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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:
    19d
    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)
    1m
    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
    |
    Votrient (pazopanib) • siremadlin (HDM201)
    2ms
    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)
    3ms
    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)
    3ms
    A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant (clinicaltrials.gov)
    P1/2, N=8, Terminated, Novartis Pharmaceuticals | N=38 --> 8 | Trial completion date: Jan 2028 --> Oct 2023 | Recruiting --> Terminated | Trial primary completion date: Jan 2027 --> Oct 2023; Study has been stopped following to strategic decision from the Sponsor. Not based on any safety findings or safety concerns with siremadlin.
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)
    |
    TP53 mutation
    |
    siremadlin (HDM201)
    4ms
    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 | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    5ms
    MegaMOST: A Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced / Metastatic Tumors. (clinicaltrials.gov)
    P2, N=425, Recruiting, Centre Leon Berard
    Trial completion date • Trial primary completion date • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • 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) • 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)
    |
    KRAS mutation • EGFR mutation • BRAF mutation • NRAS mutation • BRAF V600 • FGFR1 amplification • CDKN2A deletion • HRAS mutation • PTPN11 mutation • CCND1 amplification • KRAS amplification • BRAF amplification
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Alecensa (alectinib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • Kisqali (ribociclib) • Ayvakit (avapritinib) • siremadlin (HDM201)
    7ms
    Use of Combination Therapies Including the XPO1 Inhibitor Selinexor in Is a Potential Effective Therapeutic Strategy to Treat Myelofibrosis Patients (ASH 2023)
    We also evaluated the ability of SEL alone to eliminate MF CD34+ cells and in combination with other candidate drugs such as HDM201 (HDM2 antagonist), ruxolitinib (RUX), pan-BET inhibitor (JQ1) or a Bcl-2/Bcl-xL inhibitor (navitoclax). The effects of SEL combined with either RUX or an HDM2 antagonist more effectively depleted mutated MF CD34+ cells than either drug alone. The combination of SEL+HDM201 spared the reservoir of WT progenitors, and reduced JAK2 mutated progenitor cells to a great degree suggesting that this combination might be associated with less hematological toxicity and greater efficacy.
    Clinical • Combination therapy • IO biomarker
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • RB1 (RB Transcriptional Corepressor 1) • BCL2L1 (BCL2-like 1) • CD34 (CD34 molecule) • XPO1 (Exportin 1) • TP63 (Tumor protein 63) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • TP73 (Tumor Protein P73) • CCNB1 (Cyclin B1)
    |
    TP53 mutation • TP53 wild-type • JAK2 V617F • JAK2 mutation
    |
    Jakafi (ruxolitinib) • Xpovio (selinexor) • JQ-1 • navitoclax (ABT 263) • siremadlin (HDM201)
    7ms
    Pharmacokinetics and Safety Study of Siremadlin (HDM201) in Participants With Mild, Moderate and Severe Hepatic Impairment (clinicaltrials.gov)
    P1, N=38, Completed, Novartis Pharmaceuticals | Recruiting --> Completed
    Trial completion
    |
    siremadlin (HDM201)
    8ms
    A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant (clinicaltrials.gov)
    P1/2, N=38, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2028 --> Jan 2028 | Trial primary completion date: Jul 2027 --> Jan 2027
    Trial completion date • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)
    |
    TP53 mutation
    |
    siremadlin (HDM201)
    8ms
    TRAHD: Trametinib + HDM201 in CRC Patients With RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type (clinicaltrials.gov)
    P1, N=12, Completed, Centre Leon Berard | Recruiting --> Completed | N=24 --> 12 | Trial completion date: Dec 2024 --> Sep 2023
    Trial completion • Enrollment change • Trial completion date • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    TP53 mutation • BRAF mutation • TP53 wild-type • HRAS mutation
    |
    Mekinist (trametinib) • 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)
    P1/2, N=56, Recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2026 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Apr 2025
    Trial completion date • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    11ms
    Combined inhibition of MDM2 and PARP lead to a synergistic anti-tumoral response in p53 wild-type rhabdomyosarcoma (EACR 2023)
    Combination of both drugs allowed to reduce the toxicity associated with Siremadlin while increasing the individual drug effect in tumor growth inhibition.ConclusionOverall, our study demonstrates the synergistic effect of the combination between Siremadlin and Olaparib in the inhibition of p53WT RMS tumor growth in vitro and in vivo. Our findings support the potential to study the combination of both drugs in clinical trials and warrants further investigation in other tumors with similar molecular features.
