ASTX295 / Otsuka, Mosaic Therapeutics - LARVOL DELTA

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2; N=191; Recruiting; Sponsor: Astex Pharmaceuticals, Inc.; N=135 ➔ 191

Clinical • Enrollment change • Lung Cancer • Oncology • Solid Tumor • MDM2 • TP53

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2; N=191; Recruiting; Sponsor: Astex Pharmaceuticals, Inc.; Active, not recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Oncology • Solid Tumor • MDM2 • TP53

Combination of the MDM2 antagonist ASTX295 and Olaparib as a novel treatment option for BRCA2 mutant, TP53 wild-type solid tumors (AACR 2026) - "In vivo, using both cell line- and patient-derived BRCA2-mutant/TP53 wild-type xenograft models, we showed superior anti-tumor activity for the combination compared to single agents, resulting in prolonged control of tumor growth and regressions at well tolerated doses. Taken together, our data provide a strong rationale for combining ASTX295 with PARP inhibitors such as Olaparib in patients with TP53-wild-type/BRCA2-mutant solid tumors."

Oncology • Solid Tumor • BRCA2 • CDKN1A • TP53

Discovery of ASTX295, a potent, next-generation small molecule antagonist of MDM2 with differentiated pharmacokinetic profile (AACR 2024) - P1 | "These data highlight the therapeutic potential of ASTX295, which is currently being tested in a Phase 1/2 clinical trial in advanced solid tumors with wild-type p53 (NCT03975387). We plan to present preliminary clinical data in a separate abstract at this meeting."

PK/PD data • Hematological Malignancies • Oncology • Solid Tumor • CDKN1A • MDM2

Targeting the MDM2-p53 interaction: Time- and concentration-dependent studies in tumor and normal human bone marrow cells reveal strategies for an enhanced therapeutic index (AACR 2024) - P1 | "Hence, intermittent exposure to an MDM2-p53 antagonist could favourably modulate its therapeutic index. The predicted short plasma half-life of ASTX295 should provide flexibility in controlling the duration of exposure in vivo, potentially enabling a more bone-marrow sparing approach to MDM2-p53 antagonism to be utilised."

Oncology • Solid Tumor • CD34 • MDM2

Phase 1 study of MDM2 antagonist ASTX295 in patients with solid tumors with wild-type TP53 (AACR 2024) - P1 | "ASTX295 was well tolerated at doses producing p53 pathway modulation with manageable toxicities, notably avoiding significant thrombocytopenia. Preliminary single agent efficacy was observed in heavily pretreated subjects across multiple solid tumor types with WT TP53."

Clinical • First-in-human • P1 data • Liposarcoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • MDM2 • TP53

Identification of biomarkers of response to MDM2 inhibition in solid tumours using computational, multi-omics approaches (AACR 2024) - "Further, pathway and transcriptional regulator analysis identified the Interferon signalling as significantly enriched in apoptotic cell lines and was confirmed in a TCGA mesothelioma patient data set and the module was found to be significantly correlated with a subgroup of P53 wild-type patients with CDKN2A loss. In conclusion, combining cell panel drug screening with co-expression networks helped to identify biomarkers associated with ASTX295 sensitivity, and provided new insights into the underlying mechanism of ASTX295 response."

Biomarker • Mesothelioma • Oncology • Solid Tumor • CDKN2A

ASTX295 engages p53-mediated apoptosis and an inflammatory response in patient derived mesothelioma explants (AACR 2024) - P1 | "In summary, inhibition of MDM2-P53 interaction triggers robust p53 activation and a pro-inflammatory phenotype, which is potentiated in EMT enriched mesothelioma PDEs. ASTX295 is currently under clinical investigation (NCT03975387)."

Clinical • Mesothelioma • Oncology • Solid Tumor • CDKN1A

Switching cell fate from senescence to apoptosis by the combination of a p53 corrector with the MDM2 antagonist ASTX295 (AACR 2025) - "We have shown that MDM2 antagonism leads to sustained corrected p53 signalling over time, which drives cell death, even in tumor cells harbouring co-mutations conferring higher apoptotic resistance. Indeed, our study provides proof of concept that efficacy could be achieved in multiple tumor types in which the p53 pathway can be targeted therapeutically through combination with ASTX295, which would drive and maintain p53 signalling levels above the apoptotic threshold."

Oncology • Pancreatic Cancer • Solid Tumor • ANXA5 • BRAF • CDKN1A • KRAS

Mosaic Therapeutics to Present Poster Highlighting Preclinical Data for Lead Program MOS101 at the American Association for Cancer Research (AACR) Annual Meeting 2026 (Yahoo Finance) - "Title: 'Combination of the MDM2 antagonist ASTX295 and olaparib as a novel treatment option for BRCA2 mutant, TP53 wild-type solid tumors'...Plans for a Phase 1b/2a study evaluating the combination of ASTX295 with olaparib (an approved PARP inhibitor) for patients with biomarker-selected solid tumors are being finalized."

New P1/2 trial • Preclinical • Solid Tumor

ASTX295 a Novel Potent MDM2 Antagonist Induces More Than One Mechanism of Programmed Cell Death (PCD) in Lymphoid Malignancies (ASH 2024) - P1 | "Previous studies have shown in vitro activity in acute myeloid leukemia both alone and in combination with decitabine...Activity of ASTX295 was compared with AMG232 and Idasanutlin...ASTX295 in combination with the specific BCL2 inhibitor Venetoclax in the GRANTA519 cell line (CI value 0.2) and KARPAS384 (CI value 0.4) demonstrated strong synergy, despite as monotherapy resulting in <50% fall in viability...ASTX295 like other MDM2i showed synergy with BCL2i in DLBCL and MCL models. ASTX295 induced multiple forms of PCD; the precise form of non-caspase dependent PCD remains under investigation."

