P1/2, N=43, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

2 months ago

Trial completion date • Trial primary completion date

Venclexta (venetoclax) • revumenib (SNDX-5613) • Inqovi (decitabine/cedazuridine)

2ms

Foundation Medicine Partners with Syndax to Develop a Companion Diagnostic in Hematology and Support Efforts to Pursue Regulatory Approval for an Assay Based on the FoundationOne Heme Platform (Businesswire)

"Foundation Medicine, Inc. today announced a collaboration with Syndax Pharmaceuticals...to develop a companion diagnostic for the identification of acute myeloid leukemia (AML) patients harboring an NPM1 mutation. As part of the collaboration, Syndax will also support Foundation Medicine’s efforts to pursue regulatory approval of an assay based on the FoundationOne Heme platform....If approved, the assay could be the first next-generation sequencing companion diagnostic to detect genomic alterations in hematologic neoplasms, including enhancing the identification of patients with NPM1 mutations who may be eligible for revumenib."

2 months ago

Licensing / partnership

FoundationOne® Heme CDx

revumenib (SNDX-5613)

3ms

Revumenib for the Treatment of Acute Leukemia in Patients Post-Allogeneic Stem Cell Transplant (clinicaltrials.gov)

P1; N=27; Not yet recruiting; Sponsor:City of Hope Medical Center

3 months ago

New P1 trial • Post-transplantation

clonoSEQ

revumenib (SNDX-5613)

3ms

AUGMENT-102: A Study of Revumenib in Combination With Chemotherapy in Participants With R/R Acute Leukemia (clinicaltrials.gov)

P1, N=30, Completed, Syndax Pharmaceuticals | Active, not recruiting --> Completed

3 months ago

Trial completion • Combination therapy

KMT2A (Lysine Methyltransferase 2A) • NUP98 (Nucleoporin 98 And 96 Precursor 2)

cytarabine • cyclophosphamide • revumenib (SNDX-5613)

3ms

Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101). (PubMed, J Clin Oncol)

Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

3 months ago

Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

revumenib (SNDX-5613)

4ms

Revumenib for patients with acute leukemia: a new tool for differentiation therapy. (PubMed, Haematologica)

It will focus on the pathophysiology of leukemias sensitive to menin inhibition, delineation of how this understanding led to targeted drug development, and data from clinical trials. The important discovery of resistance mechanisms will also be explored, as well as future directions in using menin inhibitors for treating leukemia.

4 months ago

Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

revumenib (SNDX-5613)

4ms

Study of Radiolabeled Revumenib in Adults With Acute Leukemia (clinicaltrials.gov)

P1, N=8, Recruiting, Syndax Pharmaceuticals | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: May 2024 --> Sep 2024

4 months ago

Trial completion date • Trial primary completion date

revumenib (SNDX-5613)

5ms

A Phase II Study of the Menin Inhibitor Revumenib in Leukemia Associated With Upregulation of HOX Genes (clinicaltrials.gov)

P2, N=15, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

5 months ago

Enrollment open

revumenib (SNDX-5613)

5ms

Preclinical efficacy of potent and selective menin-KMT2A inhibitor JNJ-75276617 in KMT2A- and NPM1-altered leukemias. (PubMed, Blood)

JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice...A co-crystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory (R/R) acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903).

5 months ago

Preclinical • Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1)

Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • revumenib (SNDX-5613) • bleximenib (JNJ-6617)

5ms

Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia. (PubMed, Int J Mol Sci)

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.

5 months ago

Journal

KMT2A (Lysine Methyltransferase 2A) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • MEN1 (Menin 1)

revumenib (SNDX-5613) • pinometostat (EPZ-5676)

7ms

A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia. (PubMed, Hematol Rep)

To date, this new class of drugs has been tested in phase I and II clinical trials, both alone and in combination with synergistic drugs showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this brief review, we summarize the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data on the treatment of acute myeloid leukemia with this promising new class of agents, particularly revumenib and ziftomenib.

