Methods of treating acute leukemias with a menin inhibitor in a combination therapy

Abstract

Provided herein are methods of treating acute leukemia, such as acute myeloid leukemia (AML), in an individual, comprising administering to the individual a menin inhibitor and a standard-of-care therapy.

Description

WSGR Reference No.47535-753.601 METHODS OF TREATING ACUTE LEUKEMIAS WITH A MENIN INHIBITOR IN A COMBINATION THERAPY CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 728,567 filedDecember 5, 2024, U.S. Provisional Application No.63 / 716,107 filed November 4, 2024, U.S. Provisional Application No.63 / 680,376 filed August 7, 2024, U.S. Provisional Application No. 63 / 641,611 filed May 2, 2024, and U.S. Provisional Application No.63 / 626,432 filed January 29, 2024, each of which is incorporated herein by reference in their entirety. BACKGROUND

[0002] Acute leukemia is a group of blood cancers characterized by a rapid increase in thenumber of immature blood cells, and includes acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). AML is a diverse group of highly fatal blood cancers and is characterized by the proliferation of myeloid precursors (myeloid blasts or progranulocytes) that fail to undergo normal differentiation. AML develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. These changes alter normal hematopoietic growth and differentiation, resulting in an abnormal accumulation of large numbers of these immature myeloid blasts in the bone marrow in peripheral blood, which, in turn, interfere with production of normal blood cells. As with other malignancies, genetic alterations in AML include mutation of oncogenes as well as the loss of tumor suppressor genes. In contrast to most solid tumors, however, many hematologic malignancies are associated with a single characteristic cytogenetic abnormality. This clinically heterogeneous disease is characterized by a multitude of chromosomal abnormalities and gene mutations, which translate to marked differences in responses and survival following chemotherapy, and significant challenges for successful and durable AML treatment. (Kumar, C.C., Genes Cancer 2011, 2(2), 95-107.) Analogously, ALL involves genetic changes that lead to creating of leukemic lymphoblasts in the bone marrow that impact production of new red blood cells, white blood cells, and platelets. ALL is the most common type of leukemia in young children, and the most common cause of death from cancer in children. While most cases of ALL occur in children, 80% of deaths from ALL occur in adults.WSGR Reference No.47535-753.601 SUMMARY

[0003] Described herein are methods of treating acute leukemia with a menin inhibitor incombination with a standard-of-care therapy. In particular, described herein are methods, compositions, and kits that relate to the unexpected discovery that risk of differentiation syndrome events such as differentiation syndrome (DS) and / or severe DS (e.g., Grade 3 or higher), which is a known risk related to differentiation of leukemic blasts that may be induced by treatment with a menin inhibitor monotherapy in AML patients, such as NPM1-m or KMT2A- r patients, and optionally relapsed / refractory (R / R) patients of these genetic subtypes, are mitigated by combining the menin inhibitor with a standard-of-care (SOC) therapy. In some embodiments, the risk is mitigated by starting treatment with the menin inhibitor following a lead-in period with the SOC therapy, for example, a lead-in period of about 3 to 14 days. Without being bound by theory, treatment with the SOC during a lead-in period may allow for disease “debulking” and may decrease the amount of blast cells available to contribute to a DS event when the menin inhibitor is added. The lead-in approach, optionally along with a TLS mitigation strategy, was also unexpectedly found to reduce the risk of tumor lysis syndrome, which can occur with or without concurrent DS and is a consequence of rapid cell death and the release of electrolytes, nucleic acids, and cytokines into the bloodstream that overwhelm the body’s homeostatic clearance mechanisms. In addition, the combination therapies were surprisingly found to exhibit beneficial clinical activity for AML patients with high unmet need, such as KMT2A-r and NPM1-m AML patients in both newly diagnosed and R / R settings, for whom there are no approved targeted therapies, including significant clinical responses in patients who were heavily pre-treated, and even patients who were resistant to (e.g., relapsed following) prior treatment with ven, a combination of ven and aza (ven / aza), and / or a menin inhibitor.

[0004] Provided and described herein is a method of treating acute leukemia in an individualcomprising administering to the individual a standard-of-care therapy and a menin inhibitor. Also provided and described herein is a method of reducing the risk of a differentiation syndrome-suspect adverse event in an individual with acute leukemia comprising administering to the individual a menin inhibitor and a standard-of-care therapy. In some aspects, the methods comprise administering to the individual the standard-of-care therapy without a menin inhibitor during a lead-in period of an induction cycle; and administering to the individual the menin inhibitor for the remainder of the induction cycle, optionally in combination with the standard- of-care therapy or a component thereof. In some embodiments, the acute leukemia is AML. In some embodiments, the AML is menin-dependent. In some embodiments, the AML is NPM1-mWSGR Reference No.47535-753.601 AML. In some embodiments, the AML is KMT2A-r AML. In some embodiments, the menin inhibitor is ziftomenib or a pharmaceutically acceptable form thereof. INCORPORATION BY REFERENCE

[0005] All publications, patents, and patent applications mentioned in this specification areherein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE FIGURES

[0006] FIG. 1: Plots of ziftomenib area under the curve (AUC) / dose (ng*hr / mL / mg) insubjects administered ziftomenib without antifungal azoles (none) or with moderate or strong antifungal azoles. DETAILED DESCRIPTION

[0007] Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults.AML is characterized by the clonal expansion of myeloid blasts in the bone marrow (BM), peripheral blood and extramedullary tissues, and is defined by World Health Organization (WHO) as a myeloid neoplasm with 20% or more blasts in the peripheral blood or BM. The estimated number of new cases is 20,240 and 11,400 deaths in 2021 in the United States (US). (American Cancer Society, Cancer Facts & Figures 2021, American Chemical Society (Atlanta), 2021.) The incidence is approximately 119,000 cases worldwide. The median age of diagnosis is 67 years, with 55% of the patients diagnosed at 65 years or older, and approximately one-third of patients diagnosed over the age of 75. AML comprises approximately 30% of all adult leukemia cases and 80% of all acute leukemia cases in adults. Outcomes for patients with AML are often considered dire or poor and are characterized by high mortality rates.

[0008] AML is a clinically, morphologically, and genetically heterogeneous disease arising asa consequence of genetic and epigenetic dysregulation in hematopoietic precursor cells. Genetic abnormalities include chromosomal abnormalities, such as nonrandom translocations, gain or loss of entire (or portions of) chromosomes, and other karyotypic abnormalities as well as other specific mutations. In some cases, the chromosomal translocations generate chimeric fusion genes that are never expressed in normal cells.

[0009] Epigenetic modifications in the lysine methyltransferase 2A (KMT2A) gene (previouslyknown as mixed lineage leukemia gene, or MLL) result in KMT2A fusions with more than 60 partner genes and play a causative role in the onset, development, and progression of a subset ofWSGR Reference No.47535-753.601 acute leukemias. (Borkin et al., Cancer Cell 2015, 27(4), 589-602.) AML (as well as acute lymphoid leukemia) with translocations of KMT2A gene 11q23 are an aggressive group of blood cancers known as KMT2A-r leukemias, which overexpress the key oncogenes, HOXA9 and MEIS1. (Thiel et al., Bioessays 2012, 34(9), 771-780.) The HOXA9 and MEIS1 transcription factors drive AML by upregulating stem cell programs and blocking myeloid differentiation. KMT2A rearrangements alter normal histone methyltransferase function of KMT2A and deregulate these HOX genes, resulting in sustained high HOX levels and blockage of hematopoietic (myeloid) differentiation, ultimately leading to acute leukemia. (Kühn et al., Cancer Discov.2016, 6(10), 1166-1181; Klossowski et al., J. Clin. Invest.2020, 130(2), 981- 997; Issa et al., Blood Cancer J.2021, 11(9), 162; Chan et al., Front. Cell Dev. Biol.2019, 7, 81.) KMT2A rearrangements occur in 5-10% of AML patients; the 5-year survival rate of these patients following first-line therapy is less than 20% (Issa, 2021), medial overall survival (OS) drops and relapse rates increase significantly in later lines of therapy (55% and 82% following first-line and second-line therapies, respectively).

[0010] In AML, a key common factor in the regulation of these leukemogenic genes byKMT2A is the interaction between the KMT2A N-terminal portion and menin, which is essential for the vectoring of the gene activating effect of both wild-type KMT2A and KMT2A fusion proteins to HOXA9 and MEIS1 promoter regions. Menin is a highly specific and direct binding partner of KMT2A and KMT2A fusion proteins that is required for regulation of their target genes (Yokoyama et al., Cell 2005, 123(2), 207-218.) Numerous studies have demonstrated that menin plays a critical role as an oncogenic cofactor in leukemic transformation mediated by KMT2A fusion proteins. (Yokoyama 2005; Caslini et al., Cancer Res.2007, 67(15), 7275-7283; Yokoyama et al., Cancer Cell 2008, 14(1), 36-46.; Kühn, 2016.)

[0011] Other AML genetic subtypes expressing normal karyotype KMT2A (KMT2A wt)likewise have dysregulation of menin-KMT2A signaling as a result of mutations in downstream epigenetic regulators (e.g., nucleophosmin 1 (NPM1), DNA methyltransferase 3 alpha (DNMT3A), and isocitrate dehydrogenase 1 / 2 (IDH1 / 2)). (Yokoyama 2005; Caslini et al., Cancer Res.2007, 67(15), 7275-7283; Yokoyama et al., Cancer Cell 2008, 14(1), 36-46.; Kühn, 2016.) NPM1 encodes for a protein involved in cellular protein transport to the nucleolus and is dependent on the interaction between menin and wild-type KMT2A to drive leukemogenic gene expression. (Kühn, 2016.) NPM1 mutations occur in about 30% of AML patients (with or without co-mutations) and the 5-year survival rate is about 50%. (Angenendt et al., J. Clin. Oncol.2019, 37(29), 2632-2642; Thiede et al., Blood 2006, 107(10), 4011-4020.) Patients with NPM1 mutations who relapse following treatment have a dismal prognosis, with a medianWSGR Reference No.47535-753.601 overall survival of 6.1 months and median relapse-free survival of 5.5 months. As in the KMT2A-r setting, survival outcomes for the NPM1-m population worsen by increasing line of treatment and age. NPM1 mutations frequently co-occur with FLT3, DNMT3A, and IDH1 / 2 mutations, and the presence of these co-mutations negatively impacts clinical prognoses. Internal tandem duplications in FLT3 (FLT3-ITD) occur in about 15-30% of AML patients, and at a higher rate (approximately 40%) in patients with NPM1 mutations.

[0012] Additional genetic modifications that negatively impact disease progression andprognosis include mutations to another histone methyltransferase gene, called SET domain containing 2 (SETD2), including truncating mutations, which are found in 1-2% of AML cases, and the gene that encodes for runt-related transcription factor 1, also known as acute myeloid leukemia 1 protein (RUNX1), which is a transcription factor that regulates the differentiation of hematopoietic stem cells into mature blood cells. Chromosomal translocations involving RUNX1 are associated with several types of leukemia including AML. Overall, the heterogeneity of acute leukemia complicates treatment selection and limits treatment options. There are no approved targeted therapies for menin-dependent acute leukemias such as KMT2A- r or NPM1-m AML. Additional menin-dependent genetic alterations include NUP98 rearrangements.

[0013] Standard-of-care (SOC) treatment for newly diagnosed AML in medically fit patientsincludes remission induction (“induction”) therapy with intensive chemotherapy – cytarabine combined with an anthracycline, usually daunorubicin or idarubicin, in a “7+3” regimen (or an alternative regimen, such as VYXEOS®, a daunorubicin / cytarabine liposomal formulation), followed by consolidation therapy; this approach has been used for more than 40 years. However, intensive chemotherapy has a range of challenging side effects and is inappropriate for certain patients, such as the elderly or patients with significant cardiac, pulmonary, or other comorbidities. The majority of elderly or unfit patients are treated with less intensive therapies such as BCL-2 inhibitors, hypomethylating agents (HMAs), low-dose cytarabine, or best supportive care. With the recent approval of venetoclax (ven) in combination with an HMA (azacitidine (aza) or decitabine) or low-dose cytarabine or arabinosylcytosine cytarabine (Ara- C), these ven combinations have become SOC for newly diagnosed AML in elderly (75 years or older) or unfit adults. Although the combination of ven and aza is not approved for relapsed / refractory (R / R) AML patients, physicians commonly prescribe this combination based on evidence of clinical activity reported in retrospective analyses and guidelines from the National Comprehensive Cancer Network.WSGR Reference No.47535-753.601

[0014] Despite the broad use of these approaches, outcomes with standard chemotherapy,particularly for KMT2A-r and NPM1-m AML patients, remain unsatisfactory. Although improvements in supportive care have improved overall survival (OS), up to 30-40% of patients will have refractory disease, and these patients have a median survival of less than one year. (Horibata et al., Proc. Natl. Acad. Sci.2019, 116(21), 10494-10503.) The presence of an NPM1 mutation is correlated with refractory risk to standard intensive induction therapy, as more than 50% of adult patients and about 80% of elderly NPM1-m AML patients who respond to induction therapy will relapse, e.g., within one to three years, or will suffer from treatment- related mortality. (Horibata, 2019; Wang et al., Blood 2020, 136(Suppl.1), 7.) While patients with NPM1-m AML have high response rates to frontline therapy, relapse rates are high and survival outcomes are poor, with only 30% overall survival at 12 months in the R / R setting. Adult patients with NPM1-m AML and select co-mutations, such as FLT3, DNMT3A and IDH1 / 2, and / or R / R disease have a poor prognosis, with median overall survival of only approximately 7.8 months in 2nd line, 5 months in 3rd line, and 3.5 months following the 4th line. Adult patients with KMT2A-r AML have a poor prognosis with high rates of resistance and relapse following standard of care, with median overall survival for this patient population of only 6 months following 2nd line and 2.4 months following 3rd line. No FDA-approved therapies targeting NPM1-m and KMT2A-r AML currently exist.

[0015] There remains a need for new therapeutic treatments for acute leukemias, includingmenin-dependent subtypes with high unmet need such as NPM1-m and KMT2A-r AML. Menin inhibition downregulates HOXA9 / MEIS1 expression, leading to differentiation of leukemic blasts. Thus, menin inhibitors may provide targeted therapeutic options for these difficult to treat leukemias and may demonstrate improve response rates, prolonged response durations, suitable preparation for stem cell transplants, and other beneficial impacts, with lower risk of significant toxicity, such as differentiation syndrome-suspect adverse events, differentiation syndrome, tumor lysis syndrome, QTc prolongation or other cardiac adverse events, or myelosuppression (e.g., neutropenia or cytopenia), and without significant CYP3A inhibition (e.g., CYP3A4 inhibition) that would require co-administration of a CYP3A or CYP3A4 inhibitor and / or without significant risk of drug-drug interactions. Described herein are methods of treating acute leukemia with a menin inhibitor as part of a combination therapy, where the combination provides one or more of these advantages relative to standard-of-care treatment or relative to comparative menin inhibitor treatments.WSGR Reference No.47535-753.601 Menin Inhibitors

[0016] In some embodiments, the menin inhibitor is a compound that inhibits the menin-KMT2A interaction. As used herein, reference to a menin inhibitor includes the menin inhibitor compound, an isotopolog thereof, or a pharmaceutically acceptable salt of such compound or isotopolog, or a solvate of any of the foregoing (collectively, the menin inhibitor or “a pharmaceutically acceptable form thereof”).

