the BCL2 inhibitor venetoclax, and the HDAC inhibitor abexinostat in preclinical models, which has shown promising initial results...Cell viability assays revealed that ibrutinib treatment in vivo and in vitro sensitizes CLL cells to compounds such as the proteasome inhibitor bortezomib, the JAK inhibitor ruxolitinib, the PLK1 inhibitor volasertib, and the bisphosphate zoledronate...This approach may be useful for designing personalized therapies as well as the rational planning of clinical studies. Our approach is directly transferable to other leukemic diseases in which malignant cells can be obtained for chromatin profiling and drug sensitivity analysis, thus providing a widely applicable tool for the rational development of combination therapies."

Biosimilar • Chronic Lymphocytic Leukemia • Indolent Lymphoma

Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer. (PubMed, Front Immunol) - "In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer."

Epigenetic controller • IO biomarker • Journal • Review • Breast Cancer • Oncology • Solid Tumor

RENAVIV: A randomized phase III, double-blind, placebo-controlled study of pazopanib with or without abexinostat in patients with locally advanced or metastatic renal cell carcinoma. (ASCO-GU 2019) - P3; "A pre-specified minimum of 50% of patients are required to have received prior immunotherapy. The first patient was enrolled in October 2018."

Clinical • IO biomarker • P3 data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

A Study of Temodar With PCI-24781 for Patients With Recurrent Glioma (clinicaltrials.gov) - P1 | N=18 | Not yet recruiting | Sponsor: University of Nebraska

New P1 trial • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Gliosarcoma • Oligodendroglioma • Oncology • Sarcoma • Solid Tumor