guadecitabine (SGI-110) / Otsuka - LARVOL DELTA

Final results of phase Ib/II study of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma (ccRCC) and biomarker analysis. (ASCO-GU 2023) - P1/2 | "The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396."

Biomarker • Clinical • Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD4 • CD8 • CXCL10 • CXCL9 • FOXP3 • IFNG • IL17A

The phase II NIBIT-ML1 study of nivolumab plus ipilimumab and ASTX727 or nivolumab plus ipilimumab in PD-1 resistant metastatic melanoma: Tumor methylation landscape and correlation with clinical outcomes. (ASCO 2025) - P2 | "Funded by No funding sources reported Clinical Trial Registration Number: NCT04250246 Background: In the NIBIT Foundation-sponsored phase Ib NIBIT-M4 study, we firstly showed that the hypomethylating agent (HMA) guadecitabine (guade), a prodrug of decitabine (D), followed by ipilimumab (I) was safe with promising clinical and immunologic activity in cutaneous metastatic melanoma (MM) patients (pts) (Di Giacomo, Clin Cancer Res 2019; Noviello, Nat Commun 2023). Treatment with ASTX727 plus I+N is feasible and has meaningful clinical and immunologic activity in PD-1 refractory MM pts."

Clinical • Clinical data • Late-breaking abstract • Metastases • P2 data • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-1

Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: randomized phase 3 ASTRAL-2 trial. (PubMed, Blood Adv) - P3 | "Patients with relapsed/refractory acute myeloid leukemia (AML) were randomized to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy; low-intensity treatment with HMAs, or low-dose cytarabine; or best supportive care (BSC). There was an OS benefit for guadecitabine in several prespecified subgroups. This study was registered as ClinicalTrials.gov as NCT02920008."

Journal • P3 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology

A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-associated Renal Cell Carcinoma. (PubMed, Clin Cancer Res) - "Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. While 4/9 patients had prolonged stable disease there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, though signs of biologic activity were noted."

Journal • P2 data • CNS Tumor • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Genito-urinary Cancer • Hematological Disorders • Neuroendocrine Tumor • Neutropenia • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • PDGFRA

Durvalumab and guadecitabine in advanced clear cell renal cell carcinoma: results from the phase Ib/II study BTCRC-GU16-043. (PubMed, Nat Commun) - P1/2 | "Asymptomatic neutropenia was the most common adverse event. Even though the trial did not meet the primary objective in cohort 1, the tolerability and PFS signal in CPI naive patients are worth further investigation."

Journal • Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Neutropenia • Oncology • Solid Tumor

HYPOMETHYLATING AGENTS WITH OR WITHOUT VENETOCLAX IN TREATMENT-NAÏVE MYELODYSPLASTIC SYNDROMES WITH EXCESS BLASTS: RESULTS FROM A LARGE RETROSPECTIVE COHORT (EHA 2026) - "The Phase 3 randomized VERONA trial (Azacitidine [Aza] ± Ven) did not improve overall survival (OS)...Treatment included Aza (HMA 28% vs HMA-Ven 41%, P=ns), decitabine (HMA 47% vs HMAVen 59%, P=ns) and guadecitabine (HMA 25% vs HMAVen 0%, P<0.001)...B. OS (red line) and stacked transition probabilities in ASXL1mut patients HMA vs HMA Ven (blue: HMA/HMA Ven treatment, green: HSCT, yellow: death)"

Retrospective data • Bone Marrow Transplantation • Hematological Malignancies • Myelodysplastic Syndrome • ASXL1 • DNMT3A • TP53

DNA Methyltransferase Inhibitors, Decitabine and Guadecitabine Overcome Immune-Checkpoint Blockade Resistance and Achieve Tumor Regression in the E0771 and 4T1 Murine Models of Triple-Negative Breast Cancer. (PubMed, Cancers (Basel)) - "These pre-clinical findings support the further investigation of incorporating DNMTi as a new immunotherapy modality for TNBC."

Checkpoint inhibition • Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Pembrolizumab (Immunotherapy Drug) in Combination With Guadecitabine and Mocetinostat (Epigenetic Drugs) for Patients With Advanced Lung Cancer. (clinicaltrials.gov) - P1 | N=28 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2026 ➔ Jul 2027 | Trial primary completion date: Jul 2026 ➔ Jul 2027

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

NCI-2016-01233: Guadecitabine and Atezolizumab in Treating Patients With Advanced Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia That Is Refractory or Relapsed (clinicaltrials.gov) - P1/2 | N=33 | Active, not recruiting | Sponsor: University of Southern California | Trial primary completion date: Dec 2026 ➔ Jun 2027

Checkpoint inhibition • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Bone marrow immunosuppressive states associate with survival after guadecitabine and atezolizumab therapy in HMA-R/R MDS. (PubMed, Blood Neoplasia) - "These findings suggest that chronic inflammatory and senescent microenvironmental states constrain effective immune activation despite combined epigenetic and immune checkpoint therapy. Here, we identify distinct bone marrow microenvironments associated with patient survival after combined epigenetic and immune checkpoint therapy and suggest candidate biomarkers to guide patient stratification in HMA-R/R MDS."