[0017] In some embodiments, the menin inhibitor is a menin inhibitor described in any of U.S.Patent Nos.8,993,552, 9,216,993, 9,505,781, 9,505,782, 10,077,271, 10,160,769, 10,174,041, 10,246,464, 10,588,907, 10,752,639, 10,781,218, 11,542,248, 11,555,041, 11,649,251, 11,673,898, or RE49,687, each of which disclosure is incorporated by reference herein.

[0018] In some embodiments of the method described herein, the menin inhibitor is acompound of Formula (I-A):or a pharmaceutically acceptable form thereof, wherein: (a) H is selected from C5-12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50; A is selected from bond, C3-12carbocycle, and 3- to 12-membered heterocycle; B is selected from C3-12 carbocycle and 3- to 12-membered heterocycle; and C is 3- to 12-membered heterocycle; or (b) H is selected from C3-12carbocycle and 3- to 12-membered heterocycle;each of Z1, Z2, Z3, and Z4is independently selected from -C(RA1)(RA2)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(O)-, wherein no more than one of Z1, Z2, Z3, and Z4is -C(O)- or -C(RA1)(RA2)-C(O)-; RA1is, at each occurrence, independently selected from hydrogen and R50; RA2is, at each occurrence, independently selected from hydrogen and R50; each of Z5and Z6is independently selected from -C(H)- and -N-;WSGR Reference No.47535-753.601 B is selected from C3-12 carbocycle and 3- to 12-membered heterocycle; and C is selected from bond, C3-12 carbocycle, and 3- to 12-membered heterocycle; L1, L2, and L3are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)-; and alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R50, wherein two R50groups attached to the same atom or different atoms of any one of L1, L2, or L3can together optionally form a bridge or ring; RA, RB, and RCare each independently selected at each occurrence from R50; or two RAgroups, two RBgroups, or two RCgroups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50is independently selected at each occurrence from: halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), and -P(O)(NR52)2; or two R50groups attached to the same atom taken together form =O, =S, or =N(R52); C1-10alkyl, C2-10alkenyl, and C2-10alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52),WSGR Reference No.47535-753.601 -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12- membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R50is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R51is independently selected at each occurrence from: hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12carbocycle, and 3- to 12- membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R51is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6WSGR Reference No.47535-753.601 alkenyl, and C2-6 alkynyl; R52is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20alkynyl, 1- to 6-membered heteroalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6- membered heterocycle; R53and R54are taken together with the nitrogen atom to which they are attached to form a heterocycle; and R57is selected from: halogen, -NO2, -CN, -SR52, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)NH(C1-6alkyl), -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =S, and =N(R52); and C1-10alkyl, C2-10alkenyl, and C2-10alkynyl, each of which is substituted at each occurrence with one or more substituents independently selected from -NO2, -CN, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =S, and =N(R52).

[0019] In some embodiments, the menin inhibitor is a compound of Formula (I-B):or a pharmaceutically acceptable form thereof, wherein: H is selected from C5-12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50; A, B, and C are each independently selected from C3-12 carbocycle and 3- to 12-membered heterocycle;WSGR Reference No.47535-753.601 L1and L2are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)-; and alkylene,alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R50; L3is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56and optionally further substituted with one or more R50; RA, RB, and RCare each independently selected at each occurrence from R50; or two RAgroups, two RBgroups, or two RCgroups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50is independently selected at each occurrence from: halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), and -P(O)(NR52)2; or two R50groups attached to the same atom taken together form =O, =S, or =N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12carbocycle, and 3- to 12- membered heterocycle; andWSGR Reference No.47535-753.601 C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6 alkynyl; R51is independently selected at each occurrence from: hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54; C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12- membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6 alkynyl;WSGR Reference No.47535-753.601 R52is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12carbocycle, or 3- to 6- membered heterocycle; R53and R54are taken together with the nitrogen atom to which they are attached to form a heterocycle; R56is independently selected at each occurrence from: -NO2, -OR59, -SR52, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; or two R56groups attached to the same atom taken together form =O, =S, or =N(R52); wherein each C1-10alkyl, C2-10alkenyl, and C2-10alkynyl in R56is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12- membered heterocycle; wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R56is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52),WSGR Reference No.47535-753.601 -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and further wherein R56optionally forms a bond to ring C; and R59is independently selected at each occurrence from C1-20alkyl, C2-20alkenyl, C2-20alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12carbocycle, or 3- to 6-membered heterocycle.

[0020] In some embodiments, for a compound of Formula (I-A) or (I-B), RC is selected from-C(O)R52, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, =O, C1-3alkyl, and C1-3haloalkyl; or two RCgroups attached to different atoms can together form a C1-3bridge.

[0021] In some embodiments of Formula (I-B):each of Z1, Z2, Z3, and Z4is independently selected from -C(RA1)(RA2)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(O)-, wherein no more than one of Z1, Z2, Z3, and Z4is -C(O)- or -C(RA1)(RA2)-C(O)-; RA1is, at each occurrence, independently selected from hydrogen and R50; RA2is, at each occurrence, independently selected from hydrogen and R50; and each of Z5and Z6is independently selected from -C(H)- and -N-;

[0022] In some embodiments of Formula (I-A) or Formula (I-B), A isWSGR Reference No.47535-753.601

[0023] In some embodiments, the menin inhibitor is a compound of Formula (II-A):or a pharmaceutically acceptable form thereof, wherein: C is selected from C3-12carbocycle and 3- to 12-membered heterocycle; L2is selected from bond, -C(O)-, -C(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -C(NR51)-, -S(O)2-, -S(O)O-, -S(O)-, -S(O)2O-, S(O)2N(R51)-, and -S(O)N(R51)-; and alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R50; L3is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56and optionally further substituted with one or more R50; R1and R3are each independently selected from hydrogen and R50; R2is R50; RA, RB, and RCare each independently selected at each occurrence from R50; or two RAgroups, two RBgroups, or two RCgroups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50is independently selected at each occurrence from: halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, and -P(O)(R52)2; or two R50groups attached to the same atom taken together form =O,WSGR Reference No.47535-753.601 =S, or =N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C3-12carbocycle, and 3- to 12-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R51is independently selected at each occurrence from: hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, and -C(O)NR53R54; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R51is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52,WSGR Reference No.47535-753.601 -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl; R52is independently selected at each occurrence from hydrogen; and C1-20alkyl, C2-20alkenyl, C2-20 alkynyl, C1-6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12carbocycle, or 3- to 6-membered heterocycle; R53and R54are taken together with the nitrogen atom to which they are attached to form a heterocycle; R56is independently selected at each occurrence from: -NO2, -OR59, -SR52, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle; or two R56groups attached to the same atom taken together form =O, =S, or =N(R52); wherein each C1-10alkyl, C2-10alkenyl, and C2-10alkynyl in R56is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C3-12carbocycle, and 3- to 12-membered heterocycle; wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R56is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;WSGR Reference No.47535-753.601 and further wherein R56optionally forms a bond to ring C; and R59is independently selected at each occurrence from C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C1-6heteroalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12carbocycle, or 3- to 6-membered heterocycle.

[0024] In some embodiments, the menin inhibitor is a compound of Formula (III-A):or a pharmaceutically acceptable form thereof, wherein R2, each RB, each RC, L3, C, and p are each defined as described for Formula (II-A).

[0025] In some embodiments, the menin inhibitor is a compound of Formula (IV-A) orFormula (IV-B):or a pharmaceutically acceptable form thereof, wherein R2, R56, and RCare each defined as described for Formula (II-A).

[0026] In some embodiments, the menin inhibitor is ziftomenib:WSGR Reference No.47535-753.601 or a pharmaceutically acceptable form thereof, such as a pharmaceutically acceptable salt or solvate thereof.

[0027] In some embodiments, the menin inhibitor is a compound of Formula (I-A), (I-B), (II-A), (III-A), (IV-A), or (IV-B), or a pharmaceutically acceptable form thereof. In some embodiments, wherein the menin inhibitor is ziftomenib or a pharmaceutically acceptable form thereof.

[0028] The compound of Formula (I-A), Formula (I-B), Formula (II-A), Formula (III-A),Formula (IV-A), or Formula (IV-B) (e.g., ziftomenib) may be synthesized by methods described in U.S. Pat. No.10,781,218 or other U.S. patents described herein.

[0029] In some embodiments, the menin inhibitor is a menin inhibitor described in U.S. PatentNo.10,683,302, which disclosure is incorporated by reference herein. In some embodiments, the menin inhibitor is a compound of Formula (A-I):or a pharmaceutically acceptable form thereof, wherein: A, B, D, and E are each independently selected from —C(RA1)(RA2)—, —C(RA1)(RA2)— C(RA1)(RA2)—, —C(RA1)(RA2)—O—, —C(RA1)(RA2)—NRA3—, —C(═O)—, C(RA1)(RA2)—C(═O)—, and —N═C(NH2)— wherein no more than one of A, B, D, and E is —C(RA1)(RA2)—O—, —C(RA1)(RA2)—NRA3—, —C(RA1)(RA2)—C(═O)—, —C(═O)—, or —N═C(NH2)—; U is N or CRU, wherein RUis H, halo, CN, OH, C1-4alkyl, C1-4alkoxy, amino, C1-4alkyl amino, or C2-8 dialkylamino; W is N or CRW, wherein RWis H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, amino, C1-4 alkyl amino, or C2-8dialkylamino; X is N or CRX, wherein RXis H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, amino, C1-4 alkyl amino, or C2-8 dialkylamino, wherein when X is N, the atom of L that is directly bonded with X is other than N, O, or S; L is selected from —C1-6alkylene- and —(C1-4alkylene)a-Q-(C1-4alkylene)b-, wherein the C1-6 alkylene group and any C1-4 alkylene group of the —(C1-4 alkylene)a-Q-(C1-4 alkylene)b-WSGR Reference No.47535-753.601 group is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3alkyl)amino; Q is —O—, —S—, —S(═O)—, —S(═O)2—, —C(═O)—, —C(═O)NRq1—, —C(═O)O—, —OC(═O)NRq1—, —NRq1—, —NRq1C(═O)O—, —NRq1C(═O)NRq1—, —S(═O)2NRq1—, —C(═NRq2)—, or —C(═NRq2)—NRq1—, wherein each Rq1is independently selected from H or C1-6alkyl, and wherein each Rq2is independently selected from H, C1-6alkyl, and CN; Cy is a linking C6-14 aryl, C3-18 cycloalkyl, 5-16 membered heteroaryl, or 4-18 membered heterocycle group, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each RCyis independently selected from halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2- 6 alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycle, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycle are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; R1is H, Cy1, halo, C1-6alkyl, C1-4haloalkyl, C1-4cyanoalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -NO2, -ORa2, -SRa2, -C(O)Rb2, -C(O)NRc2Rd2, -C(O)ORa2, -OC(O)Rb2, -OC(O)NRc2Rd2, -C(═NRe2)NRc2Rd2, -NRc2C(═NRe2)NRc2Rd2, -NRc2Rd2, -NRc2C(O)Rb2, -NRc2C(O)ORa2, -NRc2C(O)NRc2Rd2, -NRc2S(O)Rb2, -NRc2S(O)2Rb2, -NRc2S(O)2NRc2Rd2, -S(O)Rb2, -S(O)NRc2Rd2, -S(O)2Rb2and -S(O)2NRc2Rd2, wherein said C1-6alkyl, C2-6alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, -CN, -NO2, -ORa2, -SRa2, -C(O)Rb2, -C(O)NRc2Rd2, -C(O)ORa2, -OC(O)Rb2, -OC(O)NRc2Rd2, -C(═NRe2)NRc2Rd2, -NRc2C(═NRe2)NRc2Rd2, -NRc2Rd2,WSGR Reference No.47535-753.601 -NRc2C(O)Rb2, -NRc2C(O)ORa2, -NRc2C(O)NRc2Rd2, -NRc2S(O)Rb2, -NRc2S(O)2Rb2, -NRc2S(O)2NRc2Rd2, -S(O)Rb2, -S(O)NRc2Rd2, -S(O)2Rb2, and -S(O)2NRc2Rd2; Y is O, S, CRY1RY2or NRY3, wherein RY1, RY2, and RY3are each independently selected from H and C1-4alkyl; Z is Cy2, halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, -CN, -NO2,S(O)NRc3Rd3, S(O)2Rb3, S(O)2NRc3Rd3, and P(O)Rc3Rd3wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Cy2, halo, CN, NO2, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; each R2and R3is independently selected from H, halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6alkenyl, C2-6alkynyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(═NRe4)NRc4Rd4, NR4C(═NRe4)NRc4Rd4, NRc4Rd4, NR4C(O)Rb4, NR4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; each RA1is independently selected from H, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, amino, C1-4alkylamino, C2-8dialkylamino, CN, NO2, and OH; each RA2is independently selected from H, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1- 4 haloalkoxy, amino, C1-4alkylamino, C2-8dialkylamino, CN, NO2, and OH; each RA3is independently selected from H, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C(O)Rz, and C(O)ORz, wherein said C1-4 alkyl is optionally substituted by phenyl, C1-4 alkoxy, C1- 4 haloalkoxy, CN, NO2, or OH; Rzis H, C1-4alkyl, or phenyl;WSGR Reference No.47535-753.601 each Cy1is independently selected from C6-14 aryl, C3-18 cycloalkyl, 5-16 membered heteroaryl, and 4-18 membered heterocycle, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy1, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each Cy2is independently selected from C6-14 aryl, C3-18 cycloalkyl, 5-16 membered heteroaryl, and 4-18 membered heterocycle, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy2, wherein the heteroaryl or has 1-3 rings and 1- 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each RCy1and RCy2is independently selected from halo, C1-6alkyl, C1-4haloalkyl, C1-4cyanoalkyl, C2-6alkenyl, C2-6alkynyl, phenyl, C3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycle, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5,NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRC5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycle are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5,NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, Rd4, Ra5, Rb5, Rc5, and Rd5is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycle, C6-10 aryl- C1-6alkyl, C3-10cycloalkyl-C1-6alkyl, (5-10 membered heteroaryl)-C1-6alkyl, and (4-10 membered heterocycle)-C1-6alkyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycle, C6-10 aryl- C1-6alkyl, C3-10cycloalky-C1-6alkyl, (5-10 membered heteroaryl)-C1-6alkyl, and (4-10 membered heterocycle)-C1-6alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each Re1, Re2, Re3, Re4, and Re5is independently selected from H, C1-4alkyl, and CN;WSGR Reference No.47535-753.601 each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkyl, HO—C1-3alkyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, thiol, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carboxy, aminocarbonyl, C1-6alkylcarbonyl, and C1-6 alkoxycarbonyl; n is 0 or 1; m is 0 or 1; p is 0, 1, 2, or 3; q is 0, 1, or 2; a is 0 or 1; and b is 0 or 1, wherein any cycloalkyl or heterocycle group is optionally further substituted by 1 or 2 oxo groups.

[0030] In one embodiment, the menin inhibitor is SNDX-5613 (revumenib):(revumenib) or a pharmaceutically acceptable form thereof.

