milademetan (RAIN-32)
/ Daiichi Sankyo, Rigel, Pathos
- LARVOL DELTA
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August 11, 2025
Milademetan in advanced solid tumors with MDM2 amplification and wild-type TP53: pre-clinical and phase 2 clinical trial results.
(PubMed, Clin Cancer Res)
- "Milademetan had a manageable safety profile and achieved responses against a variety of refractory MDM2amp, TP53 -wt solid tumors, but tumor reductions were short-lived. Subsequent MDM2 inhibitor efforts should focus on combination strategies or treatment in earlier lines of therapy to achieve more durable clinical benefit."
Journal • P2 data • Preclinical • Hematological Disorders • Leukopenia • Neutropenia • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • Uterine Cancer • MDM2 • TP53
June 25, 2025
Clinical MDM2 inhibitors Idasanutlin and Milademetan as a new approach to targeted apoptos induction in the p53-mutated triple-negative breast cancer (TNBC)
(DGS 2025)
- "Since P53 is mutated in the TNBC cell lines used, other mechanisms, such as a P73-MDM2 inhibition, allegedly explain the observed antitumer effect. MDM2 inhibitors could therefore also have a therapeutic potential in P53-mutated TNBC cells and form a promising basis for the further development of targeted therapy options of the TNBC."
Clinical • P53mut • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • TP53
May 06, 2025
Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias.
(PubMed, Clin Cancer Res)
- P1 | "Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML."
Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • TP53 • YTHDF2
February 13, 2025
Pharmacological Inhibition of MDM2 Induces Apoptosis in p53-Mutated Triple-Negative Breast Cancer.
(PubMed, Int J Mol Sci)
- "We here selected the clinical-stage MDM2 inhibitors Idasanutlin and Milademetan and investigated their anti-tumoral effects in TNBC. This effect was observed despite an inactivating p53 mutation and was apparently independent of p53 expression. Our data suggest that MDM2 is a promising target in TNBC and clinical-stage MDM2 inhibitors should be further evaluated for their potential therapeutic application."
Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP7
November 09, 2024
TARGETING PRIMARY AND SECONDARY ONCOGENIC DRIVERS IN RETROPERITONEAL DEDIFFERENTIATED LIPOSARCOMAS
(CTOS 2024)
- "Cabazitaxel and ifosfamide resulted in the highest maximum tumor volume inhibition (mTVI%), which was 94-100% and 83-98%, respectively. MDM2 inhibition with milademetan resulted in different effects in the two analyzed models, which were higher in LS-MP (mTVI% 83%) compared to LS-NV (mTVI%35%). Conversely, the AURKA inhibitor alisertib resulted in a higher mTVI% in the LS-NV (93%) compared to the LS-MP (50%) model. We identified and validated therapeutic targets for DDLPS beyond the oncogenic drivers of this disease. These findings have significant implications for developing combination treatments, which will be tested in new in vivo experiments to prioritize innovative treatment strategies for clinical trials."
Liposarcoma • Oncology • Sarcoma • Solid Tumor • CDK4 • CHEK1 • HMGA2 • MDM2
September 08, 2024
The MDM2 degraders KTX-049 and KT-253 are highly active in wild-type TP53 (WT p53) Merkel cell carcinoma (MCC)
(EORTC-NCI-AACR 2024)
- "Here, we analyze the in vitro and in vivo efficacy of MDM2 degraders in MCC tumor models and compare their efficacy to an MDM2 small molecule inhibitor, DS-3032.Materials and Established MCCP cell lines with WT or mutant (MUT) p53 and two MCCP patient derived cell lines (PDCLs) with WT p53 were treated with KTX-049, a tool MDM2 degrader, or DS-3032. Selective and potent MDM2 degraders including clinical stage KT-253 show promising efficacy in WT p53 MCC preclinical models. These results support exploration of KT-253 clinical activity in WT p53 MCC where degradation of MDM2 is one of the key mechanisms for impeding tumor growth."
Tumor mutational burden • Endocrine Cancer • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • ANXA5 • CASP3 • CASP7 • EP400 • MYCL • TMB • TP53
September 30, 2024
Effects of Mdm2 Inhibitors on Cellular Viability of Breast Cancer Cell Lines HP100, MCF7.
(PubMed, Bratisl Lek Listy)
- "Our research concluded that Nutlin 3 has a superior effect over Yh239-EE and Miladometan in treating Breast cancer; moreover, the combination group has shown to be more effective than treatment with Doxorubicin or MDM2 inhibitors alone. Interesting information is that Doxorubicin also causes an increase in P53 levels. This result provided us with a promising therapeutic strategy for the treatment of breast cancer. However, more research is required to be conducted on more types of cell lines and in human or animal models (Tab. 4, Fig. 8, Ref. 33). Text in PDF www.elis.sk Keywords: breast cancer, Miladometan, cell viability, proliferation, therapeutic strategy."
Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • MDM2
September 11, 2024
Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and MDM2 Amplification.
(PubMed, JCO Precis Oncol)
- "These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach."
Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MDM2 • RET • TP53
July 20, 2024
Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.
(PubMed, Cancer Med)
- "Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal."
Combination therapy • Journal • Monotherapy • P1 data • Acute Myelogenous Leukemia • Fatigue • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53
July 02, 2024
Analysis of correlation between high expression of nucleoporin 85 (NUP85) and immune cell infiltration in hepatocellular carcinoma
(PubMed, Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi)
- "The expression of NUP85 was significantly correlated with multiple drugs, such as Milademetan (PD0325901), a structural analog of Vemurafenib (PLX4720), and Regorafenib (PD0325901). These factors significantly and unfavorably affected the OS of HCC patients, and the areas under the ROC curve (AUC) for the 1-year, 3-year, and 5-year OS prognostic diagnosis of HCC patients were all greater than 0.7. Conclusion The high expression of NUP85 in HCC is correlated with a poor prognosis and is related to various immune cells and drugs, making it a potential biomarker for di-agnosis, treatment, and prognosis in HCC."
Immune cell • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor
May 26, 2024
Twist1 forms a trimeric complex with p53 and MDM2 and attenuates the efficacy of MDM2 inhibitors
(EACR 2024)
- "The interaction is direct, as demonstrated by GST pull downs, and occurs under para-physiological conditions, as shown by TurboID proximity-dependent biotinylation experiments.Modulation of Twist1 expression in p53 wild type/MDM2 overexpressing sarcoma cell models affects p53 and the response to MDM2i (Nutlin-3a, Milademetan/DS-3032, Idasanutlin/RG7388, SAR405838). Conversely, ectopic Twist1 expression attenuates MDM2i efficacy. This effect depends on Twist1 binding to p53 and MDM2, as a Twist1 mutant defective for this binding loses the inhibitory capacity.Conclusion Twist forms a p53:Twist:MDM2 trimeric complex and, by enhancing MDM2-mediated degradation of p53, attenuates the efficacy of MDM2i"
Clinical • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • MDM2 • TWIST1
December 21, 2023
DEMETER: Milademetan and Fulvestrant in GATA3-mutant, ER+HER- Advanced or Metastatic Breast Cancer
(clinicaltrials.gov)
- P2 | N=1 | Terminated | Sponsor: Institut Curie | N=48 ➔ 1 | Trial completion date: Dec 2026 ➔ Nov 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2025 ➔ Nov 2023; Financial partner providing study drug could no longer support the trial
Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • GATA3 • HER-2
November 04, 2023
DEMETER: A phase 2 multicenter trial of milademetan and fulvestrant in patients with ER+, HER2- advanced breast cancer
(SABCS 2023)
- No abstract available
Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • ER • HER-2
October 07, 2023
Efficacy and safety findings from MANTRA: A global, randomized, multicenter, phase III study of the MDM2 inhibitor milademetan vs trabectedin in patients with dedifferentiated liposarcomas
(ESMO Asia 2023)
- P3 | "TEAEs were consistent with previous reports and manageable by dose interruptions/modifications. Further evaluation of milademetan is warranted in populations that may benefit from MDM2 inhibition."
Clinical • P3 data • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2
November 22, 2023
DEMETER: Milademetan and Fulvestrant in GATA3-mutant, ER+HER- Advanced or Metastatic Breast Cancer
(clinicaltrials.gov)
- P2 | N=48 | Active, not recruiting | Sponsor: Institut Curie | Recruiting ➔ Active, not recruiting
Enrollment closed • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • GATA3 • HER-2
August 16, 2023
MILADEMETAN VS. TRABECTEDIN IN PATIENTS WITH DEDIFFERENTIATED LIPOSARCOMA: RESULTS FROM THE PHASE 3 MANTRA STUDY
(CTOS 2023)
- No abstract available
Clinical • P3 data • Liposarcoma • Oncology • Sarcoma • Solid Tumor
July 27, 2023
Efficacy and safety findings from MANTRA: A global, randomized, multicenter, phase III study of the MDM2 inhibitor milademetan vs trabectedin in patients with dedifferentiated liposarcomas
(ESMO 2023)
- P3 | "Further evaluation of milademetan is warranted in populations that may benefit from MDM2 inhibition. Table: LBA89 Study findings Efficacy population Milademetan (n=86) Trabectedin (n=89) Median PFS by BICR, m 3.6 2.2 HR=0.89 (95% CI 0.61–1.29; p=0.53) Median PFS by investigator, m 3.7 2.1 HR=0.80 (95% CI 0.55–1.15; p=0.22) Median OSa, m 9.5 10.2 HR=1.27 (95% CI 0.80–2.04; p=0.31) ORR, n (%) 4 (4.7) 3 (3.4) p=0.67 DCR, n (%) 29 (33.7) 24 (27.0) p=0.33 Safety population n=86 n=79 Most common milademetan TEAEs, %NauseaThrombocytopeniaAnemiaVomiting 70.961.644.244.2 58.225.336.719.0 Most common grade 3/4 milademetan TEAEs, %ThrombocytopeniaNeutropeniaAnemia 39.525.618.6 13.926.619.0 TEAEs – fatal/grade 5, % 0 6.3 TEAEs leading to dose reductions, % 44.2 29.1 TEAEs leading to discontinuations, % 11.6 19.0"
Clinical • Late-breaking abstract • P3 data • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2
October 28, 2023
An Updated Review of the Biomarkers of Response to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: Merkel Cell Carcinoma and Immunotherapy.
