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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:
    1m
    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)
    4ms
    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)
    7ms
    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)
    10ms
    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)
    11ms
    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)
    1year
    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)
    1year
    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)
    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, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed
    Trial completion • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    Venclexta (venetoclax) • azacitidine • 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, 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)
    over1year
    AMPHISARC: HDM201 and Pazopanib in Patients With P53 Wild-type Advanced/Metastatic Soft Tissue Sarcomas (clinicaltrials.gov)
    P1/2, N=58, Recruiting, Centre Leon Berard | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Jan 2025 --> Jan 2026
    Trial completion date • Trial primary completion date • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type
    |
    pazopanib • 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)
    P1/2, N=14, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2026 --> May 2024 | Trial primary completion date: May 2025 --> May 2024
    Trial completion date • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    almost2years
    ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov)
    P1/2, N=45, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Jul 2024
    Trial completion date
    |
    Jakafi (ruxolitinib) • sabatolimab (MBG453) • rineterkib (LTT462) • siremadlin (HDM201) • Adakveo (crizanlizumab-tmca) • nisevokitug (NIS793)