[0031] In another embodiment, the menin inhibitor is VTP-50469:; or a pharmaceutically acceptable form thereof.WSGR Reference No.47535-753.601

[0032] In some embodiments, the menin inhibitor is a menin inhibitor described in U.S. Pat.Publ. No.20210269454, which disclosure is incorporated by reference herein. In some embodiments, the menin inhibitor is a compound of Formula (A-II):wherein the dotted circle indicates that the ring is aromatic, R1and R2are each independently a hydrogen atom or a C1-6 alkyl group, one of R3and R4is a hydrogen atom, a hydroxy group, a halogen atom, a C1-6 alkoxy group, a di(C1-6 alkyl)carbamoyl group, or an oxazolyl group, and the other of R3and R4is a hydrogen atom, a hydroxy group, a halogen atom, or a C1-6alkoxy group, R5is a hydrogen atom, a C1-6 alkyl group, or a hydroxy C1-6 alkyl group, R6is a hydrogen atom, a C1-6 alkyl group, a halogen atom, a C1-6 alkoxy group, an amino group, or a C1-6alkylamino group, R7and R8are taken together with the carbon atom to which R7is bonded and the carbon atom to which R8is bonded to form any of the following formulas (2A) to (2C):wherein the dotted circle indicates that the ring is aromatic, the carbon atom marked with a is the carbon atom to which R8is bonded, the carbon atom marked with b is the carbon atom to which R7is bonded, X is CH or a nitrogen atom, and R9is a halogen, C1-6 alkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl C1-6 alkyl group, a C1-6 alkoxy C1-6 alkyl group, or an oxetanyl group, or R7is a hydrogen atom, and R8is the following formula (3):WSGR Reference No.47535-753.601 wherein * indicates a bonding site, R10is a di(C1-6alkyl) carbamoyl group, a (C1-6alkyl)pyrimidinyl group, a (C1-6alkyl)phenyl group, or a (C1-6alkyl)pyrazolyl group, R11is a hydrogen atom or a halogen atom, and R12is a halogen atom, m is 1 or 0, n is 1 or 2, Ring Q1is a 6-membered aromatic ring optionally containing one nitrogen atom in the ring (the aromatic ring optionally has one or two substituents independently selected from the following Group A), a 5-membered aromatic heterocycle containing, in the ring, one or two heteroatoms independently selected from the group consisting of a nitrogen atom and a sulfur atom (the aromatic heterocycle optionally has one substituent independently selected from the following Group A), a C3-8cycloalkane ring optionally having one substituent independently selected from the following Group A, a C4-8 cycloalkene ring optionally having one substituent independently selected from the following Group A, a 4- to 8-membered saturated heterocycle containing one nitrogen atom in the ring (the saturated heterocycle optionally has one substituent independently selected from the following Group A), or a 9-membered bicyclic aromatic heterocycle containing one nitrogen atom in the ring (the bicyclic aromatic heterocycle optionally has one or two substituents independently selected from the following Group B), and W is the following formula (4A) or (4B):wherein * indicates a bonding site, Ring Q2is a 6-membered aromatic ring optionally containing one nitrogen atom in the ring (the aromatic ring optionally has one to three substituents independently selected from the following Group C), a 6-membered aromatic heterocycle containing two nitrogen atoms in the ring (the aromatic heterocycle optionally has one to three substituents independently selected from the following Group C), a 5-membered aromatic heterocycle containing, in the ring, one to threeWSGR Reference No.47535-753.601 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (the aromatic heterocycle optionally has one substituent independently selected from the following Group C), a 9- or 10-membered bicyclic aromatic or partially unsaturated heterocycle containing, in the ring, one to three heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom (the bicyclic aromatic or partially unsaturated heterocycle optionally has one or two substituents independently selected from the following Group D), a 5- to 8-membered saturated heterocycle containing, in the ring, one or two heteroatoms independently selected from the group consisting of an oxygen atom and a nitrogen atom (the saturated heterocycle optionally has one substituent independently selected from the following Group E), or a C3-8cycloalkane ring optionally having one substituent independently selected from the following Group E, Ring Q3is a 4- to 8-membered saturated heterocycle containing one nitrogen atom or one oxygen atom in the ring (the saturated heterocycle optionally has one C1-6alkylsulfonyl group), or a 6-membered aromatic ring optionally containing one nitrogen atom in the ring (the aromatic ring optionally has one substituent independently selected from the following Group F), Y is a single bond or an oxygen atom, and Z is a single bond, an oxygen atom, —NH—, —SO2—, a C1-6alkylene group, *—R13—wherein * is bonded to Ring Q2, ** is bonded to Ring Q1, and R13, R14and R15are each independently a C1-6alkylene group, Group A: a halogen atom, a hydroxy group, a C1-6 alkyl group, a C1-6 alkoxy group, a hydroxy C1-6 alkoxy group, a vinylsulfonylamino(C1-6 alkyl)carbamoyl group, and a prop-2- enoylamino(C1-6alkyl)carbamoyl group, Group B: a cyano group, a C1-6 alkyl group, a halogen atom, and a C1-6 alkoxy group, Group C: a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyl(C1-6alkylsulfonyl)amino group, a cyano group, a C1-6alkylsulfonyl group, a C1-6alkylamino group, a di(C1-6alkyl)amino group, a halogeno C1-6alkyl group, a C1-6alkoxy C1-6alkoxy group, a halogeno C1-6 alkoxy group, a C1-6 alkylsulfonyl C1-6 alkyl group, a di(C1-6 alkyl)sulfamoyl group, a C1-6alkylenedioxy group, a (C1-6alkyl)carbamoyl group, a hydroxy C1-6alkyl group, a 2-C3-6alkenoylamino group, a C1-6alkyl (2-C3-6alkenoyl)amino group, a hydroxy group, an oxo group, a -OC(2H)3 group, and a -N[(C(2H)3]2 group, Group D: a halogen atom, a C1-6 alkyl group, and a C1-6 alkylsulfonyl group, Group E: an oxo group, a hydroxy group, and a C1-6alkoxy group, and Group F: a halogen atom, and a C1-6 alkoxy group.WSGR Reference No.47535-753.601

[0033] In some embodiments, the menin inhibitor is Compound A:Compound A, or a pharmaceutically acceptable form thereof.

[0034] In some embodiments, the menin inhibitor is a menin inhibitor described in PCT Publ.No. WO2021 / 121327, which disclosure is incorporated by reference herein. In some embodiments, the menin inhibitor is a compound of Formula (A-III):or a pharmaceutically acceptable form thereof, wherein R1arepresentsHet represents a 5- or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein said 5- or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C3-6cycloalkyl and C1-4alkyl; Rxaand Rxbare each independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6cycloalkyl; R1brepresents F or Cl; Y1represents -CR5aR5b-, -O- or -NR5c-; R2is selected from the group consisting of hydrogen, halo, C1-4alkyl, -O-C1-4alkyl, and - NR7aR7b; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2;WSGR Reference No.47535-753.601 X1represents CH, and X2represents N; R4represents isopropyl; R5a, R5b, R5c, R7a, and R7b, are each independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6cycloalkyl; R3represents -C1-6alkyl-NR8aR8b, C1-6alkyl-C(=O)-NR9aR9b, -C1-6alkyl-OH, or -C1-6alkyl-NR11- C(=O)-O-C1-4alkyl-O-C(=O)-C1-4alkyl; wherein each of the C1-4alkyl or C1-6alkyl moieties in the R3definitions independently of each other may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-C1-4alkyl; R8aand R8bare each independently selected from the group consisting of hydrogen; C1-6alkyl; - C(=O)-C1-4alkyl; -C(=O)-O-C1-4alkyl; -C(=O)-NR12R12b); and C1-6a1ky1 substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-C1-4alkyl, -O-C1-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-C1-4alkyl; R9a, R9b, R10a, R10b, R10c, R11, R12a, and R12bare each independently selected from the group consisting of hydrogen and C1-6alkyl.

[0035] In one embodiment, the menin inhibitor is Compound B1:or a pharmaceutically acceptable form thereof.

[0036] In one embodiment, the menin inhibitor is Compound B2:or a pharmaceutically acceptable form thereof.WSGR Reference No.47535-753.601

[0037] In some embodiments, the menin inhibitor is a menin inhibitor described in U.S. PatentNo.11,084,825, which disclosure is incorporated by reference herein. In some embodiments, the menin inhibitor is a compound of Formula (A-IV):(A-IV) or a pharmaceutically acceptable form thereof, wherein: A is N; Cy is:wherein: Q is =N—, —NH—, —O—, or —S—; and Z is —CR5a= or —N=; wherein Cy is optionally substituted with one or more independently selected R7substituents; X is —C(R3b)2—, —NR3a-, or —O—; W is —C(O)—, —S(O)—, or —S(O)2—;WSGR Reference No.47535-753.601 Y is a single bond, —C(R3b)2—, —NR3a—, or —O—; (i) R1is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; and R2is CH2—Cy2-NHC(O)—C(R6a)═C(R6b)(R6c) or Cy2-NHC(O)—C(R6a)═C(R6b)(R6c); or (ii) R1is CH2—Cy2-NHC(O)—C(R6a)═C(R6b)(R6c) or Cy2-NHC(O)—C(R6a)═C(R6b)(R6c); and R2is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; each R3ais independently H or C1-6alkyl; each R3bis independently H or C1-6alkyl; each R4ais independently H, halo, CN, C1-6 alkyl, C(O)R, C(O)N(R)2, C(O)OR, N(R)2, NRC(O)R, OR, S(O)2R, C3-7cycloalkyl, a 4- to 7-membered heterocycloalkyl ring, phenyl, an 8- to 10-membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the 4- to 7- membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each R4bis independently H, halo, CN, C1-6 alkyl, C(O)R, C(O)N(R)2, C(O)OR, N(R)2, NRC(O)R, OR, S(O)2R, C3-7cycloalkyl, a 4- to 7-membered heterocycloalkyl ring, phenyl, an 8- to 10-membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the 4- to 7- membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each R7is independently a 4- to 7-membered heterocycloalkyl ring, phenyl, an 8- to 10- membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein each 4- to 7- membered heterocycloalkyl ring independently has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and each 5- or 6-membered heteroaryl ring independently has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each 4- to 7-membered heterocycloalkyl ring, phenyl, 8- to 10-membered bicyclic aryl ring, and 5- or 6-membered heteroaryl ring is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, OH, and O(C1-6 alkyl); each R is independently H, C1-6 aliphatic, a saturated or partially unsaturated 4- to 7-membered heterocyclic ring, phenyl, an 8- to 10-membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the saturated or partially unsaturated 4- to 7-membered heterocyclicWSGR Reference No.47535-753.601 ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or two geminal R groups, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 4- to 7-membered heterocyclic ring or a 5- or 6-membered heteroaryl ring, wherein the 4- to 7-membered heterocyclic ring or the 5- or 6-membered heteroaryl ring has 0, 1, 2, or 3 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R5ais H, halo, CN, C1-6alkyl, or C1-6haloalkyl; R6ais H or C1-6alkyl; R6bis H or C1-6 alkyl; or R6aand R6b, joined together, form a single bond; R6cis H or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with N(CH3)2; Cy2is a 4- to 7-membered heterocycloalkyl ring, phenyl, or pyridyl, wherein the 4- to 7- membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; m is 1, 2, or 3; and n is 1, 2, 3, or 4.

[0038] In one embodiment, the menin inhibitor is Compound C:Compound C, or a pharmaceutically acceptable form thereof.

[0039] In some embodiments, the menin inhibitor is ziftomenib, SNDX-5613 (revumenib),VTP-50469, JNJ-75276617, DS-1594, DS-1594a, DS-1594b, DSP-5336, MI-3454, M-808, A300-105A, BN104, Compound A, Compound B1, Compound B2, or Compound C, or a pharmaceutically acceptable form thereof.

[0040] The compound DSP-5336 has the following structure:WSGR Reference No.47535-753.601.

[0041] In some embodiments, the menin inhibitor is ziftomenib, SNDX-5613 (revumenib),VTP-50469, JNJ-75276617, Compound A, Compound B1, Compound B2, or Compound C, or a pharmaceutically acceptable form thereof.

[0042] In some embodiments, the menin inhibitor is ziftomenib, SNDX-5613 (revumenib),VTP-50469, or Compound A, or a pharmaceutically acceptable form thereof. Ziftomenib and Pharmaceutically Acceptable Forms

[0043] Ziftomenib (KO-539; alternatively named as (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4- (methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile) is potent and selective inhibitor of the menin-KMT2A(MLL) complex that has downstream effects on HOXA9 / MEIS1 expression. (Burrows et al., Proceedings of the AACR EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl): Abstract nr LB-A27.)

[0044] Ziftomenib is in clinical development for the treatment of acute leukemias, includingas a monotherapy in relapsed / refractory NPM1-m or KMT2A-r AML, and other genetically defined acute leukemia subgroups with high unmet need. KOMET-001 (NCT04067336) is a Phase 1 / 2 open-label study to evaluate the safety and tolerability, pharmacokinetics, and anti- tumor activity of ziftomenib in adult patients with relapsed and / or refractory AML, including select NPM1 mutations or KMT2A rearrangements. (See https: / / kuraoncology.com / clinical- trials / clinical-trials-komet-001 / , accessed October 2023.) The primary objective of Phase 1 was to determine the recommended phase 2 dose (RP2D) based on safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. A dose of ziftomenib, 600 mg, once daily, was recommended as the monotherapy RP2D for patients with R / R NPM1- m AML. In 20 patients with NPM1-m AML treated at the RP2D during Phase 1 (once daily, inWSGR Reference No.47535-753.601 28-day cycles), the complete remission (CR) rate was 35% (95% confidence interval [CI], 15.4- 59.2), the composite CR rate was 40%, and the overall response rate was 45% (95% CI, 23.1- 68.5). Median time to response was 51 days (range, 26-225). Median remission duration of composite CR was 7.7 months (95% CI, 1 to not evaluable) in all NPM1-m patients (all doses). Ziftomenib induced marrow blast reduction, neutrophil and platelet recovery, transfusion independence, and clearance of measurable residual disease.

[0045] Treatment-emergent adverse events (TEAEs) of any grade and any dose occurred in98.8% of 83 patients. The most frequent TEAEs (≥10% of patients) were diarrhea (31.3%), nausea (28.9%), anemia (25.3%), febrile neutropenia (22.9%), hypokalemia (22.9%), differentiation syndrome (DS; 21.7%), pneumonia (20.5%), and epistaxis (20.5%). Grade (G) 3 or higher TEAEs (≥10% of patients) were anemia (24.1%), febrile neutropenia (21.7%), pneumonia (19.3%), thrombocytopenia (13.3%), and DS (13.2%). Post-baseline, potentially drug-related QTc prolongation was reported in 1 of 83 (1.2%) patients in the context of DS- induced myocardial ischemia. Two DLTs (G3 pneumonitis at 400 mg and G4 DS at 1000 mg) were reported in phase 1a. The G4 DS culminated in death due to cardiac arrest, resulting in closure of the 1000-mg dose and 800 mg being declared as the MTD. Based on preliminary safety, PK, and activity observed in phase 1a, the 200-mg and 600-mg doses were selected for randomized comparison in KMT2A-r or NPM1-m AML patients to determine the RP2D in phase 1b. In phase 1b, the most common (>10%) G3 or higher TEAEs regardless of dose or subtype were febrile neutropenia (28.3%), anemia (26.4%), DS (20.8%), pneumonia (17%), sepsis (15.1%), thrombocytopenia (15.1% each), and hypoxia (11.3%).