(PubMed, Cancers (Basel))
- "Avelumab therapy has shown promising results in Merkel cell polyomavirus (MCPyV)-negative MCC patients with TMB-H, while pembrolizumab therapy has shown better response in patients with low TMB. A study evaluating neoadjuvant nivolumab therapy found no significant difference in treatment response between the tumor etiologies and TMB levels. In addition to ICI therapy, other treatments that induce apoptosis, such as milademetan, have demonstrated positive responses in MCPyV-positive MCC, with few somatic mutations and wild-type TP53. This review summarizes current knowledge and discusses emerging and potentially predictive biomarkers for MCC therapy with ICI."
Biomarker • Checkpoint inhibition • IO biomarker • Journal • Review • Tumor mutational burden • Merkel Cell Carcinoma • Microsatellite Instability • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • MSI • PD-L1 • TMB • TP53
October 18, 2023
MANTRA: Treatment of Milademetan Versus Trabectedin in Patient With Dedifferentiated Liposarcoma
(clinicaltrials.gov)
- P3 | N=175 | Terminated | Sponsor: Rain Oncology Inc | Trial completion date: Jul 2025 ➔ Oct 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jul 2025 ➔ Oct 2023; Sponsor Decision
Trial completion date • Trial primary completion date • Trial termination • Liposarcoma • Oncology • Sarcoma • Solid Tumor
October 20, 2023
An Updated Review of the Biomarkers of Response to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: Merkel Cell Carcinoma and Immunotherapy
(Multidisciplinary Digital Publishing Institute)
- "Avelumab therapy has shown promising results in Merkel cell polyomavirus (MCPyV)-negative MCC patients with TMB-H, while pembrolizumab therapy has shown better response in patients with low TMB. A study evaluating neoadjuvant nivolumab therapy found no significant difference in treatment response between the tumor etiologies and TMB levels. In addition to ICI therapy, other treatments that induce apoptosis, such as milademetan, have demonstrated positive responses in MCPyV-positive MCC, with few somatic mutations and wild-type TP53."
Review • Merkel Cell Carcinoma
October 18, 2023
MANTRA-2: Milademetan in Advanced/Metastatic Solid Tumors
(clinicaltrials.gov)
- P2 | N=40 | Terminated | Sponsor: Rain Oncology Inc | N=65 ➔ 40 | Trial completion date: Aug 2024 ➔ Oct 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2024 ➔ Oct 2023; Sponsor Decision
Enrollment change • Metastases • Pan tumor • Trial completion date • Trial primary completion date • Trial termination • Adrenal Cortex Carcinoma • Biliary Cancer • Bladder Cancer • Breast Cancer • Cervical Cancer • Cholangiocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Germ Cell Tumors • Head and Neck Cancer • Hepatology • Lung Adenocarcinoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Sarcoma • Solid Tumor • Testicular Cancer • Urothelial Cancer • MDM2 • TP53
October 12, 2023
DEMETER: Milademetan and Fulvestrant in GATA3-mutant, ER+HER- Advanced or Metastatic Breast Cancer
(clinicaltrials.gov)
- P2 | N=48 | Recruiting | Sponsor: Institut Curie | Not yet recruiting ➔ Recruiting
Enrollment open • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • GATA3 • HER-2
September 16, 2023
A phase 2 basket study of the oral MDM2 inhibitor milademetan for MDM2-amplified advanced solid tumors (MANTRA-2).
(AACR-NCI-EORTC 2023)
- No abstract available
Metastases • P2 data • Pan tumor • Oncology • Solid Tumor • MDM2
August 10, 2023
Rain Oncology Reports Second Quarter 2023 Financial Results and Provides Corporate Update
(GlobeNewswire)
- "Phase 3 Dedifferentiated Liposarcoma (DD LPS) Trial (MANTRA): (i) Submitted abstracts to upcoming medical conferences; anticipate presentations in 4Q23; Phase 2 Basket Trial (MANTRA-2) of Milademetan for MDM2-Amplified Advanced Solid Tumors: (i) Suspended enrollment in May 2023 and trial will be discontinued in 4Q23; (ii) Submitted abstract to upcoming medical conference; anticipate presentation in 4Q23."
P2 data • P3 data • Trial termination • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor
August 08, 2023
A Study of Milademetan Administration on Cardiac Repolarization in Healthy Subjects
(clinicaltrials.gov)
- P1 | N=6 | Terminated | Sponsor: Rain Oncology Inc | N=50 ➔ 6 | Trial completion date: Sep 2023 ➔ Jun 2023 | Not yet recruiting ➔ Terminated; sponsor decision
Enrollment change • Trial completion date • Trial termination
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