    PARP Biomarker
    |
    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MDM2 (E3 ubiquitin protein ligase) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    TP53 mutation • TP53 wild-type • CDKN2A deletion • TP53 expression • MDM2 overexpression • BAX expression
    |
    Lynparza (olaparib) • siremadlin (HDM201)
    1year
    TRAHD: Trametinib + HDM201 in CRC Patients With RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type (clinicaltrials.gov)
    P1, N=24, Recruiting, Centre Leon Berard | Trial completion date: Dec 2023 --> Dec 2024
    Trial completion date • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    TP53 mutation • BRAF mutation • TP53 wild-type • HRAS mutation
    |
    Mekinist (trametinib) • siremadlin (HDM201)
    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, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2023 --> Dec 2023 | Trial primary completion date: Apr 2023 --> Dec 2023
    Trial completion date • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • GDF15 (Growth differentiation factor 15)
    |
    TP53 wild-type
    |
    Venclexta (venetoclax) • sabatolimab (MBG453) • siremadlin (HDM201)
    1year
    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=56, Recruiting, Novartis Pharmaceuticals | Trial primary completion date: Dec 2025 --> Oct 2024
    Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    1year
    TRAHD: Trametinib + HDM201 in CRC Patients With RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type (clinicaltrials.gov)
    P1, N=24, Recruiting, Centre Leon Berard | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Sep 2022 --> Sep 2023
    Trial completion date • Trial primary completion date • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    TP53 mutation • BRAF mutation • TP53 wild-type • HRAS mutation
    |
    Mekinist (trametinib) • siremadlin (HDM201)
    over1year
    A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant (clinicaltrials.gov)
    P1/2, N=38, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2028 --> Jul 2028 | Trial primary completion date: Apr 2027 --> Jul 2027
    Trial completion date • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)
    |
    TP53 mutation
    |
    siremadlin (HDM201)
    over1year
    MegaMOST: A Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced / Metastatic Tumors. (clinicaltrials.gov)
    P2, N=425, Recruiting, Centre Leon Berard | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Feb 2024 --> Feb 2026
    Trial completion date • Trial primary completion date • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • 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) • 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)
    |
    KRAS mutation • EGFR mutation • BRAF mutation • NRAS mutation • BRAF V600 • FGFR1 amplification • CDKN2A deletion • HRAS mutation • PTPN11 mutation • CCND1 amplification • KRAS amplification • BRAF amplification
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Alecensa (alectinib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • Kisqali (ribociclib) • siremadlin (HDM201)
    over1year
    A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant (clinicaltrials.gov)
    P1/2, N=38, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy
    |
    TP53 (Tumor protein P53) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)
    |
    TP53 mutation
    |
    siremadlin (HDM201)
    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, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=80 --> 52
    Enrollment closed • Enrollment change • Combination therapy
    |
    TP53 (Tumor protein P53) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • GDF15 (Growth differentiation factor 15)
    |
    TP53 wild-type
    |
    Venclexta (venetoclax) • sabatolimab (MBG453) • siremadlin (HDM201)
    over1year
    Siremadlin in Combination with Venetoclax (VEN) Plus Azacitidine (AZA) in Adult Patients with Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy: A Phase Ib/II Trial (ASH 2022)
    Conclusion s : This Phase Ib/II trial investigates siremadlin in combination with VEN+AZA in patients with AML who are ineligible for intensive chemotherapy and will aid in the understanding of the effectiveness of an MDM2 inhibitor with venetoclax combination in patients with AML. The trial is in progress and expected to enroll approximately 55 patients.
    Clinical • P1/2 data • Combination therapy
    |
    FLT3 (Fms-related tyrosine kinase 3) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 mutation • TP53 wild-type
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    over1year
    P62SQSTM1 Affects Interacting Substrates MDM2, MDMX and Casein Kinase 1alpha to Yield Protection of Beta-Catenin Along with p53 Silencing for Refractory AML (ASH 2022)
    Primary p53-wild-type AML blasts or isogenic cell lines were treated in vitro with graded doses of the MDM2 inhibitors Pevonedistat (PEVO) or Siremadlin, either added alone, or in combination with Ixazomib at pharmacokinetically-achievable dose ranges typical in patients. In addition, a combination of PEVO/Ixazomib was as effective for apoptosis as was Flt3 inhibitor among certain Flt3mutant primary AML blasts. A clinical test of this strategy is warranted in high-risk relapsed/refractory p53WT/p62SQSTM1-expressing AML.