[0046] As a result of a fatal G5 DS event in a KMT2A-r patient at the 200-mg dose in Phase1b, the FDA placed the Phase 1b study on a partial clinical hold in November 2021. Following implementation of DS mitigation strategies, including guidance on recognizing signs and symptoms of emerging menin inhibitor DS especially in extramedullary disease, and when to consider early initiation of systemic steroids and cytoreduction, the FDA lifted the partial clinical hold in January 2022. Although the rate of DS in KMT2A-r patients was similar at the 200-mg and 600-mg doses (46.2% and 43.8%), the rate in KMT2A-r patients was higher than in NPM1-m patients (0% 200 mg and 20.0% 600 mg) and the episodes more severe (22.2% ≥G3 vs 5.0% G3). Further patient enrollment in Phase 1b was limited to NPM1-m AML.

[0047] Across 112 R / R NPM1-m Phase 1b / 2 patients, DR was 18%, CR / CRh was 25%, andORR was 35% (for 92 Phase 2 patients, CR was 14% and CR / CRh was 23%).

[0048] In some embodiments, the menin inhibitor described herein is ziftomenib or apharmaceutically acceptable form thereof. In some embodiments, the methods described hereinWSGR Reference No.47535-753.601 employ a pharmaceutically acceptable form of ziftomenib. In some embodiments, the methods described herein employ ziftomenib or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein employ ziftomenib or a solvate thereof. In certain embodiments, ziftomenib comprises the free base form or a solvate thereof. Also included, in some embodiments, are stereoisomers and / or metabolites of ziftomenib. AML and ALL; Standard-of-Care Therapies for Acute Leukemias

[0049] In some embodiments, the methods provided herein are directed to treating an acuteleukemia. In some embodiments, the acute leukemia is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndrome (MDS).

[0050] AML is a disease of the bone marrow and a disorder of hematopoietic stem cellscharacterized by genetic alterations in blood-cell precursors resulting in overproduction of neoplastic clonal myeloid stem cells. While extramedullary manifestations can occur (e.g., myeloid sarcomas, leukemia cutis), the underlying disease is generally due to abnormalities in hematologic cellular production. In certain embodiments, the AML comprises relapsed AML, refractory AML, or both relapsed and refractory AML. In certain embodiments, AML is refractory AML. In certain embodiments, refractory disease is refractory to intensive chemotherapy (first line standard of care), including cytarabine and an anthracycline (idarubicin or daunorubicin), typically administered as a “7+3” combination of a continuous infusion of cytarabine and intermittent dosing of the anthracycline administered over 7 days and 3 days, respectively. In some embodiments, the AML has progressed during or after treatment with 7+3 therapy. In certain embodiments, the first line standard of care for newly diagnosed AML in patients ineligible or unfit for the 7+3 regimen is ven / aza. In some embodiments, the AML is resistant or refractory to ven or ven / aza. In some embodiments, the AML has progressed during or after treatment with ven or ven / aza. In some embodiments, the AML is resistant to or refractory to a different menin inhibitor than that administered in the present methods. In some embodiments, a different menin inhibitor than that administered in the present methods is not tolerated by the subject (e.g., due to adverse events or dose-limiting toxicity, or due to the level of risk of an adverse event such as QTc prolongation, or due to other medications the subject is taking, such as CYP3A4 inhibitors). In some embodiments, the AML is relapsed AML. In some embodiments, the AML is both refractory and relapsed AML. In some embodiments, the AML is acute promyelocytic leukemia, acute myeloblastic leukemia, or acute megakaryoblastic leukemia.WSGR Reference No.47535-753.601

[0051] In some embodiments, the methods provided herein are directed to ALL. ALL is atype of cancer of the blood and bone marrow involving uncontrolled proliferation of abnormal, immature lymphocytes, leading to the replacement of bone marrow and invasion of the blood. In certain embodiments, the ALL comprises relapsed ALL, refractory ALL, or both relapsed and refractory ALL. In certain embodiments, ALL is refractory ALL. In some embodiments, the ALL is relapsed ALL. In some embodiments, the ALL is both refractory and relapsed ALL. In some embodiments, the ALL is precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, or acute biphenotypic leukemia.

[0052] MDS is a cancer in which immature blood cells in bone marrow do not mature orbecome healthy blood cells. In some embodiments, the MDS is refractory anemia, refractory anemia with ring sideroblasts, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, MDS (unclassifiable), MDS associated with an isolated del(5q) chromosome abnormality, or chronic myelomonocytic leukemia (CMML).

[0053] In some embodiments, described herein is a method of treating acute leukemia with amenin inhibitor and a standard-of-care therapy. In some embodiments, the standard-of-care therapy comprises: a BCL-2 inhibitor, a hypomethylating agent, a nucleoside metabolic inhibitor (such as a cytosine arabinoside), a topoisomerase inhibitor, a DNA synthesis inhibitor, or a granulocyte colony-stimulating factor, or any combination thereof.

[0054] In some embodiments, the standard-of-care therapy comprises the BCL-2 inhibitor, thehypomethylating agent, or the BCL-2 inhibitor and the hypomethylating agent. In some embodiments, the BCL-2 inhibitor is ven, navitoclax, obatoclax, oblimersen sodium, or ABT- 737. In some embodiments, the BCL-2 inhibitor is ven. In some embodiments, ven is administered at a dose of from 10 to 400 mg per day. In some embodiments, ven is administered using a 3-day ramp-up of 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 and thereafter (e.g., for combinations with an HMA), or 400 mg on day 3, and 600 mg thereafter (e.g., for combinations with low-dose cytarabine). In the case of co-administration of a CYP3A inhibitor or P-gp inhibitor, ven may be administered using a 4-day ramp-up of 10 mg, 20 mg, 50 mg, and 70 mg thereafter (e.g., combination with posaconazole), or of 10 mg, 20 mg, 50 mg, and 100 mg thereafter (e.g., combination with a strong CYP3A inhibitor), or using a reduced dose of at least 50% (e.g., combinations with a moderate CYP3A inhibitor or P-gp inhibitor). In some embodiments, the BCL-2 inhibitor, such as ven, is administered at a dose and dosing regimen as described in the manufacturer’s Prescribing Information.WSGR Reference No.47535-753.601

[0055] In some embodiments, the hypomethylating agent is aza. In some embodiments, aza isadministered subcutaneously or intravenously at a dose of 75 mg / m2on 5 to 7 of the first 7 days of an induction cycle (e.g., Days 1-7 or 5 days on 2 off during Days 1-7). In some embodiments, aza is administered during Cycle 1 and optionally in subsequent cycles, for example, depending on bone marrow biopsy results. In some embodiments, the hypomethylating agent is decitabine. In some embodiments, the hypomethylating agent, such as aza, is administered at a dose and dosing regimen as described in the manufacturer’s Prescribing Information.

[0056] In some embodiments, the standard-of-care therapy comprises the nucleosidemetabolic inhibitor (e.g., a cytosine arabinoside), the topoisomerase inhibitor, or the nucleoside metabolic inhibitor (e.g., a cytosine arabinoside) and the topoisomerase inhibitor. In some embodiments, the cytosine arabinoside is cytarabine or cytarabine arabinoside (Ara C). In some embodiments, the topoisomerase inhibitor is an anthracycline agent, or is daunorubicin, idarubicin, doxorubicin, or mitoxantrone, optionally wherein the anthracycline agent is daunorubicin. In some embodiments, the standard-of-care therapy is “7+3” or VYXEOSTM. In some embodiments, the nucleoside metabolic inhibitor (e.g., cytosine arabinoside) and the topoisomerase inhibitor (e.g., an anthracycline) are administered as a “7+3” regimen, with, for example, iv infusion (over 24 hours) of cytarabine at a dose of 100 to 200 mg / m2, or 100 mg / m2, such as continuous iv infusion, on Days 1-7, or 100 to 200 mg / m2, or 100 mg / m2, iv infusion every 12 hours (Days 1-7), and iv infusion of the topoisomerase inhibitor (e.g., an anthracycline), such as 60 to 90 mg / m2daunorubicin or 12 mg / m2idarubicin, on Days 1-3, or 7 mg / m2mitoxantrone on Days 1, 3, and 5, of each induction cycle, for example, one or two induction cycles. In some embodiments, in the second induction cycle, if needed, the anthracycline may be administered on Days 1-2 or Days 1-3. Alternatively, patients may receive the combination via VYXEOSTM, a liposomal combination of daunorubicin and cytarabine, during induction by iv infusion (e.g., on Days 1, 3, and 5 of a first induction cycle at a dose of, for example, 44 mg / m2daunorubicin and 100 mg / m2cytarabine, and on, for example, Days 1 and 3 for subsequent induction cycles, if needed). During one or more consolidation cycles, patients may receive a nucleoside metabolic inhibitor, optionally in combination with a topoisomerase inhibitor, for example: HiDAC (e.g., 3000 mg / m2cytarabine iv over 3 hours every 12 hours on Days 1, 3, and 5 per cycle for patients younger than 60 and w / creatinine clearance of at least 50 mL / min); IDAC (e.g., 1500 mg / m2cytarabine iv over 3 hours every 12 hours on days 1, 3, and 5 for patients 60 and older w / creatinine clearance of 30 to less than 50WSGR Reference No.47535-753.601 mL / min); or VYXEOSTM(e.g., at a dose of 29 mg / m2daunorubicin and 65 mg / m2by iv infusion on Days 1 and 3).

[0057] In some embodiments, the standard-of-care therapy comprises the DNA synthesisinhibitor, the nucleoside metabolic inhibitor (e.g., the cytosine arabinoside), the granulocyte colony-stimulating factor, or the topoisomerase inhibitor, or a combination thereof. In some embodiments, the standard-of-care therapy comprises the DNA synthesis inhibitor, the nucleoside metabolic inhibitor (e.g., the cytosine arabinoside), the granulocyte-colony stimulating factor, and the topoisomerase inhibitor. In some embodiments, the DNA synthesis inhibitor is fludarabine. In some embodiments, the DNA synthesis inhibitor is clofarabine. In some embodiments, the nucleoside metabolic inhibitor is a cytosine arabinoside, such as cytarabine or Ara C. In some embodiments, the topoisomerase inhibitor is an anthracycline agent, or is daunorubicin, idarubicin, doxorubicin, or mitoxantrone, optionally wherein the anthracycline agent is daunorubicin or idarubicin. In some embodiments, the DNA synthesis inhibitor is fludarabine; the cytosine arabinoside is cytarabine; the granulocyte colony- stimulating factor is G-CSF; the topoisomerase inhibitor is daunorubicin or idarubicin, optionally idarubicin; or a combination thereof. In some embodiments, the standard-of-care therapy is FLAG-IDA. In some embodiments, the patient is administered one or more of the agents according to the dosing regimen on the applicable Prescribing Information. For example, components of FLAG-IDA (fludarabine + cytarabine + G-CSF + idarubicin) may be administered according to the details outlined in their respective Prescribing Information during induction (1 or 2 induction cycles). Fludarabine may be administered 30 mg / m2 / day IV on Days 1 to 4, idarubicin may be administered 6 to 10 mg / m2 / day intravenously (IV) on Days 1 to 3, cytarabine may be administered 1500 to 2000 mg / m2 / day IV on Days 1 to 5, and G-CSF should be administered 300 mcg / m2 / day SC from Days 1 to 5. Additional G-CSF may be administered starting Day 6 following completion of chemotherapy until ANC > 1000 / μL. Consolidation cycles may include HiDAC (3000 mg / m2dose of cytarabine by IV over 3 hours every 12 hours on Days 1, 3, and 5 (total dose 18,000 mg / m2)) or IDAC (1500 mg / m2dose of cytarabine by IV over 3 hours every 12 hours on Days 1, 3, and 5 (total dose 9000 mg / m2)) per consolidation cycle.

[0058] In some embodiments, standard-of-care therapy is LDAC, optionally administered as a20 mg dose of cytarabine twice a day (BID) subcutaneously (SC) on Days 1 to 10 of each 28- day cycle (induction and consolidation).

[0059] As described herein, the standard-of-care treatments may be combined with a menininhibitor. In some embodiments, the standard-of-care treatment and the menin inhibitor may beWSGR Reference No.47535-753.601 further combined with another combination agent, such as a targeted therapy. Such combination targeted therapies may include, for example, a FLT3 inhibitor (e.g., midostaurin, gilteritinib, or quizartinib), an IDH inhibitor (such as ivosidenib, olutasidenib, or enasidenib), an XPO1 inhibitor (e.g., selinexor), or an anti-CD33 monoclonal antibody (e.g., gemtuzumab or gemtuzumab ozogamicin). In such embodiments, the menin inhibitor administration is initiated after the lead-in period for the standard-of-care therapy, as described herein, and the combination targeted therapy may be initiated before, at the same time as, or after initiation of the standard-of-care therapy.

[0060] In some embodiments, following induction, and optionally consolidation, patients mayproceed to auto- or allo-HSCT, optionally followed by menin inhibitor treatment as maintenance therapy.

[0061] In some embodiments, the individual to be treated with the menin inhibitor has AML.In some embodiments, the AML is NPM1-m AML. In some embodiments, the AML is R / R NPM1-m AML. In some embodiments, the individual has failed at least one prior line of therapy. In some embodiments, the at least one prior line of therapy comprises a BCL-2 inhibitor, a hypomethylating agent, a nucleoside metabolic inhibitor (such as a cytosine arabinoside), a topoisomerase inhibitor, a DNA synthesis inhibitor, a granulocyte colony- stimulating factor, a menin inhibitor, HSCT, donor lymphocyte infusion (DLI), or any combination thereof. In some embodiments, the at least one prior line of therapy comprises ven, aza, or a menin inhibitor, or any combination thereof. In some embodiments, the patient has not been treated with the at least one prior line of therapy for at least 14 days prior to initiation of the combination therapy described herein. In some embodiments, the individual is treated with the menin inhibitor in combination with a standard-of-care (SOC) therapy. In some embodiments, the standard-of-care therapy comprises the BCL-2 inhibitor, the hypomethylating agent, or the BCL-2 inhibitor and the hypomethylating agent. In some embodiments, the standard-of-care therapy comprises ven, aza or decitabine, or ven and aza or decitabine. In some embodiments, the standard-of-care therapy comprises ven and aza. In some embodiments, the standard-of-care therapy comprises ven.

[0062] In some embodiments, the individual has newly diagnosed NPM1-m AML (e.g., hasnot received a prior therapy for AML). In some embodiments, the individual is a candidate for intensive chemotherapy. In some embodiments, the individual is treated with the menin inhibitor in combination with a standard-of-care (SOC) therapy. In some embodiments, the SOC therapy comprises the nucleoside metabolic inhibitor (e.g., cytosine arabinoside), the topoisomerase inhibitor, or the nucleoside metabolic inhibitor (e.g., cytosine arabinoside) andWSGR Reference No.47535-753.601 the topoisomerase inhibitor. In some embodiments, the cytosine arabinoside is cytarabine. In some embodiments, the topoisomerase inhibitor is an anthracycline agent, optionally wherein the anthracycline agent is daunorubicin or idarubicin, optionally wherein the anthracycline agent is daunorubicin.

[0063] In some embodiments, the individual has newly diagnosed NPM1-m AML. In someembodiments, the individual is treated with the menin inhibitor in combination with a SOC therapy. In some embodiments, the standard-of-care therapy comprises the BCL-2 inhibitor, the hypomethylating agent, or the BCL-2 inhibitor and the hypomethylating agent. In some embodiments, the standard-of-care therapy comprises ven, aza or decitabine, or ven and aza or decitabine. In some embodiments, the standard-of-care therapy comprises ven and aza. In some embodiments, the standard-of-care therapy comprises ven.

