- |||||||||| pinometostat (EPZ-5676) / Ipsen, revumenib (SNDX-5613) / Syndax Pharma
Journal: Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia. (Pubmed Central) - Jun 19, 2024 Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia.
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma
Enrollment open, Trial completion date, Trial initiation date, Trial primary completion date, Combination therapy: Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/KMT2A Gene (clinicaltrials.gov) - Mar 12, 2024 P1, N=28, Recruiting, Active, not recruiting --> Recruiting Not yet recruiting --> Recruiting | Trial completion date: Feb 2024 --> Dec 2027 | Initiation date: Feb 2024 --> Nov 2024 | Trial primary completion date: Feb 2024 --> Dec 2027
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma, FHD-286 / Foghorn Therap, birabresib (OTX015) / Merck (MSD)
Novel combination therapies to overcome non-genetic/adaptive menin inhibitor resistance in AML with MLL1r or mtNPM1 (Ballroom 6 B - Upper Level - Convention Center) - Mar 5, 2024 - Abstract #AACR2024AACR_3342; In vivo treatment with FHD-286 and OTX015 or SNDX-5613 significantly reduced the AML burden in mice bearing OCI-AML3-MITR xenografts. These findings underscore preclinical activity of epigenetically-targeted agent-based combinations and highlight their promise in overcoming MI resistance in AML with MLL1r or mtNPM1.
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma
Deciphering the mechanism of the menin-MLL complex dependency in HCC (Section 23) - Mar 5, 2024 - Abstract #AACR2024AACR_2658; Moreover, treatment of HCC cell lines (HLF, PLC/PRF5, HepG2) with recently developed menin inhibitor SNDX-5613 (revumenib) revealed a dose-dependent reduction in cell proliferation...Integration of our genomics data revealed a list of 30 genes, which are downregulated upon menin inhibition in both HLF and PLC/PRF5 cells (FC?1.5) and the direct targets of the menin-MLL complex in HLF cells, suggesting their potential role in HCC cell survival. Altogether, we anticipate that menin and ASH2L serve as promising targets and represent an appealing therapeutic strategy for HCC treatment.
- |||||||||| Biomarker, Trial completion date, Trial primary completion date: Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - Feb 21, 2024
P1/2, N=2000, Recruiting, Altogether, we anticipate that menin and ASH2L serve as promising targets and represent an appealing therapeutic strategy for HCC treatment. Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma
Phase classification, Combination therapy: Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/KMT2A Gene (clinicaltrials.gov) - Dec 15, 2023 P1, N=28, Not yet recruiting, These findings emphasize the critical role of epigenetic regulation, particularly H3K4me3, H3K9me3, and HDAC5, in shaping stem cell fate and directing lineage-specific differentiation. Phase classification: P1b --> P1
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma
Journal: Menin Inhibitors Trigger Leukemia Remissions. (Pubmed Central) - Dec 14, 2023 A phase II study of revumenib yielded a response rate of 63% in patients with relapsed or refractory disease and KMT2A rearrangements; a phase I trial combining the drug with three chemotherapies also yielded complete remissions in patients with acute myeloid leukemia. A phase I study of a different menin inhibitor detected responses in 63% of patients with acute leukemia and certain gene alterations.
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma
Phase 1/2 evaluation of revumenib in patients with advanced colorectal cancer and other solid tumors. (Level 1, West Hall; Poster Bd # N15) - Dec 6, 2023 - Abstract #ASCOGI2024ASCO_GI_640; P1/2 A phase I study of a different menin inhibitor detected responses in 63% of patients with acute leukemia and certain gene alterations. Patients with CRC must be unable to receive or have disease that progressed on oxaliplatin, irinotecan, and bevacizumab; if left-sided RAS wild-type CRC, the patient must have received anti
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma
Revumenib Maintenance Therapy Following Revumenib-Induced Remission and Transplant (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_6412; P1/2 With 3 patients on revumenib maintenance therapy for more than a year, long-term responses, including conversion to MRD-negative status, were seen in these heavily pretreated patients with AML. Resuming revumenib post HSCT had a tolerable safety profile consistent with that previously reported for the AUGMENT-101 study.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute, revumenib (SNDX-5613) / Syndax Pharma, VTP-50469 / Syndax Pharma
Decoding the Epigenetic Drivers of Menin-MLL Inhibitor Resistance in KMT2A-Rearranged Acute Myeloid Leukemia (Marriott Marquis - Pacific Ballroom) - Nov 3, 2023 - Abstract #ASH2023ASH_3264; Consistent with our screen results, the depletion of PRC1.1 components led to a markedly increase in IC50 values when treated with the Menin inhibitor VTP50469 in both human and murine KMT2A-rearranged cell models...This is consistent with recent data from phase I clinical trial of revumenib (SNDX-5613) and preclinical patient derived xenograft models, wherein the Menin inhibitor persistently inhibited key KMT2A targets, even in resistant samples...In summary, our study identifies the non-canonical PRC1.1 as a key epigenetic driver of Menin-MLL resistance through a KMT2A target gene-independent mechanism which involves aberrant activation of MYC. We have further provided evidence that AML cells with loss of PRC1.1 are hypersensitive to BCL-2 inhibitor Venetoclax, opening a new therapeutic avenue for tackling Menin-resistant AMLs driven by polycomb inactivation.
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma, Koselugo (selumetinib) / Merck (MSD), AstraZeneca, VTP-50469 / Syndax Pharma
Combining Menin and MEK Inhibition to Target Poor Prognostic KMT2A-Rearranged RAS Pathway-Mutant Acute Leukemia (Marriott Marquis - Pacific Ballroom) - Nov 3, 2023 - Abstract #ASH2023ASH_1181; The findings in our preclinical study suggest a promising, readily translatable targeted treatment for this patient population. Mechanistically, enhanced downregulation of both MYC signaling and the RAS/MAPK pathway with the combinatorial therapy is likely a strong contributor to the observed efficacy.
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma
Journal: Acute myeloid leukemias with UBTF tandem duplications are sensitive to Menin inhibitors. (Pubmed Central) - Oct 27, 2023 Finally, we demonstrate that primary cells from UBTF-TD leukemias are sensitive to the Menin inhibitor SNDX-5613, resulting in markedly reduced in vitro and in vivo tumor growth, myeloid differentiation, and abrogation of the UBTF-TD leukemic expression signature. These findings provide a viable therapeutic strategy for patients with this high-risk AML subtype.
- |||||||||| revumenib (SNDX-5613) / Syndax Pharma
Journal: The MLL-Menin Interaction is a Therapeutic Vulnerability in NUP98-rearranged AML. (Pubmed Central) - Jul 31, 2023 Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors.
- |||||||||| Review, Journal: Targeting the undruggable: menin inhibitors ante portas. (Pubmed Central) - Apr 27, 2023
The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.
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