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    DRUG:

    siremadlin (HDM201)

    i
    Other names: HDM201, HDM 201, HDM-201, NVP-HDM201, NVP-HDM-201, NVP-HDM 201
    Company:
    Novartis
    Drug class:
    MDM2 inhibitor
    Related drugs:
    10d
    A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov)
    P1, N=14, Completed, Novartis Pharmaceuticals | Terminated --> Completed
    Trial completion
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    23d
    MegaMOST: A Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced / Metastatic Tumors. (clinicaltrials.gov)
    P2, N=455, Recruiting, Centre Leon Berard | Trial completion date: Nov 2026 --> Oct 2027 | Trial primary completion date: Feb 2026 --> Oct 2026
    Trial completion date • Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • FLT3 (Fms-related tyrosine kinase 3) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • AXL (AXL Receptor Tyrosine Kinase) • CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SMAD4 (SMAD family member 4) • RAF1 (Raf-1 Proto-Oncogene Serine/Threonine Kinase) • FLT1 (Fms-related tyrosine kinase 1) • CDK6 (Cyclin-dependent kinase 6) • CCND3 (Cyclin D3) • TYRO3 (TYRO3 Protein Tyrosine Kinase) • NTRK (Neurotrophic receptor tyrosine kinase)
    |
    BRAF mutation • NRAS mutation • BRAF V600 • KIT mutation • CDKN2A deletion • HRAS mutation • KRAS G12 • PDGFRA mutation • KRAS amplification • NRAS G12
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Alecensa (alectinib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • Kisqali (ribociclib) • Ayvakit (avapritinib) • siremadlin (HDM201)
    3ms
    AMPHISARC: HDM201 and Pazopanib in Patients With P53 Wild-type Advanced/Metastatic Soft Tissue Sarcomas (clinicaltrials.gov)
    P1/2, N=47, Active, not recruiting, Centre Leon Berard | Recruiting --> Active, not recruiting | Trial completion date: Jul 2026 --> Feb 2027 | Trial primary completion date: Jan 2026 --> Feb 2027
    Enrollment closed • Trial completion date • Trial primary completion date • P53WT
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type
    |
    pazopanib • siremadlin (HDM201)
    7ms
    Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status. (PubMed, Oncol Res)
    The efficacy of the mouse double minute 2 homolog (MDM2) inhibitor (HDM201) and the Wee1 G2 checkpoint kinase (Wee1) inhibitor (adavosertib) was confirmed in both p53 wild-type (p53 WT) and p53 mutant (p53 MT) GIST cells. Our results highlight the importance of p53 status in guiding GIST treatment. p53 WT tumors respond to MDM2 inhibitors, while p53 MT tumors show greater sensitivity to Wee1 inhibitors, supporting p53 pathway targeting as a promising strategy for GIST patients.
    Preclinical • Journal
    |
    TP53 (Tumor protein P53) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • CDK1 (Cyclin-dependent kinase 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    TP53 mutation • TP53 wild-type
    |
    adavosertib (AZD1775) • siremadlin (HDM201)
    9ms
    ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov)
    P1/2, N=45, Terminated, Novartis Pharmaceuticals | Completed --> Terminated; Sponsor Decision
    Trial termination
    |
    Jakafi (ruxolitinib) • sabatolimab (MBG453) • rineterkib (LTT462) • siremadlin (HDM201) • Adakveo (crizanlizumab-tmca) • nisevokitug (NIS793)
    1year
    ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis. (PubMed, Blood Adv)
    Forty-four patients were enrolled in Part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821.
    Journal
    |
    GDF15 (Growth differentiation factor 15)
    |
    Jakafi (ruxolitinib) • sabatolimab (MBG453) • rineterkib (LTT462) • siremadlin (HDM201) • Adakveo (crizanlizumab-tmca) • nisevokitug (NIS793)
    over1year
    Targeting the MDM2-p53 Interaction with Siremadlin: A Promising Therapeutic Strategy for Treating TP53 Wild-Type Chronic Lymphocytic Leukemia. (PubMed, Cancers (Basel))
    The results underline the importance of TP53 status in predicting treatment efficacy and highlight the potential of HDM201 as a valuable addition to explore in CLL therapy. Future research should focus on identifying additional biomarkers of response and exploring the optimal way to include HDM201 in combination therapies to improve treatment outcomes in CLL.
    Journal
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation • TP53 wild-type
    |
    siremadlin (HDM201)
    over1year
    A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov)
    P1, N=14, Terminated, Novartis Pharmaceuticals | Consequently, enrollment for Part 2 did not commence. This decision was not influenced by any safety concerns.
    Trial termination
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    over1year
    ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov)
    P1/2, N=45, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed
    Trial completion
    |
    Jakafi (ruxolitinib) • sabatolimab (MBG453) • rineterkib (LTT462) • siremadlin (HDM201) • Adakveo (crizanlizumab-tmca) • nisevokitug (NIS793)
    over1year
    HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS) (clinicaltrials.gov)
    P1, N=52, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business decision
    Trial termination • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    TP53 wild-type
    |
    Venclexta (venetoclax) • sabatolimab (MBG453) • siremadlin (HDM201)
    almost2years
    A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov)
    P1, N=14, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed
    Trial completion • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    2years
    A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov)
    P1, N=14, Active, not recruiting, Novartis Pharmaceuticals | Phase classification: P1/2 --> P1
    Phase classification • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)