Promising Results in Phase 1 Study of Novel Menin Inhibitor for Aggressive Leukemia

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MSK's team of experts discussing advanced therapies available to treat acute leukemia, myeloproliferative neoplasms, myelodysplastic syndromes, and chronic myeloid leukemia.

MSK's team of experts discussing advanced therapies available to treat acute leukemia, myeloproliferative neoplasms, myelodysplastic syndromes, and chronic myeloid leukemia.

The oral menin inhibitor SNDX-5613 (Syndax Pharmaceuticals) demonstrated promising antileukemic activity and an acceptable safety profile in patients with heavily pretreated acute leukemias with specific genetic mutations, according to results from phase 1 of the AUGMENT-101 trial (NCT04065399).

Overall, more than half of patients with mixed-lineage leukemia (MLL) rearrangements or NPM1-mutant (mNPM1) leukemia responded to the drug. The overall response rate was 55%, observed in 28 of 51 efficacy-evaluable patients. To date, nine responding patients have proceeded to allogeneic stem cell transplant. (1)

On December 13, 2021, I presented these results at the American Society of Hematology’s Annual Meeting and Exposition on behalf of my colleagues from eight collaborating cancer centers. Based on these encouraging findings, we are now testing the drug in phase 2 of the AUGMENT-101 trial among expanded cohorts of patients with MLL-rearranged acute myeloid leukemia (AML), MLL-rearranged acute lymphoblastic leukemia (ALL), and NPM1-mutant AML.

Eytan Stein, MD, Hematology/Oncology, specializes in caring for people with acute and chronic leukemias, myelodysplastic syndromes, and myeloproliferative neoplasms. He is also a clinical researcher who develops new and innovative approaches to treating acute myeloid leukemia (AML)

Eytan Stein, MD, Hematology/Oncology, specializes in caring for people with acute and chronic leukemias, myelodysplastic syndromes, and myeloproliferative neoplasms. He is also a clinical researcher who develops new and innovative approaches to treating acute myeloid leukemia (AML)

At MSK, I established the Program for Drug Development in Leukemia (PDD-L) to offer patients the most advanced therapies for acute leukemia, myeloproliferative neoplasms, myelodysplastic syndromes, and chronic myeloid leukemia through participation in phase 1 clinical trials. We partner with the Center for Hematologic Malignancies (CHM), which includes clinical investigators and researchers from the Human Oncology and Pathogenesis Program and the Sloan Kettering Institute. Trialists with expertise in each hematology subspecialty work together with CHM scientists to rapidly translate preclinical science to novel therapies for first-in-human clinical studies.

MLL-Rearranged and NPM1-Mutant Acute Leukemias

MLL rearrangements are found in about 5% to 10% of AML cases and more than 70% of infant ALL. They arise de novo or after exposure to topoisomerase 2 inhibitors like etoposide or, less frequently, anthracyclines. (2)NPM1 mutations in AML are the most frequent genetic abnormalities in adult AML, found in about 35% of cases. NPM1 mutations are far less frequent in children, occurring in about 8% to 10% of AML cases. (3)

MLL-rearranged leukemia is characterized by chromosomal translocations involving the MLL gene on chromosome 11q23. Translocations with 10 or more other genes result in chimeric proteins that form complexes upregulating transcription of the leukemogenic HOX and MEIS1 genes. The protein menin plays an essential role in these complexes, locating them to chromatin. Similarly, in NPM1-mutant AML, an interaction between wild-type MLL protein and menin results in leukemogenic transcription mediated by HOX and MEIS1(1)

Previously, groundbreaking preclinical models of MLL-rearranged and NPM1-mutant leukemias determined that inhibiting the interaction between MLL and menin downregulated HOX and MEIS1 transcription and reversed the development of leukemia. (4), (5)

The initial research for menin inhibition was initiated at MSK more than five years ago by Scott Armstrong, MD, PhD, formerly Director of our Center for Epigenetics Research who subsequently became Chairman of the Department of Pediatric Oncology at Dana-Farber Cancer Institute in 2016. (2), (6)Ross Levine, MD, Chief of the Molecular Cancer Medicine Service in MSK’s Human Oncology Pathogenesis Program and Laurence Joseph Dineen Chair in Leukemia Research, also participated in the foundational research.