[0064] In some embodiments, the individual to be treated with the menin inhibitor has AML.In some embodiments, the AML is KMT2A-r AML. In some embodiments, the AML is R / R KMT2A-r AML. In some embodiments, the individual has failed (e.g., is resistant to or refractory to) at least one prior line of therapy. In some embodiments, the at least one prior line of therapy comprises a BCL-2 inhibitor, a hypomethylating agent, a nucleoside metabolic inhibitor (such as a cytosine arabinoside), a topoisomerase inhibitor, a DNA synthesis inhibitor, a granulocyte colony-stimulating factor, a menin inhibitor, HSCT, donor lymphocyte infusion (DLI), or any combination thereof. In some embodiments, the at least one prior line of therapy comprises ven, aza, or a menin inhibitor, or any combination thereof. In some embodiments, the patient has not been treated with the at least one prior line of therapy for at least 14 days prior to initiation of the combination therapy described herein. In some embodiments, the individual is newly diagnosed with KMT2A-r AML. In some embodiments, the individual is treated with the menin inhibitor in combination with a standard-of-care (SOC) therapy. In some embodiments, the standard-of-care therapy comprises the BCL-2 inhibitor, the hypomethylating agent, or the BCL-2 inhibitor and the hypomethylating agent. In some embodiments, the standard-of-care therapy comprises ven, aza or decitabine, or ven and aza or decitabine. In some embodiments, the standard-of-care therapy comprises ven and aza. In some embodiments, the standard-of-care therapy comprises ven.

[0065] In some embodiments, the individual has newly diagnosed KMT2A-r AML (e.g., hasnot received a prior therapy for AML). In some embodiments, the individual is a candidate for intensive chemotherapy. In some embodiments, the individual is treated with the menin inhibitor in combination with a standard-of-care (SOC) therapy. In some embodiments, the SOC therapy comprises the nucleoside metabolic inhibitor (e.g., cytosine arabinoside), theWSGR Reference No.47535-753.601 topoisomerase inhibitor, or the nucleoside metabolic inhibitor (e.g., cytosine arabinoside) and the topoisomerase inhibitor. In some embodiments, the cytosine arabinoside is cytarabine. In some embodiments, the topoisomerase inhibitor is an anthracycline agent, optionally wherein the anthracycline agent is daunorubicin or idarubicin, optionally wherein the anthracycline agent is daunorubicin.

[0066] In some embodiments, the individual (a) has NPM1-m AML with EuropeanLeukemiaNet (ELN) adverse risk genetics, (b) has NPM1-m AML and is greater than or equal to 60 years of age, (c) has KMT2A-r AML, including KMT2A-r t(9;11) MLLT3-KMT2A, or (d) has treatment-related NPM1-m or KMT2A-r AML. Genetic Alterations in Acute Leukemias

[0067] In some embodiments, the acute leukemia or leukemia cell is characterized by a (e.g.,one or more) genetic alteration. In some embodiments, the acute leukemia or leukemia cell is menin dependent. In some embodiments, the acute leukemia or leukemia cell exhibits a mutation associated with MEIS1 overexpression (e.g., an epigeneric regulator such as ASLX1, DNMT3A, EZH2, IDH1, IDH2, or SETD2; a cohesion complex member such as STAG2; a spliceosome component such as SRSF2 or U2AF1; a myeloid transcription factor such as RUNX1 or CEPBPα; a non-KMT2A fusion such as PICALM-AF10, NUP98-X, NUP214-X, MYST3-X). In some embodiments, the acute leukemia or leukemia cell comprises an NPM1 mutation, a KMT2A rearrangement, a KMT2A-PTD mutation, an SETD2 mutation, a RUNX1 mutation, a FLT3 mutation, a FLT3-ITD, a FLT3-TKD, an IDH mutation, an IDH1 mutation, an IDH2 mutation, a TERT mutation, or a BRAF mutation, or any combination thereof.

[0068] In some embodiments, the acute leukemia or leukemia cell comprises an NPM1mutation. In some embodiments, the acute leukemia or leukemia cell comprises a KMT2A rearrangement. In some embodiments, the acute leukemia or leukemia cell comprises a KMT2A- PTD. In some embodiments, the acute leukemia or leukemia cell comprises an SETD2 mutation. In some embodiments, the acute leukemia or leukemia cell comprises a RUNX1 mutation. In some embodiments, the acute leukemia or leukemia cell comprises an SETD2 mutation and a RUNX1 mutation. In some embodiments, the acute leukemia or leukemia cell comprises a FLT3 mutation. In some embodiments, the acute leukemia or leukemia cell comprises FLT3 mutation. In some embodiments, the acute leukemia or leukemia cell comprises a FLT3-ITD. In some embodiments, the acute leukemia or leukemia cell comprises a FLT3-TKD. In some embodiments, the acute leukemia or leukemia cell comprises an IDH mutation. In some embodiments, the acute leukemia or leukemia cell comprises an IDH1WSGR Reference No.47535-753.601 mutation. In some embodiments, the acute leukemia or leukemia cell comprises an IDH2 mutation. In some embodiments, the acute leukemia or leukemia cell comprises a TERT mutation. In some embodiments, the acute leukemia or leukemia cell comprises a BRAF mutation. In some embodiments, the acute leukemia or leukemia cell comprises an NPM1 mutation and one or more mutations selected from FLT3 (such as FLT3-ITD or FLT3-TKD), IDH (such as an IDH1 mutation or an IDH2 mutation), TERT, or BRAF. In some aspects, the acute leukemia comprises an NPM1 mutation, optionally in combination with a FLT3 mutation (such as a FLT3-ITD mutation or a FLT3-TKD mutation) or an IDH mutation (such as an IDH1 mutation or an IDH2 mutation), or a combination thereof. In some embodiments, the acute leukemia or leukemia cell comprises a NUP98 rearrangement.

[0069] In certain embodiments, a mutated NPM1 gene comprises one or more mutationsrelative to the wildtype NPM1 gene sequence. NPM1 generally refers to and encompasses the gene encoding the NPM1 protein (e.g., see UniProt ID P06748). In certain instances, the NPM1 gene encompasses NCBI Gene ID 4869 and / or NCBI Reference Sequence: NG_016018.1 (5001..28181). NPM1 mutations are generally characterized by the presence a canonical 4-base pair insertion that generates a new N-terminal nuclear export signal, leading to aberrant cytoplasmic accumulation of the mutant NPM1c protein. NPM1 mutations include Type A, B, and D mutations characterized by a 4-nucleotide insertion in exon 12 that results in cytoplasmic localization of NPM1 (NPM1-c). In certain instances, NPM1-c binds to and, consequently, mislocalizes transcription factors, which normally promote myeloid lineage differentiation but may also be re-imported into the nucleus by XPO1 and directly affect gene expression.

[0070] In certain embodiments, the NPM1 mutation comprises a Type A, Type B, Type C, orType D mutation. In certain embodiments, the NPM1 mutation comprises a Type A mutation. In certain embodiments, the NPM1 mutation comprises a Type B mutation. In certain embodiments, NPM1 mutation comprises a Type C mutation. In certain embodiments, NPM1 mutation comprises a Type D mutation. In certain embodiments, NPM1 mutation results in cytoplasmic localization of NPM1. In certain embodiments, the NPM1 mutation comprises an insertion (e.g., a 4-nucleotide insertion) in exon 12 of an NPM1 gene.

[0071] Multiple translocations involving the KMT2A gene have been reported in both AMLand ALL. The KMT2A-MLLT3 fusion caused by t(9;11)(p21.3;q23.3) is the most common KMT2A rearrangement in adults with AML, but more than 80 different fusion partners have been described. The translocation (9;11)(p22;q23) (MLLT3; KMT2A) or t(10;11)(p12;q23) (AF10; KMT2A) have been reported in 4% of adult myeloid leukemias. Similarly, multipleWSGR Reference No.47535-753.601 SETD2 mutations and RUNX1 mutations that are implicated in acute leukemias have been reported.

[0072] In some embodiments, the acute leukemia or leukemia cell comprises more than onemutation or rearrangement. In some embodiments, the acute leukemia or leukemia cell comprises (a) an NPM1 mutation or a KMT2A rearrangement, and (b) at least one mutation selected from FLT3 (such as FLT3-ITD or FLT3-TKD), IDH (such as IDH1 or IDH2) TERT, and BRAF. In some embodiments, the acute leukemia or leukemia cell comprises (a) an NPM1 mutation and (b) at least one mutation selected from a FLT3 mutation (such as FLT3-ITD orFLT3-TKD), or IDH (such as IDH1 or IDH2).

[0073] In certain instances, characterization of a genetic alteration, such as a mutation, pointmutation, duplication, deletion, or rearrangement, can be achieved via collection of bone marrow (BM aspirate), a whole blood sample, tumor sample, cell-free DNA, exosomes, or circulating tumor cells, followed by known assays for the analysis of nucleic acids or protein sequences in the sample. In certain embodiments, a genetic alteration is detected by sequencing (e.g., genomic sequencing), next-generation sequencing (NGS), polymerase chain reaction (PCR), RT-PCR, quantitative PCR (qPCR), or SNP array, such as by a companion diagnostic assay or a CLIA-validated, next-generation sequencing assay. In certain embodiments, a particular alteration is detected by next-generation sequencing, polymerase chain reaction (e.g., followed by fragment analysis and / or capillary gel electrophoresis). In certain embodiments, a particular mutation is detected by molecular testing, such as by PCR, RT-PCR, or quantitative PCR (qPCR) (optionally followed by fragment analysis and / or capillary gel electrophoresis). In certain embodiments, an alteration is detected by PCR using primers that are specific to the alteration and not the wild-type DNA sequence (e.g., allele-specific PCR). In certain embodiments, an alteration is detected by RT-PCR or qPCR. In certain embodiments, qPCR and RT-qPCR include quantifying mutations, duplications, or substitutions. In some embodiments, the methods provided herein comprise detecting a mutation, such as a duplication, deletion, or substitution, or receiving an identification of the mutation, optionally by a next- generation sequencing assay or a PCR assay, prior to administering the menin inhibitor such as ziftomenib. In some embodiments, the methods provided herein comprise detecting an alteration or receiving an identification of the alteration prior to administering the menin inhibitor such as ziftomenib, in particular an NPM1 mutation or KMT2A rearrangement, optionally wherein the alteration is detected by a next-generation sequencing assay or a PCR assay. In some embodiments, an alteration is detected by a diagnostic test such as byWSGR Reference No.47535-753.601 MyAML®, a CLIA-validated, next-generation sequencing assay for mutations in 194 genes associated with AML. Doses and Dosing Regimens of Menin Inhibitors

[0074] In certain embodiments, dosages, treatment regimens, and effective amounts varydepending on the severity of the disease, the age and relative health of the subject, the potency of the compound(s) used, the particular therapeutic combination, the stage in which the menin inhibitor is used, and other factors. In some embodiments, the methods provided herein comprise administering a menin inhibitor to an individual. In some embodiments, the methods provided herein comprise administering an effective amount of a menin inhibitor to an individual.

[0075] In some embodiments, the amount of the menin inhibitor administered in the methodsprovided herein is from 5 mg / day up to, and including, 2000 mg / day. In some embodiments, the daily dosage of the menin inhibitor is from about 50 mg to about 800 mg. In some embodiments, the daily dosage of the menin inhibitor is from about 50 mg to about 600 mg. In some embodiments, the daily dosage of the menin inhibitor is from about 50 mg to about 400 mg. In some embodiments, the daily dosage of the menin inhibitor is from about 100 to about 600 mg. In some embodiments, the daily dosage of the menin inhibitor is from about 200 to about 600 mg. In some embodiments, the daily dosage of the menin inhibitor is about 50 mg, about 100 mg, about 200 mg, about 400 mg, or about 600 mg. In some embodiments, the daily dosage of the menin inhibitor is about 50 mg. In some embodiments, the daily dosage of the menin inhibitor is about 100 mg. In some embodiments, the daily dosage of the menin inhibitor is about 200 mg. In some embodiments, the daily dosage of the menin inhibitor is about 400 mg. In some embodiments, the daily dosage of the menin inhibitor is about 600 mg. In some embodiments, the daily dosage of the menin inhibitor is about 800 mg. In some embodiments, the menin inhibitor is ziftomenib and the daily dosage is about 200, 400, 600, or 800 mg. In some embodiments, the menin inhibitor is administered at a dose of about 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 360, 400, 450, 500, 550, 600, or 800 mg / day. In some embodiments, the product labeling for the menin inhibitor does not require it to be administered in combination with a CYP3A4 inhibitor. In some embodiments, the menin inhibitor is administered without a CYP3A4 inhibitor or a strong CYP3A4 inhibitor.

[0076] In some embodiments, the menin inhibitor dose (e.g., ziftomenib, 600 mg) does notneed to be adjusted (e.g., reduced) when the menin inhibitor is administered in combination withWSGR Reference No.47535-753.601 a CYP3A inhibitor. In some embodiments, the CYP3A4 inhibitor dose does not need to be adjusted (e.g., reduced) when the menin inhibitor is administered in combination with a CYP3A inhibitor. In some embodiments, the menin inhibitor is classified as having weak DDI (drug- drug interaction) with a CYP3A inhibitor. In some embodiments, the CYP3A inhibitor is one or more of a CYP3A4 inhibitor, a strong CYP3A4 inhibitor (e.g., itraconazole), a moderate CYP3A4 inhibitor (e.g., fluconazole or erythromycin), a CYP2D6 inhibitor (e.g., bupropion), or a CYP1A2 inhibitor (e.g., fluvoxamine).

[0077] In some embodiments, the dose of a CYP3A4 substrate does not need to be adjusted(e.g., increased or decreased) when administered in combination with the menin inhibitor. In some embodiments, the menin inhibitor (e.g., ziftomenib) has a weak or no interaction with a CYP3A4 substrate. In some embodiments, the CYP3A4 substrate is midazolam or venetoclax. In some embodiments, the menin inhibitor is suitable for administration in combination with a CYP3A4 substrate, such as venetoclax, without required dose adjustment of the CYP3A4 substrate. In some embodiments, the menin inhibitor is suitable for administration in combination with a CYP3A4 substrate, such as venetoclax, without required dose adjustment of the menin inhibitor.

[0078] In some embodiments, the menin inhibitor (e.g., ziftomenib) has a weak interactionwith a weak CYP3A4 inducer (e.g., dexamethasone). In some embodiments, the dose of the menin inhibitor and / or the CYP3A4 inducer does not need to be adjusted (e.g., increased or decreased) when the two agents are administered in combination.

[0079] In some embodiments, the menin inhibitor (e.g., ziftomenib) is not prohibited fromadministration with a proton pump inhibitor, H2 receptor antagonist, and / or locally acting antacid, wherein a proton pump inhibitor may be administered from 2 to 12 hours after administration of the menin inhibitor (e.g., ziftomenib) and the H2 receptor antagonist or locally acting antacid may be administered on a staggered schedule, such as either at least 10 hours before and / or at least 2 hours after administration of the menin inhibitor (e.g., ziftomenib). In some embodiments, the proton pump inhibitor is lansoprazole, dexlansoprazole, omeprazole, pantoprazole, rabeprazole, or esomeprazole. In some embodiments, the H2 receptor antagonist is famotidine, cimetidine, or ranitidine. In some embodiments, the antacid is calcium carbonate, alginate, aluminum hydroxide, magnesium carbonate, magnesium hydroxide, magnesium trisilicate, or sodium bicarbonate, or a combination thereof.