7 months ago

Review • Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1)

NPM1 mutation • MLL rearrangement • KMT2A expression

revumenib (SNDX-5613) • ziftomenib (KO-539)

7ms

Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia (clinicaltrials.gov)

P1, N=24, Recruiting, St. Jude Children's Research Hospital | Not yet recruiting --> Recruiting

7 months ago

Enrollment open

Venclexta (venetoclax) • cytarabine • azacitidine • methotrexate • revumenib (SNDX-5613)

7ms

Synergistic Effects of the RARalpha Agonist Tamibarotene and the Menin Inhibitor Revumenib in Acute Myeloid Leukemia Cells with KMT2A Rearrangement or NPM1 Mutation. (PubMed, Cancers (Basel))

The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics.

7 months ago

Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • RARA (Retinoic Acid Receptor Alpha) • CDK6 (Cyclin-dependent kinase 6) • CEBPA (CCAAT Enhancer Binding Protein Alpha)

NPM1 mutation • KMT2A rearrangement • MLL rearrangement

revumenib (SNDX-5613) • Amnolake (tamibarotene)

8ms

A Study of SNDX-5613 in Combination With Intensive Chemotherapy in Participants With Acute Myeloid Leukemias (clinicaltrials.gov)

P1, N=76, Recruiting, Syndax Pharmaceuticals | Not yet recruiting --> Recruiting

8 months ago

Enrollment open • Combination therapy

cytarabine • revumenib (SNDX-5613)

8ms

A Study of SNDX-5613 in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia (clinicaltrials.gov)

P2, N=78, Recruiting, Children's Oncology Group | Active, not recruiting --> Recruiting

8 months ago

Enrollment open • Combination therapy

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement

cytarabine • methotrexate • vincristine • revumenib (SNDX-5613) • fludarabine IV • Asparlas (calaspargase pegol-mknl) • Starasid (cytarabine ocfosfate)

8ms

Phase I Trial of Revumenib in Combination With 7+3+Midostaurin (clinicaltrials.gov)

P1, N=22, Not yet recruiting, Maximilian Stahl, MD

8 months ago

New P1 trial • Combination therapy

Rydapt (midostaurin) • daunorubicin • revumenib (SNDX-5613)

8ms

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)

P1, N=28, Recruiting, National Cancer Institute (NCI) | 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

8 months ago

Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Combination therapy

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • MLL rearrangement • FLT3 wild-type • MLL mutation

daunorubicin • revumenib (SNDX-5613) • Starasid (cytarabine ocfosfate)

9ms

A Multi-Site Break Through Cancer Trial: Phase II Study Investigating Dual Inhibition of BCL2 and Menin in AML MRD Using the Combination of Venetoclax and Revumenib (clinicaltrials.gov)

P2, N=8, Not yet recruiting, M.D. Anderson Cancer Center

9 months ago

New P2 trial

Venclexta (venetoclax) • revumenib (SNDX-5613)

9ms

A Study of SNDX-5613 in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia (clinicaltrials.gov)

P2, N=78, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

9 months ago

Enrollment closed • Combination therapy

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement

cytarabine • methotrexate • vincristine • revumenib (SNDX-5613) • fludarabine IV • Asparlas (calaspargase pegol-mknl) • Starasid (cytarabine ocfosfate)

10ms

Small Molecule Menin Inhibitors: Novel Therapeutic Agents Targeting Acute Myeloid Leukemia with KMT2A Rearrangement or NPM1 Mutation. (PubMed, Oncol Ther)

Recent phase 1/2 clinical trials confirmed the efficacy of SNDX-5613 (revumenib) and KO-539 (ziftomenib) and their acceptable tolerability. Several small molecule menin inhibitors are currently being evaluated as a combination therapy with standard of care treatments. The current paper reviews the recent progress in exploring the inhibitors of menin-KMT2A interactions and their application prospects in the treatment of acute leukemias.