    IO biomarker
    |
    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • EP300 (E1A binding protein p300) • NSD1 (Nuclear Receptor Binding SET Domain Protein 1) • SQSTM1 (Sequestosome 1) • HOTAIR (HOX Transcript Antisense RNA) • NQO1 (NAD(P)H dehydrogenase, quinone 1) • CSNK1A1 (Casein Kinase 1 Alpha 1) • PRDM16 (PR/SET Domain 16)
    |
    TP53 mutation • FLT3 mutation • TP53 wild-type • EP300 mutation • HOTAIR overexpression
    |
    Ninlaro (ixazomib) • pevonedistat (MLN4924) • siremadlin (HDM201)
    over1year
    Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma. (PubMed, Front Oncol)
    Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS.
    Review • Journal • Tumor Mutational Burden
    |
    TMB (Tumor Mutational Burden) • MDM2 (E3 ubiquitin protein ligase)
    |
    TMB-L • MDM2 amplification • MDM2 overexpression
    |
    siremadlin (HDM201) • MI-773 • RG7112
    over1year
    Siremadlin Monotherapy and in Combination with Donor Lymphocyte Infusion for Patients with Acute Myeloid Leukemia Post Allogeneic Stem Cell Transplantation Who Are in Complete Remission but at High Risk for Relapse (ASH 2022)
    This Phase Ib/II study investigates siremadlin monotherapy and siremadlin in combination with DLI in pts with AML in remission but at high risk of relapse post SCT. The study will evaluate the unique immunomodulatory potential of siremadlin to reduce risk of relapse in this population with high unmet need.
    Clinical • Combination therapy
    |
    HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)
    |
    siremadlin (HDM201)
    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=80, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2022 --> Apr 2023 | Trial primary completion date: Dec 2022 --> Apr 2023
    Trial completion date • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • GDF15 (Growth differentiation factor 15)
    |
    TP53 wild-type
    |
    Venclexta (venetoclax) • sabatolimab (MBG453) • siremadlin (HDM201)
    over1year
    HDM201 and Midostaurin (HDMM) in Relapsed/Refractory AML With FLT3mut and TP53wt. (clinicaltrials.gov)
    P1, N=2, Terminated, University Hospital Inselspital, Berne | N=24 --> 2 | Trial completion date: Jun 2023 --> Sep 2022 | Recruiting --> Terminated | Trial primary completion date: Apr 2023 --> Sep 2022; Insufficient recruitment
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • TP53 wild-type
    |
    Rydapt (midostaurin) • siremadlin (HDM201)
    over1year
    p52-ZER6: a determinant of tumor cell sensitivity to MDM2-p53 binding inhibitors. (PubMed, Acta Pharmacol Sin)
    In HCT116 cell xenograft nude mouse model, administration of shp52-ZER6 combined with an MDM2-p53 binding inhibitor nutlin-3 exerted synergistic antitumor response. In conclusion, this study reveals that p52-ZER6 might be a potential biomarker for determining patients appropriate for MDM2-p53 binding inhibition-based antitumor therapy, and demonstrates the potential of combinatorial therapy using MDM2-p53 binding inhibitors and p52-ZER6 inhibition.