[0080] In some embodiments, the individual is a patient age 18 or younger, such as age 1 to18, or age 12 to 18, and the daily dose is adjusted based by the ratio of the body surface area (BSA) of the individual to a 60-kg adult, optionally wherein the dose does not exceed 400 mg orWSGR Reference No.47535-753.601 600 mg, optionally wherein the dose is 100 to 400, or 100 to 150, or 200 to 250, or 300 to 375, or 115, or 235, or 350 mg / m2BSA.

[0081] In some embodiments, a daily dose of the menin inhibitor is given once a day, or isdivided and given twice a day, three times per day, four times per day to equal the daily dose. In some embodiments, the menin inhibitor is administered at a unit dose of 25 to 300 mg, or of 25 mg, 50 mg, 200 mg, or 300 mg, in a number of unit doses necessary to provide the daily dose. In some embodiments, a unit dose is given once a day, given twice a day, given three times per day, or given four times per day. In some embodiments, one unit dose is given per day, two unit doses are given per day, three unit doses are given per day, or four unit doses are given per day. In some embodiments, two unit doses are given twice per day. In some embodiments, three unit doses are given once per day. In some embodiments, four unit doses are given once per day. In some embodiments, the menin inhibitor is ziftomenib, which is administered at a dose of 200 mg once per day. In some embodiments, the 200 mg once per day dose comprises one 200 mg unit dose. In some embodiments, the menin inhibitor is ziftomenib, which is administered at a dose of 400 mg once per day. In some embodiments, the 400 mg once per day dose comprises two 200 mg unit doses. In some embodiments, the menin inhibitor is ziftomenib, which is administered at a dose of 600 mg once per day. In some embodiments, the 600 mg once per day dose comprises three 200 mg unit doses.

[0082] In some embodiments, the dose is an optimal biological dose for the menin inhibitor ina combination therapy, a recommended Phase 2 dose for the menin inhibitor in a combination therapy, a safe and effective dose of the menin inhibitor in a combination therapy, or a dose of the menin inhibitor in a combination therapy that is below the maximum tolerated dose of the menin inhibitor daily to an individual. In some embodiments, the optimal biological dose of the menin inhibitor is 600 mg per day. In some embodiments, the recommended Phase 2 dose (RP2D) is 600 mg per day. In some embodiments, the safe and effective dose is 600 mg per day. In some embodiments, the dose below the maximum tolerated dose is 600 mg per day. In some embodiments, the 600 mg dose per day is a safe and effective amount. In some embodiments, the menin inhibitor has a breakthrough therapy designation. In some embodiments, the dose is administered once daily.

[0083] In some embodiments, the menin inhibitor is ziftomenib or a pharmaceuticallyacceptable form thereof.

[0084] In some embodiments, the menin inhibitor is SNDX-5613 (revumenib) and the amountadministered is 75 mg, 113 mg, 163 mg, 164 mg, or 226 mg once or twice per day, or is from about 163 mg to about 276 mg, or is about 163 mg, or is about 226 mg, or is about 276 mg, inWSGR Reference No.47535-753.601 each case every 8 hours or every 12 hours. In some embodiments, revumenib is administered in combination with a CYP3A4 inhibitor. In some embodiments, revumenib is administered at 160 mg orally twice daily (with a strong CYP3A4 inhibitor) or 270 mg orally twice daily (without a strong CYP3A4 inhibitor) for patients of body weight of 40 kg or more, or at 95 mg / m2orally twice daily or 160 mg / m2orally twice daily, respectively, for patients of body weight less than 40 kg, or at a dose from 25 to 135 mg twice daily or 50 to 220 mg twice daily, respectively, ro patients with a BSA from 0.4 to 1.4 m2. In some embodiments, the menin inhibitor is Compound C and the amount administered is 25, 50, 75, 100, 15, 175, 200, 325, 500, or 650 mg once per day. In some embodiments, the menin inhibitor is Compound B1 or Compound B2 and the daily dose is 5 to 1000 mg / day.

[0085] In some embodiments, the methods comprise administering a menin inhibitor to theindividual daily. In some embodiments, the methods comprise administering a menin inhibitor to the individual for at least 3 days, or for at least 5 days, or for at least 7 days, or for at least 10 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for a cycle comprising at least 28 days, or for a cycle comprising 28 days, or for at least one 28-day cycle.

[0086] In certain embodiments, the menin inhibitor is administered daily to the individual fora cycle comprising at least 28 days, or comprising 28 days, for N cycles, wherein N is at least 1. In certain embodiments, N is at least 2. In certain embodiments, N is at least 3. In certain embodiments, N is at least 4. In certain embodiments, N is 2. In certain embodiments, N is 3. In certain embodiments, N is 4. In certain embodiments, N is 5. In certain embodiments, N is 6. In certain embodiments, N is 7. In certain embodiments the cycles are continuous (i.e., 0 days between cycles).

[0087] In some embodiments, the menin inhibitor is administered in combination with astandard-of-care therapy during an induction cycle. In some embodiments, the standard-of-care therapy is administered without the menin inhibitor during a lead-in period of the induction cycle, wherein the lead-in period comprises the first 3 days of the induction cycle. In some embodiments, the lead-in period comprises the first at least 3 days, or at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days, or 3 to 21 days, or 3 to 14 days, or 3 to 10 days, or 3 to 7 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 8 days, or 9 days, or 10 days of the induction cycle, e.g., a 28-day induction cycle. In some embodiments, the lead-in period is Days 1 to 14, Days 1 to 10, Days 1 to 9, Days 1 to 8, Days 1 to 7, Days 1 to 6, Days 1 to 5, Days 1 to 4, or Days 1 to 3 of a 28-day induction cycle. In some embodiments, the menin inhibitor is administered for the remainder of the induction cycle following the lead-in period with or without the standard-of-care therapy. In some embodiments, the standard-of-care therapy isWSGR Reference No.47535-753.601 administered on Days 1 to 14, Days 1 to 10, Days 1 to 9, Days 1 to 8, Days 1 to 7, Days 1 to 6, Days 1 to 5, Days 1 to 4, or Days 1 to 3 of a 28-day induction cycle, and the menin inhibitor is administered daily on the remaining days of the 28-day induction cycle. When the standard-of- care therapy comprises more than one medication, the medications are administered on their respective dosing regimens within the lead-in period, even if administration of each component of the SOC combination does not occur on each day of the lead-in period.

[0088] In some embodiments, after a first induction cycle, the menin inhibitor is administeredduring a second or more induction cycles, if needed, for example, administering the menin inhibitor for N additional induction cycles, wherein N is 1, 2, 3, 4, 5, or 6, or is 1, or is 2, optionally and independently for each cycle in combination with the standard-of-care therapy or a component thereof. The additional induction cycles are conducted without a lead-in period, and the menin inhibitor is administered for example, daily on Days 1 to 28 of a 28-day second or subsequent induction cycle. In some embodiments, the menin inhibitor is administered during P consolidation cycles, such as at least 1, or 1, or 1 to 4, or 1 to 2 consolidation cycles, optionally and independently for each consolidation cycle in combination with the standard-of-care therapy or a component thereof. Consolidation cycles are conducted without a lead-in period, and the menin inhibitor is administered daily during each consolidation cycle, for example, daily on Days 1 to 28 of each 28-day consolidation cycle. In some embodiments, the menin inhibitor is administered daily during one or more 28-day consolidation cycles. In some embodiments, during consolidation, the daily dose of the menin inhibitor may be reduced relative to the induction cycle or second induction cycle, e.g., from 600 mg to 400 mg daily, or 600 mg to 200 mg daily, such as once daily.

[0089] In some embodiments, following induction, or induction and consolidation, a patientmay proceed to HSCT, such as auto- or allo-HSCT. Following HSCT, a patient may be administered the menin inhibitor as a maintenance therapy, optionally at the same dose as the induction cycle or at a lower dose, e.g., from 50 to 600 mg daily, or 100 mg, 200 mg, 400 mg, or 600 mg daily, such as once daily.

[0090] In some embodiments, daily dosing of the menin inhibitor comprises dose reductionsand / or temporary interruptions as needed based on the prescribing physician’s discretion.

[0091] In certain embodiments, ziftomenib or a pharmaceutically acceptable form thereof isadministered orally.

[0092] In some embodiments, administering daily is administering once or twice daily. Insome embodiments, administering daily is once daily.WSGR Reference No.47535-753.601

[0093] Dose amounts of a menin inhibitor (e.g., ziftomenib) as presented herein refer to thefree base amount (if using the free form) or to the free base equivalent amount (if using a salt and / or solvate form). Thus, for example, if a salt form were used for a daily dose of 600 mg, the total mass amount of drug substance needed to provide the daily dose would exceed 600 mg, but the total mass amount would be selected to provide 600 mg ziftomenib free base equivalent.

[0094] In some embodiments, ziftomenib or a pharmaceutically acceptable form thereof isadministered in combination with a P-gp inhibitor or breast cancer resistance protein (BCRP) inhibitor. Pharmaceutical Compositions

[0095] Also provided herein is a pharmaceutical composition comprising an optimalbiological dose, a recommended Phase 2 dose, a safe and effective dose, or a sub-maximum tolerated dose of the menin inhibitor, such as ziftomenib, for use in the combination therapy methods described herein. In some embodiments, the pharmaceutical composition comprises one or more dosage forms, such as one or more oral dosage forms, optionally wherein each oral dosage form comprises from 50 to 600 mg of the menin inhibitor, such as ziftomenib, or comprises 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg of the menin inhibitor, such as ziftomenib. In some embodiments, the total menin inhibitor or ziftomenib in the one or more oral dosage forms is 200 mg or 400 mg. In some embodiments, the total menin inhibitor or ziftomenib in the one or more oral dosage forms is 600 mg. In some embodiments, each oral dosage form comprises 50 mg, 100 mg, 200 mg, or 300 mg of ziftomenib. In some embodiments, each oral dosage form comprises 200 mg or 300 mg of ziftomenib. In some embodiments, the ziftomenib administered in the methods provided herein is administered using such pharmaceutical composition or oral dosage form(s). In some embodiments, the ziftomenib in the oral dosage form is a crystalline form of ziftomenib. Clinical Activity

[0096] Clinical activity assessments for patients treated with a menin inhibitor, such asziftomenib, in combinations as described herein are evaluated according any one or more of the following: CR rate, CR / CRh rate, CRc rate, MLFS rate, ORR, PFS, MRD, median OS, proportion of patients alive at 1 year, EFS at 1 year, median duration of remission (DOR), proportion of patients who under HSCT, and rate of transfusion independence, or a combination thereof. In some embodiments, the CR or CR / CRh rate is at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%,WSGR Reference No.47535-753.601 or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%. In some embodiments, the CRc rate is at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%. In some embodiments, the ORR is at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%.

[0097] In some embodiments, the median DOR for patients who achieve CRc is at least 2months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 12 months, or at least about 18 months, or at least about 24 months.

[0098] In some embodiments, median overall survival (OS) is at least about 5 months, or atleast about 6 months, or at least about 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 12 months, or at least about 18 months, or at least about 24 months.

[0099] In some embodiments, administering the menin inhibitor according to the methodsdescribed herein may produce a transient increase in white blood cell count or in peripheral blast count, followed by a reduction in such a count. In some embodiments, the transient increase occurs within 14 days of initiation of menin inhibitor treatment. In some embodiments, the reduction occurs within 14 days of the increase. In some embodiments, the methods described herein include transiently increasing white blood cell counts or peripheral blast counts comprising administering an effective amount of a menin inhibitor, such as ziftomenib. In some embodiments, the increase from baseline occurs within one week, two weeks, three weeks, or four weeks, from initiation of the administering. In some embodiments, the increase from baseline lasts for about one week, about two weeks, or about three weeks.

[0100] In some embodiments, one or more of the CR rate, CR / CRh rate, CRc rate, MLFS rate,ORR, PFS, MRD, median OS, proportion of patients alive at 1 year, EFS at 1 year, median DOR, proportion of patients who under HSCT, or rate of transfusion independence is improved for patients according to the methods described herein relative to treatment with a menin inhibitor or standard-of-care alone, or relative to treatment with other menin inhibitors.WSGR Reference No.47535-753.601 Safety

[0101] In some embodiments, the safety profile of the methods described herein ischaracterized by the rate of dose-limiting toxicity (DLT) and / or the rate of adverse events per the NCI CTCAE v5.0.

[0102] In some embodiments, the methods provided herein comprise administering a menininhibitor, such as ziftomenib, to the individual, wherein the risk of the individual exhibiting or developing a particular adverse event (or a severe adverse event) is reduced relative to or is comparable to the risk associated with alternative treatments, such as treatment with other menin inhibitors or traditional therapies, or for patients of one genetic subtype compared to another genetic subtype or to the overall patient population. In some embodiments, the methods provided herein comprise administering a menin inhibitor, such as ziftomenib, to the individual, in combination with a standard-of-care therapy, wherein the risk of the individual exhibiting or developing a particular adverse event (or a severe adverse event) is comparable to or lower than the risk for the standard-of-care therapy or the same or a different menin inhibitor alone. In some embodiments, a reduced risk occurs in a particular genetic subtype, such as KMT2A-r or NPM1-m AML patients, and / or a particular stage of disease (e.g., 1L or R / R). As used herein, the “risk” of an individual exhibiting or developing a particular side effect, or a particular severity of side effect, is determined based on the incidence rate for the side effect across the treated population, e.g., the modified intent-to-treat (mITT) patient population of a clinical study.

[0103] In some embodiments, the adverse event is a treatment-emergent adverse event(TEAE) regardless of causality or a severe adverse event (Grade 3 or higher, i.e., Grade 3, 4, or 5) regardless of causality. In some embodiments, the adverse event is QTc prolongation, a cardiac adverse event, myelosuppression, neutropenia, cytopenia, a differentiation syndrome- suspect adverse event, differentiation syndrome, severe differentiation syndrome, or tumor lysis syndrome.

[0104] In some embodiments, the risk of the individual developing any differentiationsyndrome-suspect adverse event, or differentiation syndrome, or tumor lysis syndrome, is less than about 80%, or less than about 75%, or less than about 70%, or less than about 65%, or less than about 60%, or less than about 55%, or less than about 50%, or less than about 45%, or less than about 40%, or less than about 35%, or less than about 30%, or less than about 25%, or less than about 20%, or less than about 15%, or less than about 10%, or less than about 5%. As used herein, a “differentiation syndrome-suspect adverse event” is differentiation syndrome, a treatment-emergent adverse event (TEAE) meeting the Norsworthy Criteria for possibleWSGR Reference No.47535-753.601 differentiation syndrome, or a TEAE meeting the Norsworthy Criteria where differentiation syndrome cannot be excluded. (Norsworthy et al., Clin. Cancer Res.2020, 26(16), 4280-4288.)

[0105] In some embodiments, the risk of the individual developing differentiation syndromeafter the administering is less than about 40%, or less than about 35%, or less than about 30%, or less than about 25%, or less than about 20%, or less than about 15%, or less than about 10%, or less than about 5%. In some embodiments, the risk of the individual developing severe differentiation syndrome of Grade 3, 4, or 5, is less than about 40%, or less than about 35%, or less than about 30%, or less than about 25%, or less than about 20%, or less than about 15%, or less than about 10%, or less than about 5%. As used herein, “severe differentiation syndrome” is defined as differentiation syndrome at Grade 3, Grade 4, or Grade 5 on the National Cancer Institute’s standardized Common Toxicity Criteria for Adverse Events (found at http: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm).