10 months ago

Review • Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • KMT2A rearrangement • MLL rearrangement

revumenib (SNDX-5613) • ziftomenib (KO-539)

10ms

A Phase II Study of the Menin Inhibitor Revumenib in Leukemia Associated With Upregulation of HOX Genes (clinicaltrials.gov)

P2, N=15, Not yet recruiting, M.D. Anderson Cancer Center

10 months ago

New P2 trial

revumenib (SNDX-5613)

10ms

A Study of SNDX-5613 in Combination With Intensive Chemotherapy in Participants With Acute Myeloid Leukemias (clinicaltrials.gov)

P1, N=76, Not yet recruiting, Syndax Pharmaceuticals

10 months ago

New P1 trial • Combination therapy

cytarabine • revumenib (SNDX-5613)

10ms

Evaluation of SNDX-5613 in Participants With Colorectal Cancer and Other Solid Tumors (clinicaltrials.gov)

P1/2, N=158, Recruiting, Syndax Pharmaceuticals | Trial completion date: Sep 2025 --> Aug 2027 | Trial primary completion date: Sep 2023 --> Dec 2024

10 months ago

Trial completion date • Trial primary completion date

Stivarga (regorafenib) • revumenib (SNDX-5613)

10ms

A Study of SNDX-5613 in Combination With Chemotherapy in Participants With R/R Acute Leukemia (clinicaltrials.gov)

P1, N=30, Active, not recruiting, Syndax Pharmaceuticals | Recruiting --> Active, not recruiting | N=54 --> 30

10 months ago

Enrollment closed • Enrollment change • Combination therapy

KMT2A (Lysine Methyltransferase 2A) • NUP98 (Nucleoporin 98 And 96 Precursor 2)

KMT2A rearrangement • MLL rearrangement

cytarabine • cyclophosphamide • revumenib (SNDX-5613)

11ms

Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia (clinicaltrials.gov)

P1, N=24, Not yet recruiting, St. Jude Children's Research Hospital

11 months ago

New P1 trial

Venclexta (venetoclax) • cytarabine • azacitidine • methotrexate • revumenib (SNDX-5613)

11ms

P1, N=28, Not yet recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1

11 months ago

Phase classification

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • MLL rearrangement • FLT3 wild-type • MLL mutation

daunorubicin • revumenib (SNDX-5613) • Starasid (cytarabine ocfosfate)

11ms

Menin Inhibitors Trigger Leukemia Remissions. (PubMed, Cancer Discov)

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.

11 months ago

Journal

KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

revumenib (SNDX-5613)

11ms

Phase 1/2 evaluation of revumenib in patients with advanced colorectal cancer and other solid tumors. (ASCO-GI 2024)

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–epidermal growth factor receptor therapy. As of September 5, 2023, 13 patients were enrolled in phase 1a of this study. Clinical trial information: NCT05731947.

11 months ago

Clinical • P1/2 data • Metastases

EGFR (Epidermal growth factor receptor) • ER (Estrogen receptor) • KMT2A (Lysine Methyltransferase 2A)

ER positive • RAS wild-type

Avastin (bevacizumab) • oxaliplatin • irinotecan • revumenib (SNDX-5613)

12ms

A Study of Revumenib in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia (clinicaltrials.gov)

P2, N=78, Recruiting, Children's Oncology Group | Not yet recruiting --> Recruiting

12 months ago

Enrollment open • Combination therapy

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement

cytarabine • methotrexate • vincristine • revumenib (SNDX-5613) • Oncaspar liquid (pegaspargase) • fludarabine IV • Asparlas (calaspargase pegol-mknl) • Starasid (cytarabine ocfosfate)

12ms

The LSD1 Inhibitor Ory-1001 (ladademstat) in Combination with Menin Inhibitor SNDX-5613 (revumenib) Has Synergistic in Vitro Activity in KMT2A-Rearranged AML Models (ASH 2023)

LSD1 Inhibitor ladademstat in Combination with Menin Inhibitor revumenib has synergistic effect in KMT2A-Rearranged AML models. Surprisingly, we also found that PSIP1, which is essential for inducing MLL-rearranged leukemia, interacts with LSD1. This suggests that PSIP1 may modulate gene expression through its ability to interact with both MLL1 and LSD1.