    Journal
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • TP53 expression
    |
    idasanutlin (RG7388) • siremadlin (HDM201) • Nutlin-3
    almost2years
    TRAHD: Trametinib + HDM201 in CRC Patients With RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type (clinicaltrials.gov)
    P1, N=24, Recruiting, Centre Leon Berard | Trial primary completion date: Feb 2022 --> Sep 2022
    Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    TP53 mutation • BRAF mutation • TP53 wild-type • HRAS mutation
    |
    Mekinist (trametinib) • siremadlin (HDM201)
    almost2years
    A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant (clinicaltrials.gov)
    P1/2, N=32, Not yet recruiting, Novartis Pharmaceuticals
    New P1/2 trial • Combination therapy
    |
    TP53 (Tumor protein P53) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)
    |
    TP53 mutation
    |
    siremadlin (HDM201)
    2years
    MegaMOST: A Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced / Metastatic Tumors. (clinicaltrials.gov)
    P2, N=375, Recruiting, Centre Leon Berard | N=100 --> 375
    Enrollment change
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • 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) • 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)
    |
    KRAS mutation • EGFR mutation • BRAF mutation • NRAS mutation • BRAF V600 • FGFR1 amplification • CDKN2A deletion • HRAS mutation • PTPN11 mutation • CCND1 amplification • KRAS amplification • BRAF amplification
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Alecensa (alectinib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • Kisqali (ribociclib) • siremadlin (HDM201)
    2years
    TRIAL IN PROGRESS: PHASE IB/II STUDY OF SIREMADLIN IN COMBINATION WITH VENETOCLAX + AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY (EHA 2022)
    Results None, trial in progress. Conclusion None, trial in progress.
    Clinical • P1/2 data • Combination therapy
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 mutation • TP53 wild-type
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    2years
    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 | Not yet recruiting --> Recruiting | Initiation date: Jan 2022 --> Apr 2022
    Enrollment open • Trial initiation date
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type
    |
    Votrient (pazopanib) • 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)
    P1/2, N=55, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    2years
    MegaMOST: A Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced / Metastatic Tumors. (clinicaltrials.gov)
    P2, N=100, Recruiting, Centre Leon Berard | Trial completion date: Nov 2022 --> Nov 2024 | Trial primary completion date: Feb 2022 --> Feb 2024
    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) • NRAS (Neuroblastoma RAS viral oncogene homolog) • 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) • 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)
    |
    KRAS mutation • EGFR mutation • BRAF mutation • NRAS mutation • BRAF V600 • FGFR1 amplification • CDKN2A deletion • HRAS mutation • PTPN11 mutation • CCND1 amplification • KRAS amplification • BRAF amplification
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Alecensa (alectinib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • Kisqali (ribociclib) • siremadlin (HDM201)
    over2years
    A study of siremadlin in combination with venetoclax plus azacitidine in adult participants with AML who are ineligible for chemotherapy. A venetoclaxszal plusz azacatidinnel kombinációban alkalmazott siremadlin vizsgálata olyan felnőtt AML-es résztvevőknél, akik nem alkalmasak kemoterápiára, ezáltal kemoterápiára nem alkalmas AML-esnek minősülnek. (clinicaltrialsregister.eu)
    P1/2, N=55, Ongoing, Novartis Pharma AG
    New P1/2 trial • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    over2years
    Tipping Growth Inhibition into Apoptosis by Combining Treatment with MDM2 and WIP1 Inhibitors in p53 Uterine Leiomyosarcoma. (PubMed, Cancers (Basel))
    RG7388, HDM201 and GSK2830371 failed to induce apoptosis as single agents; however, a combination treatment tipped cells into apoptosis from senescence. These data present the possibility of MDM2 and WIP1 inhibitor combinations as a potential treatment option for p53 uLMS patients that warrants further investigation.
    Journal
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 expression
    |
    idasanutlin (RG7388) • siremadlin (HDM201)
    over2years
    AMPHISARC: HDM201 and Pazopanib in Patients With P53 Wild-type Advanced/Metastatic Soft Tissue Sarcomas (clinicaltrials.gov)
    P1/2, N=58, Not yet recruiting, Centre Leon Berard
    Clinical • New P1/2 trial
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type
    |
    Votrient (pazopanib) • siremadlin (HDM201)
    over2years
    Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results From a Proof-of-Concept, Phase Ib Study. (PubMed, Clin Cancer Res)
    Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.
    Clinical • P1 data • Journal
    |
    MDM2 (E3 ubiquitin protein ligase) • CDK4 (Cyclin-dependent kinase 4)
    |
    Kisqali (ribociclib) • siremadlin (HDM201)
    over2years
    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=55, Not yet recruiting, Novartis Pharmaceuticals
    New P1/2 trial • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    Venclexta (venetoclax) • azacitidine • siremadlin (HDM201)
    over2years
    HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS) (clinicaltrials.gov)
    P1, N=80, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022
    Clinical • Trial completion date • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • GDF15 (Growth differentiation factor 15)
    |
    TP53 wild-type
    |
    Venclexta (venetoclax) • sabatolimab (MBG453) • siremadlin (HDM201)