IO biomarker • Journal • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CD34

IRF4 AND SERBP1 EXPRESSION ARE ASSOCIATED WITH POOR RESPONSES TO GUADECITABINE (SGI-110) THERAPY IN PERIPHERAL T CELL LYMPHOMA (EHA 2026) - P2 | "C. Boxplots show the enrichment scores of those HALLMARK gene sets that were significantly enriched in non-responders compared to responders."

Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • IRF4

Guadecitabine and Durvalumab in Treating Patients With Advanced Liver, Pancreatic, Bile Duct, or Gallbladder Cancer (clinicaltrials.gov) - P1 | N=55 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Jul 2026 ➔ Dec 2026

Trial completion date • Biliary Cancer • Cholangiocarcinoma • Gallbladder Cancer • Hepatocellular Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Transposable elements and homotypic niches as drivers of immune dynamics and resistance in melanoma epigenetic-based immunotherapy. (ASCO 2026) - P1b | "We investigated the molecular and spatial mechanisms underlying clinical response to epigenetic-based immunotherapy in the phase Ib NIBIT-M4 trial (NCT02608437), which evaluated the DNA methyltransferase inhibitor guadecitabine combined with the anti-CTLA4 antibody ipilimumab. Epigenetic-based immunotherapy dynamically reshapes the melanoma ecosystem by modulating TE activity and cell-state plasticity. Clinical response links to TE-driven immune priming, whereas resistance is maintained by spatially consolidated Neural crest-like niches stabilized by NFATC2. These findings identify spatial clustering as a principle of resistance and highlight NFATC2 as a potential therapeutic target."

Gene Therapies • Melanoma • Solid Tumor • CTNNB1

Blood Based Biomarkers of DNA Methylation Associated with Platinum Resistance in High Grade Serous Ovarian Cancer. (PubMed, bioRxiv) - P2 | "Pt resistance in HGSC is associated with epigenetic modifications and hypomethylating agents (HMAs) have been studied as carboplatin resensitizing agents...The Pt-resistant patients were enrolled in NCT02901899 clinical trial testing guadecitabine and the PD-1 inhibitor pembrolizumab...We propose new DMLs associated with Pt-naive versus Pt-resistant HGSC. These findings can lead to new biomarkers for HGSC."

Biomarker • IO biomarker • Journal • Platinum resistant • CNS Disorders • Depression • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Psychiatry • Solid Tumor • CD4

HyPeR: Combination Study of Guadecitabine/ASTX727 and Pembrolizumab (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Royal Marsden NHS Foundation Trust | Recruiting ➔ Active, not recruiting | N=34 ➔ 60

Enrollment change • Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MSI

Effects of the Hypomethylating Agent Guadecitabine on Peripheral Blood Mononuclear Cell Methylomes and Immune Cell Populations in Small-Cell Lung Cancer Patients. (PubMed, Pharmaceuticals (Basel)) - P2 | "Guadecitabine, a hypomethylating agent (HMA), has shown promising clinical activity when combined with carboplatin in preclinical models. HMA treatment has a global impact on PBMC methylomes in cancer patients. DNA methylation changes were associated with biological pathways related to PBMC function, and shifts in distinct immune cell populations were observed."

Journal • Immunology • Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Small Cell Lung Cancer • Solid Tumor

Anti-CD40 and Epigenetic Modifier Inhibitors to Augment Treatment of High-risk Neuroblastoma (ASPHO 2026) - "We identified two EMis, guadecitabine (a DNA methylation inhibitor) and entinostat (a histone methylation inhibitor), that when combined with anti-GD2 and anti-CD40, cause tumor regression in a model of murine HR-NBL. Using a therapy that combined anti-GD2, anti-CD40, and EMis, the tumor microenvironment is reinvigorated, enabling increased activity of immune cells, including T cells. We hypothesize that the T cell engagement may be via the addition of EMis, coupled with anti-CD40 reprogramming of suppressive myeloid cells, activating macrophages and dendritic cells to enhance the efficacy of anti-GD2. Therapies geared towards restoring MHCI expression, combined with effective immunotherapy regimens allowing for persistent immune responses, might augment immune responses and improve efficacy of combination immunotherapy for HR-NBL."

IO biomarker • Bone Marrow Transplantation • Neuroblastoma • Solid Tumor

Blood based biomarkers of DNA methylation associated with platinum resistance in high grade serous ovarian cancer (AACR 2025) - P2 | "The Pt-resistant patients were enrolled on NCT02901899 clinical trial testing guadecitabine and pembrolizumab. We propose new DMLs associated with Pt-sensitive vs. Pt-resistant OC. These findings can lead to new biomarkers for HGSOC."