12 months ago

Preclinical • Combination therapy

KMT2A (Lysine Methyltransferase 2A) • HDAC2 (Histone deacetylase 2) • HDAC1 (Histone Deacetylase 1)

KMT2A rearrangement • MLL rearrangement • KMT2A expression • MLL fusion

revumenib (SNDX-5613) • iadademstat (ORY-1001)

12ms

Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Topline Efficacy and Safety Results from the Pivotal Augment-101 Phase 2 Study (ASH 2023)

Rev demonstrated clinically meaningful results in a heavily pretreated KMT2Ar population, including high ORR and rates of MRD negativity and subsequent HSCT. At IA, this pivotal study met its primary endpoint and the KMT2Ar cohorts were stopped early for efficacy.

12 months ago

Clinical • P2 data • Late-breaking abstract

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • MLL rearrangement • MLL fusion

revumenib (SNDX-5613)

1year

Revumenib Maintenance Therapy Following Revumenib-Induced Remission and Transplant (ASH 2023)

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.

1 year ago

Clinical

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • NUP98 (Nucleoporin 98 And 96 Precursor 2)

NPM1 mutation • MLL rearrangement • NUP93 mutation

revumenib (SNDX-5613)

1year

Notable Efficacy of Co-Treatment with FHD-286, a Dual BRG1/BRM ATP-Ase Inhibitor, and Menin or BET Inhibitor, Decitabine or Venetoclax Against AML with MLL-r or Mutant NPM1 (ASH 2023)

BRG1 (SMARCA4) and BRM (SMARCA2) are the core ATPase within the multi-protein, ATP-dependent, chromatin remodeling BAF complexes that regulate gene transcription. Finally, co-treatment with FHD-286 and OTX015 or SNDX-5613 (oral gavage) was significantly more effective than each drug alone in reducing the AML burden and overall survival of mice engrafted with a separate PDX model of AML cells with mtNPM1 and FLT3-ITD, without significant toxicity. These findings demonstrate the pre-clinical efficacy of FHD-286-based rational combinations and underscore their promise against AML with MLL1r or mtNPM1.

1 year ago

Clinical • PARP Biomarker • IO biomarker

FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1) • MCL1 (Myeloid cell leukemia 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CDK4 (Cyclin-dependent kinase 4) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD33 (CD33 Molecule) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • ITGAM (Integrin, alpha M) • BRD4 (Bromodomain Containing 4) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • CD99 (CD99 Molecule) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • HEXIM1 (HEXIM P-TEFb Complex Subunit 1) • MEF2C (Myocyte Enhancer Factor 2C) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • CLEC12A (C-Type Lectin Domain Family 12 Member A) • PBX3 (PBX Homeobox 3)

FLT3 mutation • NPM1 mutation • CD123 expression

Venclexta (venetoclax) • decitabine • revumenib (SNDX-5613) • birabresib (OTX015) • FHD-286

1year

Transcriptomic without Clinical Response to Menin Inhibition As a Mechanism of Upfront Resistance in Samples from Mutliply Relapsed Patients with KMT2A-Rearranged Leukemia (ASH 2023)

A transcriptomic response (i.e. downregulation of KMT2A-fusion target genes) without a clinical response was the most common pattern of upfront resistance in the recently reported phase I/II clinical trial of the Menin inhibitor revumenib. We conclude that it will be critical to use Menin-inhibitors upfront or in early lines of therapy before substantial clonal evolution has occurred.