[0106] In some embodiments, the methods provided herein comprise administering a menininhibitor, such as ziftomenib, without inducing QTc prolongation. In some embodiments, the risk of QTc prolongation with the methods described herein is less than about 20%, or less than about 15%, or less than about 10%, or less than about 5%. In some embodiments, the risk of severe QTc prolongation (Grade 3, 4, or 5) is less than about 20%, or less than about 15%, or less than about 10%, or less than about 5%. In some embodiments, ziftomenib is used, and the risk of QTc adverse events is lower than for other menin inhibitors. Differentiation Disorders

[0107] In preclinical studies, ziftomenib was found to drive terminal differentiation andscheduled apoptosis. The resultant terminal differentiation of these leukemic blast cells may contribute to TEAEs of DS, which are not unexpected and have occurred (including 1 unexpected fatal event in a KMT2A-r AML patient) in patients treated with ziftomenib monotherapy. Differentiation syndrome has been noted in patients treated with isocitrate dehydrogenase (IDH) inhibitors (Norsworthy, 2020) and it has been reported in patients following administration of ziftomenib, with some fatal outcomes. However, the majority of the DS events (overall and ≥Grade 3) were reported in patients with KMT2A-r AML, suggesting that this genetic subset was potentially more susceptible to sudden and severe DS events – perhaps as a result of the monocytic nature of this AML subtype that has increased propensity for development of extramedullary disease (EMD).

[0108] Increased recognition of the signs and symptoms of DS through the framework ofMontesinos can lead to earlier diagnosis and treatment and reduced rates of severe complicationsWSGR Reference No.47535-753.601 and mortality. Montesinos et al. (Blood 2009, 113(4), 775-783) proposed diagnostic criteria for DS based on at least two of the following signs and symptoms: dyspnea, unexplained fever, weight gain, unexplained hypotension, acute kidney injury, and pulmonary infiltrates or pleuropericardial effusion. Patients with two or three criteria are classified as having moderate DS and patients with at least four criteria were classified as having severe DS.

[0109] As used herein, “differentiation disorder” refers to differentiation syndrome (with orwithout hyperleukocytosis), hyperleukocytosis, and tumor lysis syndrome. Hyperleukocytosis can be detected based on increasing white blood cell counts in the absence of an infection. Tumor lysis syndrome can occur in settings of rapidly progressive leukocytosis and can be detected by the presence of two or more of blood chemistry markers selected from hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, or by an increased serum creatinine level.

[0110] Using the algorithm based on Montesinos criteria, as described by Norsworthy (2020),the following adverse events were monitored and evaluated for treated patients, and diagnostic criteria applied as described below in those patients who received at least one dose of ziftomenib.

[0111] A differentiation disorder, such as DS, with or without hyperleukocytosis, may besuspected based on one or more of the following symptoms: ^New or worsening progressive dyspnea or hypoxia, with increasing demands forsupplemental oxygen and without a clear alternative etiology ^Radiologic evidence of new or worsened pulmonary infiltration, not attributable toanother cause; ^Radiologic evidence of new or worsened pleural or pericardial effusion that has nodefinitive etiology or is refractory to treatment for the initially suspected cause; ^New or worsened peripheral edema without definitive etiology, with rapid weight gain(e.g., > 5 kg over 7 days); ^Acute renal failure (e.g., increase in serum creatinine > 2-fold from baseline) notattributable to other cause or medication; ^Unexplained fever ≥ 38° C (100.4° F);^ Unexplained hypotension;^ Significant changes in markers of inflammation;^ Evidence of multiorgan dysfunction; or^ Rash, joint pain, bone pain, or swelling of extramedullary lesions.WSGR Reference No.47535-753.601

[0112] The presence of two or more of the above signs and symptoms may be consideredpotential DS. Patients with two or three criteria are classified as having moderate DS, and those with at least 4 criteria are classified as having severe DS.

[0113] Notably, development of differentiation syndrome in patients with NPM1-m AML withziftomenib was found to correlate with favorable outcomes. In some embodiments of the methods described herein, the treated individual develops differentiation syndrome, optionally wherein the differentiation syndrome is severe differentiation syndrome (e.g., Grade 3, 4, or 5), yet has a probability of achieving ORR of at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%.

[0114] It was also discovered that treatment of patients with ziftomenib or a pharmaceuticallyacceptable form thereof increased the level of myeloid blasts in the blood of treated individuals. Thus, in some embodiments, the methods described herein include increasing the level of myeloid blasts in the blood of an individual with AML comprising administering an effective amount of a menin inhibitor, such as ziftomenib, to the individual. In some embodiments, the AML comprises an NPM1 mutation or a KMT2A rearrangement. In some embodiments, the relative levels of myeloid blasts in the blood of the individual that has been assessed by analysis of two time-separated blood samples from the individual, optionally wherein the blood samples are taken at, for example, (a) a first timepoint and a second timepoint, wherein both timepoints are during the administering or (b) at a first timepoint prior to beginning the administering and at a second timepoint during the administering. In some embodiments, the first timepoint is prior to the administering, e.g., prior to Cycle 1, Day 1, or prior to the end of the lead-in period, or prior to Cycle 1, Day 8, and the second timepoint is at least 7, 14, 21, or 28 days later. In some embodiments, each analysis is a complete blood count (CBC), optionally with differential. In some embodiments, the first timepoint and the second timepoint are separated by one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, at least one week, at least two weeks, at least three weeks, or at least four weeks, or by the duration of one cycle (such as Cycle 1), or wherein the second timepoint is at the time when the individual reaches a complete remission (CR). In some embodiments, the first timepoint is at screening, or is on Cycle 1, Day 1, or prior to the first dose of the menin inhibitor, e.g., Cycle 1, Day 8. In some embodiments, the increase in the level of myeloid blasts in the blood of the individual is not correlated with progression of the AML. In some embodiments, the increase in the level of myeloid blasts occurs in the extramedullary space. In some embodiments, the increase in the level of myeloid blasts indicates the individual is sensitive to the menin inhibitor, in particular ziftomenib.WSGR Reference No.47535-753.601 Monitoring and Treatment of Differentiation Disorders

[0115] It was discovered that monitoring and early intervention can reduce the incidence andseverity of differentiation disorders, allowing for fewer adverse events and enabling patients to remain on treatment.

[0116] In some embodiments, the methods provided herein comprise administering aneffective amount of a steroid (e.g., dexamethasone) if a differentiation disorder is detected in the individual during the administering of the menin inhibitor.

[0117] Provided herein are methods of identifying an acute leukemia (in particular AML) inan individual as sensitive to administration of a menin inhibitor, in particular ziftomenib, comprising: administering an effective amount of the menin inhibitor, in particular ziftomenib daily, to the individual, receiving an identification of the level of myeloid blasts in a first blood sample taken from the individual at a first timepoint that is either before initiation of the administering or during the administering of the menin inhibitor, receiving an identification of the level of myeloid blasts in a second blood sample taken from the individual at a second timepoint that is after the first timepoint and that is during the administering of the menin inhibitor, and determining that the acute leukemia is sensitive to the administering if the level of myeloid blasts at the second timepoint is greater than the level at the first timepoint. In some embodiments, the AML comprises an NPM1 mutation or a KMT2A rearrangement.

[0118] In some embodiments are methods of treating a differentiation disorder, in particulartumor lysis syndrome, in an individual diagnosed with the differentiation disorder in an individual with acute leukemia, or reducing the risk of developing a severe differentiation disorder in an individual with acute leukemia, optionally wherein the acute leukemia comprises an NPM1 mutation or a KMT2A rearrangement, comprising:(a) administering an effective amount of a menin inhibitor, in particular 600 mg ofziftomenib or a pharmaceutically acceptable form thereof daily, to the individual,(b) administering IV hydration to the individual, and optionally,(c) administering an effective amount of a xanthine oxidase inhibitor to the individual,optionally wherein the xanthine oxidase inhibitor is allopurinol, optionally administering the allopurinol at a dose of about 200-400 mg / m2 / day in 1-3 divided doses, up to a maximum of about 800 mg daily.WSGR Reference No.47535-753.601

[0119] Some embodiments comprise administering the xanthine oxidase inhibitor, andcomprising, prior to administering the xanthine oxidase inhibitor, diagnosing the individual as having a low or intermediate risk of having or developing the differentiation disorder from receiving an identification that the individual has: (1) a white blood count of less than about 25 x 109L and a lactate dehydrogenase level of less than twice the upper limit of normal (e.g., where a normal level is about 280 units / L), or (2) a white blood count from about 25 to about 100 x 109 / L, or (3) a white blood count of less than about 25 x 109 / L and a lactate dehydrogenase level that is more than twice the upper limit of normal.

[0120] Provided herein are methods of treating a differentiation disorder in an individual withacute leukemia, or reducing the risk of developing a severe differentiation disorder in an individual with acute leukemia, optionally wherein the acute leukemia comprises an NPM1 mutation or a KMT2A rearrangement, comprising:(a) administering an effective amount of a menin inhibitor, in particular 600 mg ofziftomenib or a pharmaceutically acceptable form thereof daily, to the individual,(b) administering IV hydration to the individual, and(c) administering a therapeutically effective amount of rasburicase, optionally at a dose ofabout 0.2 mg / kg, optionally as an intravenous infusion over about 30 minutes daily, for up to about 5 days.

[0121] Some embodiments comprise, prior to administering the rasburicase, diagnosing theindividual as having a high risk of having or developing the differentiation disorder from receiving an identification that the individual has: (i) has a white blood count level from greater than or equal to about 100 x 109 / L, or (ii) has a white blood count level (i) from about 25 to about 100 x 109 / L, or (ii) less than about 25 x 109 / L and a lactate dehydrogenase level that is more than twice the upper limit of normal (e.g., where a normal level is about 280 units / L), and, for each of (i) and (ii), wherein the individual has renal dysfunction, or uric acid, potassium, and / or phosphate levels above the applicable upper limit of normal.

[0122] Provided herein are methods of treating a differentiation disorder, or reducing the riskof developing a severe differentiation disorder, in an individual with acute leukemia, optionally wherein the acute leukemia comprises an NPM1 mutation or a KMT2A rearrangement, comprising:WSGR Reference No.47535-753.601(a) administering a prophylactic and / or effective amount of a corticosteroid to theindividual, optionally wherein the corticosteroid is prednisone, optionally at a dose of about 0.5 mg / kg (or an equivalent dose of an alternative corticosteroid); and(b) administering a therapeutically effective amount of the menin inhibitor to the individual.

[0123] In some embodiments, wherein the corticosteroid and the menin inhibitor areadministered daily, and consecutively or simultaneously, optionally comprising administering the first dose of each of the corticosteroid and the menin inhibitor on or about the same day, or administering the first dose of the corticosteroid on a day that is before or after the first administering of the menin inhibitor.

[0124] In some embodiments, prior to administering the corticosteroid or the menin inhibitor,the individual has one or more of a white blood count of greater than 5 x 109 / L, an increased serum creatinine level, significant extramedullary disease, and proliferative acute leukemia.

[0125] In some embodiments, comprising administering the corticosteroid daily starting on afirst day, administering the menin inhibitor daily starting on the same or a subsequent day, and reducing the dose of the corticosteroid after administering the menin inhibitor for about 28 days if the individual has not been not diagnosed with the differentiation disorder (in the method of reducing the risk) or if the individual has developed the differentiation disorder and the differentiation disorder improved and bone marrow blasts are at a level of less than about 5% (in the method of reducing the risk or the method of treating).

[0126] Some embodiments comprise administering dexamethasone at a dose of about 5 mg,10 mg, or 15 mg, preferably 10 mg, or from about 5 to 10 mg, intravenously, every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) to the individual, for one, two, or three days.

[0127] Some embodiments comprise administering a therapeutically effective amount ofhydroxyurea or cytarabine to the individual if the white blood count or leukocyte count for the individual increases to greater than about 10 x 109 / L or doubles within about 24-48 hours, and, optionally, administering a therapeutically effective amount of cytarabine, idarubicin, or gemtuzumab to the individual.

[0128] Some embodiments comprise tapering the dose of and / or discontinuing theadministering of the corticosteroid, hydroxyurea, cytarabine, idarubicin, or gemtuzumab upon improvement of the differentiation disorder.

[0129] Some embodiments comprise interrupting the administering of the menin inhibitorduring all or part of the administering of one or more of IV hydration, allopurinol, rasburicase, prednisone, dexamethasone, hydroxyurea, cytarabine, idarubicin, and gemtuzumab, and re-WSGR Reference No.47535-753.601 initiating the administering after the differentiation disorder improves (for example, when the white blood count drops to less than about 20 x 109 / L) at the therapeutically effective dose or a reduced dose of the menin inhibitor.

[0130] In some embodiments, the differentiation disorder is differentiation syndrome with orwithout hyperleukocytosis. In some embodiments, the differentiation disorder is tumor lysis syndrome. Definitions

[0131] Compounds of the present disclosure also include crystalline and amorphous forms ofthose compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0132] The compounds described herein may exhibit their natural isotopic abundance, or oneor more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0133] The term “isotopolog” refers to an isotopically enriched compound. The term“isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopolog” can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., multiple myeloma therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein.WSGR Reference No.47535-753.601

[0134] “Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” include stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0135] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bondsmay exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.

[0136] The term “solvate” generally refers to a compound (e.g., free base) or a salt thereof,that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Wherein the solvent is water, the solvate is a hydrate.

[0137] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from avariety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicWSGR Reference No.47535-753.601 acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0138] The term “pharmaceutical composition” generally refers to a composition comprising amenin inhibitor, in particular ziftomenib, in combination with at least one additional pharmaceutically acceptable carrier. A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to an individual, including, e.g., an adjuvant, an excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Suitable carriers include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0139] Pharmaceutical compounds are formulated according to several factors well within thepurview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved inWSGR Reference No.47535-753.601 their selection, are found in a variety of readily available sources such as, for example, Allen, L. V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0140] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficialor desired results with respect to a disease, disorder, or medical condition (e.g., AML) including but, in certain instances, not limited to a therapeutic benefit and / or a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is also achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0141] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefitand / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0142] As used herein, the term “effective amount” in connection with a compound means anamount capable of treating, preventing, or managing a disorder, disease, or condition, or one or more symptoms thereof.

[0143] As used herein, the term “prophylactic amount” in connection with a compound meansan amount capable of preventing a disorder, disease, or condition, or one or more symptoms thereof, or reducing the ultimate severity of the disorder, disease, or condition, or of one or more symptoms thereof.

[0144] As used herein, the term “optimal biological dose” or “OBD” means the lowest dose ofdrug, such as an investigational drug, that provides the highest rate of efficacy while being safely administered.

[0145] As used herein, the term “recommended Phase 2 dose” means a dose of aninvestigational drug that has been accepted by a governmental authority (e.g., the U.S. Food and Drug Administration (FDA) or the similar authority in other countries) for evaluation in a Phase 2 study.WSGR Reference No.47535-753.601

[0146] As used herein, the term “safe and effective dose” means a dose of a drug, such as aninvestigational drug, that provides a clinical effect without unacceptable side effects.

[0147] As used herein, the term “maximum tolerated dose” means the dose means the highestdose of a drug, such as an investigational drug, that does not cause unacceptable side effects, e.g., where the observed toxicity rate (e.g., dose-limiting toxicity rate) is less than 0.33.

[0148] As used herein, “induction” is induction therapy or induction chemotherapy orremission induction, or the initial stage of treatment with a particular drug or drug combination. During induction, the goal is to reduce tumor burden. An “induction cycle” is a treatment cycle during the induction period, typically measured in 28-day cycles. Induction can occur over one or more cycles, such as one induction cycle or two induction cycles.