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Study Design and Results

Our phase 1 study of SNDX-5613 included patients with MLL-rearranged or NPM1-mutant leukemias in two parallel dose-escalation cohorts: those not taking and those taking strong CYP3A4 inhibitors. The primary objectives were to evaluate the safety, maximum tolerable dose, recommended dose to advance to phase 2 study, and the drug’s pharmacokinetic profile. Antileukemic activity and pharmacodynamics were exploratory endpoints. (1)

At the end of October 2021, a total of 59 patients had received at least one dose of the drug, and 10 remained on treatment. The median age of study participants was 47 years. They had received a median of three previous therapies: 42% had previously received venetoclax or transplant. (1)

SNDX-5613 demonstrated dose-proportional pharmacokinetic activity, which increased two- to threefold when administered together with a strong CYP3A4 inhibitor. An assessment of the molecular mechanism of action found that the novel drug disrupted menin binding to chromatin and decreased gene expression associated with leukemia development, consistent with findings established in earlier lab research. (1)

The only dose-limiting toxicities were a grade 3 prolonged QTc interval observed in seven patients (13%), and all were clinically asymptomatic. No ventricular arrhythmias were reported, and no study participants discontinued treatment due to a treatment-related event. Common treatment-related adverse events affecting more than 10% of participants were nausea (27%), vomiting (17%), differentiation syndrome (14%), and diarrhea (12%). (1)

We defined composite complete remission as inclusive of complete remission, complete remission with partial hematologic recovery, complete remission with incomplete platelet recovery, complete remission with incomplete hematologic recovery relative, and a morphologic leukemia-free state. The overall response rate was 61% among patients with MLL-rearranged leukemia (23 of 38 patients) and 38% among those with NPM1-mutant leukemia (3 of 13 patients). (1)

The median time to complete response or complete response with partial hematologic recovery was two months. The median duration of response for patients achieving a complete response or complete response with partial hematologic recovery was not reached.

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Highly Specialized Care

MSK patients participating in PDD-L phase 1 trials receive care from nurses with specialized training within the Developmental Therapeutics Unit in the David H. Koch Center for Cancer Care. Review our list of phase 1 trials currently recruiting at MSK, including the phase 2 trial of SNDX-5613.

For more information or to refer a patient to a PDD-L trial, please call 646-608-3749.

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Learn More About How MSK Is Advancing Leukemia Research and Treatments

MSK researchers recently received a prestigious SPORE (Specialized Programs of Research Excellence) grant from the National Institutes of Health to leverage translational efforts to develop targeted therapies and immunotherapeutic approaches for several molecular subtypes of AML with poor prognoses or no treatment options. Led by physician-scientist Omar Abdel-Wahab, MD, Director of MSK’s CHM and the Edward P. Evans Endowed Chair for Myelodysplastic Syndromes, and Martin Tallman, MD, Chief of the Leukemia Service and the Cassidy Family Endowed Faculty Chair at MSK, the SPORE research team will focus on developing targeted therapies for resistant leukemias and chimeric antigen receptor (CAR) T cell therapies.


The SNDX-5613 trial was funded by Syndax Pharmaceuticals.

Dr. Stein discloses consultancies with the following companies: Foghorn Therapeutics; Blueprint Medicines; Gilead Sciences, Inc.; Abbvie; Janssen Pharmaceuticals; Genentech; Jazz Pharmaceuticals; Bristol Myers Squibb; Celgene; PinotBio; Daiichi Sankyo; Astellas; Novartis; Agios Pharmaceuticals, Inc.; Syros Pharmaceuticals, Inc.; and Syndax Pharmaceuticals.

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  1. Stein EM, Aldos I, DiPersio JF, et al. Abstract 699: Safety and Efficacy of Menin Inhibition in Patients with MLL-Rearranged and NPM1 Mutant Acute Leukemia: A Phase 1, First-in-Human Study of SNDX-5613 (AUGMENT 101). American Society of Hematology Annual Meeting & Exposition 2021. Accessed at: https://ash.confex.com/ash/2021/webprogram/Paper146944.html
  2. Neff T, Armstrong SA. Recent progress toward epigenetic therapies: the example of mixed lineage leukemia. Blood. 2013;121(24):4847-4853.
  3. Rau R, Brown P. Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: towards definition of a new leukaemia entity. Hematol Oncol. 2009;27(4):171-181.
  4. Uckelmann HJ, Kim SM, Wong EM, et al. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science. 2020;367(6477):586-590.
  5. Krivtsov AV, Evans K, Gadrey JY, et al. A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia. Cancer Cell. 2019;36(6):660-673.e11.
  6. Kühn MW, Song E, Feng Z, et al. Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia. Cancer Discov. 2016;6(10):1166-1181.