IO biomarker • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • ANXA5 • CDKN1A

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1 | N=106 | Terminated | Sponsor: Taiho Oncology, Inc. | Phase classification: P1/2 ➔ P1

P53WT • Phase classification • Glioblastoma • Melanoma • Oncology • Solid Tumor • MDM2 • TP53

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2 | N=106 | Terminated | Sponsor: Taiho Oncology, Inc. | Trial completion date: Jun 2025 ➔ Aug 2024 | Active, not recruiting ➔ Terminated; Sponsor Decision

Trial completion date • Trial termination • Glioblastoma • Melanoma • Oncology • Solid Tumor • MDM2 • TP53

Pulsatile induction of the p53 pathway by MDM2 antagonist ASTX295 shows an enhanced therapeutic index in vivo (EORTC-NCI-AACR 2024) - P1/2 | "ConclusionsASTX295 showed a shorter duration of p53 pathway modulation in vivo which maintained efficacy whilst avoiding myelosuppression in preclinical studies. This was consistent with clinical observations, suggesting pulsatile exposure of ASTX295 is a route to achieve an improved therapeutic index for the MDM2 antagonist mechanism."

Preclinical • Oncology • Solid Tumor • CDKN1A

Identification of biomarkers predictive of response to ASTX295, a next-generation MDM2 antagonist, in solid tumors carrying wild-type p53 (EORTC-NCI-AACR 2024) - P1/2 | "ConclusionsThese data highlight the potential to apply a biomarker-based approach in further refining patient selection strategies. Together with its bone marrow sparing characteristics, improved patient stratification could increase the therapeutic index for ASTX295 (NCT03975387)."

Biomarker • Mesothelioma • Oncology • Solid Tumor • BAP1 • CDKN1A • CDKN2A

Astex Pharmaceuticals Announce Key Data Presentation at the 36th EORTC-NCI-AACR Symposium (GlobeNewswire) - "ASTX295 is an oral, potent inhibitor of the p53-MDM2 protein-protein interaction...ASTX295 is a potent MDM2 antagonist with a clean CYP/hERG profile and a shorter human half-life allowing for pulsatile pathway modulation while avoiding myelosuppression. ASTX295 therefore has bone-marrow sparing characteristics which permit a differentiated safety profile...Astex has an exclusive license to research, develop and commercialise ASTX295 under its drug discovery alliance agreement with Newcastle University and Cancer Research Technology Limited."

Preclinical • Hematological Malignancies

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2 | N=106 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | N=250 ➔ 106

Enrollment change • Metastases • Glioblastoma • Melanoma • Oncology • Solid Tumor • MDM2 • TP53

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2 | N=250 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | Trial primary completion date: Dec 2024 ➔ May 2024

Metastases • Trial primary completion date • Glioblastoma • Melanoma • Oncology • Solid Tumor • MDM2 • TP53

Astex Pharmaceuticals Announce Key Data Presentations at the American Association For Cancer Research (AACR) 2024 Annual Meeting (GlobeNewswire) - "Astex Pharmaceuticals...announced today that it will make five key data presentations at AACR 2024 focusing on its Phase II-ready MDM2 antagonist, ASTX295....ASTX295 therefore has bone-marrow sparing characteristics which permit a differentiated safety profile to be presented at AACR."

P1 data • Preclinical • Mesothelioma • Oncology • Solid Tumor

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2 | N=250 | Active, not recruiting | Sponsor: Astex Pharmaceuticals, Inc. | Trial primary completion date: Jun 2025 ➔ Dec 2024

Metastases • Trial primary completion date • Glioblastoma • Lung Cancer • Melanoma • Oncology • Solid Tumor • MDM2 • TP53

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2 | N=250 | Active, not recruiting | Sponsor: Astex Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Glioblastoma • Lung Cancer • Melanoma • Oncology • Solid Tumor • MDM2 • TP53

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2 | N=250 | Recruiting | Sponsor: Astex Pharmaceuticals, Inc. | N=191 ➔ 250 | Trial completion date: May 2023 ➔ Aug 2025 | Trial primary completion date: Apr 2023 ➔ Jun 2025

Enrollment change • Trial completion date • Trial primary completion date • Glioblastoma • Lung Cancer • Melanoma • Oncology • Solid Tumor • MDM2 • TP53

[VIRTUAL] ASTX295, A NOVEL SMALL MOLECULE MDM2 ANTAGONIST, DEMONSTRATES POTENT ACTIVITY IN AML IN COMBINATION WITH DECITABINE (EHA 2020) - P1/2 | "Target engagement of ASTX295 and decitabine was confirmed by upregulation of p53 transcriptional targets and decreased DNMT-1 expression. Conclusion Our findings demonstrate that the combination of ASTX295 with decitabine exhibits potent activity against p53 wild-type AML cells, and thus merits further investigation."

Combination therapy • Oncology • Targeted Protein Degradation • CD34 • DNMT1 • KIT

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2; N=191; Active, not recruiting; Sponsor: Astex Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Oncology • Solid Tumor • MDM2 • TP53

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53 (clinicaltrials.gov) - P1/2; N=135; Recruiting; Sponsor: Astex Pharmaceuticals, Inc.; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open • Gastrointestinal Cancer • Oncology • Solid Tumor • TP53