1 year ago

Clinical • IO biomarker

TP53 (Tumor protein P53) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • AFF1 (AF4/FMR2 Family Member 1) • MEN1 (Menin 1) • AFDN (Afadin, Adherens Junction Formation Factor) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor)

TP53 mutation • NPM1 mutation • RAS mutation • KMT2A rearrangement • MLL rearrangement • MLL fusion

revumenib (SNDX-5613)

1year

Single-Cell Proteomic Analysis Reveals Menin Inhibition-Induced Proteomic Alterations in AML Patients Treated with Revumenib (ASH 2023)

In conclusion, multimodal sc analysis revealed profound proteomic alterations induced by revumenib and identified potential therapeutic targets. These findings present new avenues for optimizing combinatorial treatment regimens, enhancing revumenib's efficacy, and illuminating survival mechanisms in persistent, differentiated AML blasts.

1 year ago

Clinical • IO biomarker • Omic analysis

TP53 (Tumor protein P53) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • BCL2L1 (BCL2-like 1) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD34 (CD34 molecule) • CD14 (CD14 Molecule) • CD68 (CD68 Molecule) • ITGAM (Integrin, alpha M) • MEIS1 (Meis Homeobox 1) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • PBX3 (PBX Homeobox 3)

NPM1 mutation • KMT2A rearrangement • MLL rearrangement • MCL1 expression • TP53 expression

revumenib (SNDX-5613)

1year

Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemias: Efficacy and Safety Results from the Augment-101 Phase 1/2 Study (ASH 2023)

These phase 1 data continue to demonstrate deep responses to revumenib and a manageable safety profile in heavily pretreated patients with R/R KMT2Ar acute leukemia across ages and subtypes. The lack of targeted therapies approved for KMT2Ar leukemia indicate the need for further investigation of novel, potentially transformative therapies such as revumenib. Enrollment in the AUGMENT-101 trial is ongoing.

1 year ago

Clinical • P1/2 data

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • MLL rearrangement

revumenib (SNDX-5613)

1year

Decoding the Epigenetic Drivers of Menin-MLL Inhibitor Resistance in KMT2A-Rearranged Acute Myeloid Leukemia (ASH 2023)

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.

1 year ago

IO biomarker

MYC (V-myc avian myelocytomatosis viral oncogene homolog) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • BCOR (BCL6 Corepressor) • MEIS1 (Meis Homeobox 1) • MEF2C (Myocyte Enhancer Factor 2C) • PBX3 (PBX Homeobox 3) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)

NPM1 mutation • KMT2A rearrangement • MLL rearrangement • MYC expression • KMT2A rearrangement + NPM1 mutation

Venclexta (venetoclax) • revumenib (SNDX-5613) • VTP-50469

1year

Early Results of the Phase I/II Study Investigating the All-Oral Combination of the Menin Inhibitor Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax in Acute Myeloid Leukemia (SAVE) (ASH 2023)

ASTX727 (decitabine/ cedazuridine) was administered at 35 mg/100 mg PO daily days 1-5, venetoclax at 400 mg (target dose) PO daily days 1-14, and revumenib 113 mg PO Q12h (dose level [DL] 0) or 163 mg PO Q12h (DL 1, used in phase II monotherapy), days 1-28 with either posaconazole or voriconazole (strong CYP3A4 inhibitors, for antifungal prophylaxis). Early results indicate acceptable safety and high efficacy of this combination in R/R myeloid leukemias with either KMT2Ar or NPM1mt or NUP98r. This study is ongoing with plans to establish the recommended phase 2 dose and optimize delivery of this combination.

1 year ago

P1/2 data • IO biomarker

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • NUP98 (Nucleoporin 98 And 96 Precursor 2)

Venclexta (venetoclax) • revumenib (SNDX-5613) • Inqovi (decitabine/cedazuridine) • Noxafil (posaconazole)