Biomarker • Epigenetic controller • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CD4 • CD8

Epigenetic immune reprogramming overcomes PD-1 resistance in metastatic melanoma patients: The phase II NIBIT-ML1 study (AACR 2026) - "Background: In the NIBIT Foundation-sponsored phase Ib NIBIT-M4 study, we firstly reported that the hypomethylating agent (HMA) guadecitabine (G), a prodrug of decitabine (D), followed by ipilimumab (I), was safe and had promising clinical and tumor-immunomodulatory activity in metastatic melanoma (MM) patients (pts) (CCR 2019; Nature Commun 2023). Thus, we designed the NIBIT-ML1 trial to investigate the efficacy of G plus I+nivolumab (I+N) in MM or non-small cell lung cancer (NSCLC) pts, progressing to PD-1/PDL-1 inhibitors... ASTX727 plus I+N induces clinically meaningful objective responses that correlate with epigenetic immune reprogramming in PD-1 refractory MM pts. Baseline tumor methylation profiling may identify MM pts who will benefit from the addition of a DNA hypomethylating agent to ICI therapy."

Clinical • Metastases • P2 data • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD163 • CD20 • CD4 • CD8 • PD-1

DNA methylation profiling of peripheral blood mononuclear cells from small-cell lung cancer patients treated with hypomethylating agent plus carboplatin (AACR 2025) - "Small-cell lung cancer (SCLC), representing 15% of lung cancers, is one of the deadliest malignancies, with a 5-year survival rate under 7%. These findings demonstrate that guadecitabine treatment induces significant CpG methylation changes in PBMCs, impacting genes and pathways critical to cellular signaling, tissue remodeling, and survival mechanisms. The identification of key pathways, including those involved in metastasis, lung remodeling, and tumor cell survival, highlights the potential role of HMAs in modulating epigenetic and biological processes relevant to SCLC progression and therapy."

Clinical • Epigenetic controller • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CD4 • CD8 • NGFR

Dual inhibition of chromatin remodeling and DNA methylation as a novel treatment for triple negative breast cancer (AACR 2024) - "To develop novel epigenetic based therapeutic strategies for triple negative breast cancer (TNBC) we combined the DNA methyltransferase inhibitor (DNMTi) guadecitabine (Gua) with a genetic CRISPR/Cas9 mediated knockout (KO) of the chromatin remolding protein Bromodomain PHD-finger Transcription Factor (BPTF)...We show using this GEMM that BPTF KO in the adult mouse (a tamoxifen inducible Cre) is not lethal and has beneficial effects to the control of E0771 tumors, possibly through depleting tumor resident naïve T cells, and that transplanting BPTF KO E0771 tumors into BPTF KO adult mice further improves tumor growth control. These benefits in tumor growth control are prevented with CD8 depletion. These results in total suggests that a combination therapy regimen including BPTF inhibition (a PROTAC degradation approach) with a DNMTi could provide clinical benefits to patients with TNBC through both tumor cell intrinsic and extrinsic mechanisms."

Epigenetic controller • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BMP4 • CD8 • CSF3

DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy (AACR 2025) - "Therefore, we utilized a panel of cultured PM cells of different histotype to provide preclinical evidence supporting the role of the tumor methylation landscape and of its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients. the methylome profile (EPIC array) of distinct E (n=5) and non-E (n=9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and after in vitro treatment with the DNA hypomethylating agent (DHA) guadecitabine... the study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, independent of their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state supports its potential role in clinical trials of precision epigenetic therapy combined with ICI."

Epigenetic controller • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor

A new paradigm for brain tumors treatment: Guadecitabine as a fundamental player to improve tumor immune response (AACR 2024) - "Epigenetic remodeling of GBM by DHA represents a promising strategy to enhance the efficacy of cancer immunotherapy, supporting the rationale for developing new combinatorial approaches for the treatment of brain malignancies."

IO biomarker • Brain Cancer • CNS Tumor • Glioblastoma • Melanoma • Oncology • Solid Tumor

An Assembly of the Global Phosphoproteomic Network of an Underexplored Kinase CDK17: Possible Implications in Cell Cycle Regulation. (PubMed, DNA Cell Biol) - "Notably, sequence conservation of CDK17 (S146, S137, and S180) with CDK16 (S119, S110, and S153) and CDK18 (S98, S89, and S132), respectively, was observed, where CDK16 (S119) is a part of the binding motif for multiple upstream kinases, 14-3-3 protein, and CCNYL1...Statistical analysis revealed phosphoregulation of CDK17 through other kinases, regulation of CDK17 substrates, protein-protein interactions, and conserved co-differential regulation in multiple datasets. Specifically, this analysis derived through global data integration with a replicable analytical framework lays a groundwork for experimental validation of CDK17 phosphorylation in its functional regulation."

Journal • CDK7

PagMYB74 orchestrates flavonoid-mediated plant-microbe feedback for drought resilience in poplar. (PubMed, New Phytol) - "We further found that Pseudomonas putida S110 colonization establishes positive feedback through enhanced phenylpropanoid metabolism and activation of nutrient transport pathways in PagMYB74-overexpressing plants, reinforcing the symbiotic interaction. Our findings establish a complete mechanistic continuum from a single host gene to metabolite-driven recruitment and symbiotic reprogramming, facilitating the improvement of environmental adaptation by regulating their interaction with beneficial soil microorganisms."

Journal