[0149] As used herein “consolidation” is consolidation chemotherapy or continued therapy,which is administered after induction chemotherapy. For example, a patient who achieves CR, CRi, or MLFS, or receives clinical benefit from one or more cycles of induction therapy may continue treatment during consolidation. In some situations, the dose and / or dosing regimen is the same in consolidation as in induction, and in some situations, the dose and / or dosing regimen is modified in consolidation. A “consolidation cycle” is a treatment cycle during the consolidation period, typically measured in 28-day cycles. Consolidation can be done over one or more consolidation cycles.

[0150] A “breakthrough therapy designation” refers to the designation given by agovernmental authority (e.g., the FDA or the similar authority in other countries) for an active pharmaceutical ingredient that treats a serious or life-threatening condition and for which preliminary clinical evidence (e.g., Phase 1 clinical data) indicates it may demonstrate substantial improvement on a clinically significant endpoint over available therapies. In the U.S., the status is referred to as breakthrough therapy designation; in Europe the status is Priority Medicine or PRIME. As used herein, a breakthrough therapy designation may be given for a particular indication and / or genetic sub-type, such as NPM1-m AML or R / R NPM1-m AML.

[0151] An “investigational drug” is a substance that has been tested in laboratory experimentsand has been approved by a governmental authority (e.g., the FDA or the similar authority in other countries) for testing in humans.

[0152] “Chemotherapy” means the administration of one or more chemotherapeutic drugsand / or other agents to an individual by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository. In the context of acute leukemia, chemotherapy is intensiveWSGR Reference No.47535-753.601 chemotherapy, including a combination of an anthracycline, such as daunorubicin or idarubicin, and cytarabine, in a “7+3” regimen (cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days).

[0153] “Individual” refers to an animal, such as a mammal, for example a human. Themethods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the individual is a mammal, and in some embodiments, the individual is human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. In some embodiments, the human is at least 18 years of age. In some embodiments, the human is less than 18 years of age, less than 12 years of age, less than 6, 5, 4, 3, 2, or 1 year of age.

[0154] As used herein, “intensive chemotherapy” is a chemotherapy that is suitable forotherwise healthy patients, such as patients under age 60 and without significant comorbidities. Examples of intensive chemotherapy include a nucleoside metabolic inhibitor, such as a cytosine arabinoside, for example, cytarabine) and a topoisomerase inhibitor (e.g., an anthracycline such as daunorubicin or idarubicin), for example, in a 7+3 or VYXEOSTMregimen, or FLAG-IDA.

[0155] As used herein, “nonintensive chemotherapy” is a chemotherapy that is suitable forpatients who are ineligible for intensive chemotherapy, for example, adults age 60 and over, elderly patients, or patients with significant comorbidities, such as cardiac, pulmonary, or other conditions. Examples of nonintensive chemotherapy include low dose nucleoside metabolic inhibitor, such as LDAC, a BCL-2 inhibitor (such as ven), or a combination of a BCL-2 inhibitor (e.g., ven) and an HMA (e.g., aza).

[0156] Clinical terms used herein include the following: “CR” means a complete remission(or complete response), with no visible evidence of leukemia cells in blood or bone marrow, normal bone marrow function, and normal numbers of healthy blood cells having returned to circulation as confirmed by bone marrow biopsy and blood testing; the CR rate is defined as the population of patients achieving a best overall response of CR; “CRh” means a complete remission (or complete response) with hematologic recovery; the CR / CRh response rate is defined as the proportion of patients achieving a best overall response of CR with or without MRD, or CRh; “CRi” means a complete remission (or complete response) with incomplete hematologic recovery; “CRp” means complete remission with incomplete platelet recovery; CRc means composite complete remission (or response) and the response rate is defined as the proportion of patients achieving a best overall response of CRi (including CRp), CRh, or CR (including MRD-); “MRD” means measurable residual disease and refers to levels of leukemiaWSGR Reference No.47535-753.601 that are not readily observed microscopically but can be detected by a laboratory method (e.g., MFC, molecular analysis, NGS, PCR). A CR can be with or without measurable residual disease (CR MRD+ / MRD-); “MLFS” means morphologic leukemic-free state; “PR” means partial response; “SD” means stable disease without progression; “ORR” means overall response rate and is determined by the formula, ORR = CR (including CR MRD-) + CRh + MLFS (including CRp). “PFS” refers to progression-free survival. These clinical activity data are measured using the ELN 2022 criteria.

[0157] “BC” means blast count and refers to the percentage of blasts in the bone marrow orblood. In normal bone marrow, the blast count is 5% or less, while the blood usually does not contain blasts. A level of at least 20% blasts in the marrow or blood usually indicates a diagnosis of AML.

[0158] Hydroxyurea, or hydrea, is an antimetabolite that prevents the excessive production ofblood cells in proliferative diseases, and is useful in AML to reduce elevated levels of leukemic white blood cells.

[0159] “DS” means differentiation syndrome, a potentially serious side effect that may occurin patients with acute leukemia such as AML who have been treated with certain types of anticancer drugs. Differentiation syndrome usually occurs within 1-2 weeks after starting treatment. It is caused by large, rapid release of cytokines from leukemia cells that are affected by the anticancer drugs. Signs and symptoms of differentiation syndrome include fever, cough, difficulty breathing, weight gain, swelling of arms, legs, and neck, build-up of excess fluid around the heart and lungs, low blood pressure, and kidney failure.

[0160] “SCT” or “HSCT” means hematopoietic stem cell transplant. In some embodiments ofthe methods provided herein, the subject receives an SCT after the treating or administering of ziftomenib or a pharmaceutically acceptable form thereof. In some embodiments of the methods provided herein, the subject has received an SCT prior to the treating or administration of ziftomenib or a pharmaceutically acceptable form thereof. In some embodiments, ziftomenib or a pharmaceutically acceptable form thereof is administered to a subject prior to an SCT and following the SCT (e.g., as maintenance therapy).

[0161] Extramedullary hematopoiesis is the formation and activation of blood cells outside thebone marrow, as a response to hematopoietic stress caused by leukemia.

[0162] The term “co-administration,” “administered in combination with,” and theirgrammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including a human, simultaneously in separate compositions, administration at differentWSGR Reference No.47535-753.601 times in separate compositions (e.g., during the same treatment cycle, on the same and / or different days), or administration in a composition in which both agents are present.

[0163] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to acompound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., menin, MLL1, MLL2, and / or an MLL fusion protein). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.

[0164] The term “agonist” as used herein refers to a compound having the ability to initiate orenhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0165] “Signal transduction” is a process during which stimulatory or inhibitory signals aretransmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.

[0166] As used herein, a “sample” includes and / or refers to any fluid or liquid sample which isbeing analyzed in order to detect and / or quantify an analyte. In some embodiments, a sample is a biological sample. Examples of samples include without limitation a bodily fluid, an extract, a solution containing proteins and / or DNA, a cell extract, a cell lysate, or a tissue lysate. Non- limiting examples of bodily fluids include urine, saliva, blood, serum, plasma, cerebrospinal fluid, tears, semen, sweat, pleural effusion, liquified fecal matter, and lacrimal gland secretion.

[0167] The term “in vivo” refers to an event that takes place in an individual’s body.

[0168] The term “in vitro” refers to an event that takes places outside of an individual’s body.For example, an in vitro assay encompasses any assay run outside of an individual. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.WSGR Reference No.47535-753.601

[0169] As used herein, the words “comprising” (and any form of comprising, such as“comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps. As also used herein, in any instance or embodiment described herein, “comprising” may be replaced with “consisting essentially of” and / or “consisting of”. used herein, in any instance or embodiment described herein, “comprises” may be replaced with “consists essentially of” and / or “consists of”.

[0170] As used herein, the term “and / or” is to be taken as specific disclosure of each of thetwo specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each were set out individually herein.

[0171] As used herein, the term “about,” when used in connection with doses, amounts, orweight percentages, mean a dose, amount, or weight percent within 10%, or within 5%, or within 2%, or within 1% of the stated amount.

[0172] Where a numerical value is used herein, such a value may encompass a range that is ±5% of the stated numerical value. EXAMPLES

[0173] The following examples are included for illustrative purposes only and are not intendedto limit the scope of the present disclosure. Example 1 – Ziftomenib with Ven or Ven / Aza in a KMT2A-r AML Model

[0174] Ziftomenib was tested in the disseminated MOLM13 xenograft model alone and incombination with ven and ven / aza with dosing QD for 42 days and observation out to day 55. In this experiment, ziftomenib was dosed at 100 mg / kg / day QD and 5 of 8 animals in the ziftomenib group entered long term remission with the other 3 animals succumbing between Days 45-55. Ven and the ven / aza doublet were weakly active, with all animals succumbing between days 23 and 43, but the combination of ziftomenib and ven / aza maintained all treated animals in remission for the duration of the experiment. The ziftomenib and ven combination showed similar activity to the ziftomenib group, with 5 of 8 animals entering long-term remission. In addition, Fiskus et al. (Leukemia 2022, 36(11), 2729-2733) reported treatment of mice bearing MLL-AF9, FLT3-tyrosine kinase domain Luc / GFP patient-derived xenograft (PDX) leukemia with ziftomenib at 75 mg / kg / day in combination with ven at 30 mg / kg / day for 5 days significantly reduced the leukemic burden post-2 weeks of treatment compared withWSGR Reference No.47535-753.601 treatment with either agent alone. Example 2 – Phase 1 study of ven / aza or ven in combination with ziftomenib (KO-539) or standard induction cytarabine / daunorubicin (7+3) chemotherapy in combination with ziftomenib in patients with acute myeloid leukemia (NCT 05735184) ^Study Parameters

[0175] Ziftomenib is a compound targeting the menin-KMT2A interaction that is underclinical investigation for treatment of patients with NPM1-m and KMT2A-r AML subgroups with high unmet need. The inhibitory activity of ziftomenib for the menin-KMT2A interaction has been demonstrated in both in vitro and in vivo models of both KMT2A-r and KMT2A- wildtype / NPM1-m AML. Evidence of clinical activity has been demonstrated in patients with R / R AML receiving single-agent ziftomenib in an ongoing clinical trial (KO-MEN-001). Ziftomenib in combination with SOC therapies has shown evidence of clinical activity and a promising safety profile for patients with NPM1-m or KMT2A-r AML.

[0176] This Phase 1 study assesses the safety, tolerability, and preliminary clinical activity ofziftomenib in combination with ven / aza, ven, or cytarabine and daunorubicin in NPM1-m and KMT2A-r AML patients.

[0177] Cohorts and treatments for the study are shown in Table 1.Table 1.WSGR Reference No.47535-753.601

[0178] The study endpoints include: rate of dose-limiting toxicities (DLTs) during first 28days of ziftomenib in combination with standard-of-care (SOC) therapy, statistics for adverse events during first 28 days of ziftomenib in combination with standard-of-care (SOC) therapy; complete remission (or complete response) (CR) rate, composite complete remission (CRc) or MLFS rate, measurable residual disease (MRD) (MRD negativity rate, e.g., for CR responders or CR / CRh responders, or CRc responders), median overall survival (OS), proportion of patients alive at 1 year following treatment with ziftomenib, median event-free survival (EFS), event- free survival (EFS), median duration of remission (DOR), proportion of patients who undergo HSCT, rate of transfusion independence, and pharmacokinetic properties of ziftomenib and SOC treatments.

[0179] Inclusion Criteria include: documented NPM1 mutation or KMT2A rearrangement, andeither newly diagnosed or relapsed / refractory (R / R) AML; Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; and adequate liver, renal, and cardiac function. In some aspects, newly diagnosed patients were adverse risk (or high risk), e.g., greater than 60 years of age and / or treatment-related AML regardless of age and / or adverse risk cytogenetics per ELN criteria.

[0180] Exclusion Criteria include: diagnosis of acute promyelocytic leukemia or blast chronicmyelomonocytic leukemia; known history of BCR-ABL alteration; advanced malignant hepatic tumor (for ven / aza combination); clinical signs / symptoms of leukostasis or white blood count > 25,000 / mL; for newly diagnosed patients, received prior chemotherapy for leukemia or non- HMA therapy for prior MDS; and for R / R patients, received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy within 14 days of the first dose of ziftomenib.

[0181] Ziftomenib / Ven / Aza and Ziftomenib / Ven Combinations for NPM1-m and KMT2A-rAML: Ven dosing is initiated at Cycle 1, Day 1, using a 3-day ramp-up with 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and beyond (adjusted according to the Venetoclax Prescribing Information if the patient is also taking a P-gp inhibitor (reduce by at least 50%) or CYP3A inhibitor such as posaconazole (4-day ramp up from 10 mg to 70 mg) or other strong CYP3A inhibitors (4-day ramp up from 10 mg to 100 mg)). Ven dosing continues daily thereafter with adjustments to cycle length based on Cycle 1 bone marrow biopsy results. Aza is administered at 75 mg / m2sc or iv on Cycle 1, Days 1-7, or alternatively 5 days on, 2 days off,WSGR Reference No.47535-753.601 and optionally another 2 days on, and then optionally thereafter on the same schedule in 28-day cycles based on bone marrow biopsy results. Ziftomenib treatment is initiated on Cycle 1, Day 8, at a dose of 100 mg, 200 mg, 400 mg, or 600 mg, and continued Day 1 to 28 for Cycle 2 onward. Induction with ven or ven / aza comprises 1 to 4 cycles. If a patient is in CR, CRi, MLFS, or receiving clinical benefit from the ziftomenib combination, treatment may continue with ziftomenib / ven / aza, ziftomenib / ven, or ziftomenib monotherapy until relapse, or with auto- HSCT or allo-HSCT followed by ziftomenib post-HSCT maintenance therapy.

[0182] Ziftomenib / Daunorubicin / Cytarabine Combinations for NPM1-m and KMT2A-r AML:Patients receive daunorubicin / cytarabine as the 7+3 regimen described herein, or using other formulations such as VYXEOSTM, according to the applicable Prescribing Information for each medication, during induction. For consolidation, cytarabine should be administered on Days 1, 3, and 5, for up to 4 cycles, during the consolidation phase; intermediate-dose cytarabine (IDAC) 1500 mg / m2IV should be given by IV infusion over 3 hours every 12 hours on Days 1, 3, and 5 (total dose 9000 mg / m2per cycle) for patients 60 years of age and older or younger patients who have a creatinine clearance of >30 mL / min and <50 mL / min; high-dose cytarabine (HiDAC) 3000 mg / m2should be given IV over 3 hours every 12 hours on Days 1, 3, and 5 (total dose 18000 mg / m2) per cycle for patients younger than age 60 years of age with a creatinine clearance of ≥50 mL / min. Dexamethasone 0.1% or other corticosteroid ophthalmic solution should be administered as 2 drops to each eye 4 times daily beginning 6-12 hours prior to the initiation of the cytarabine infusion and should continue for at least 24 hours after the last cytarabine dose. Daunorubicin (60 mg / m2) should be administered via IV push or short infusion daily on Days 1-3 of Induction Cycle 1, and on Days 1-2 for Induction Cycle 2, if necessary. VYXEOS™ (daunorubicin 44 mg / m2and cytarabine 100 mg / m2) liposome should be administered via IV infusion over 90 minutes on Days 1, 3, and 5 of Cycle 1 and on Days 1 and 3 for subsequent cycles of induction, if needed. During consolidation, VYXEOS™ (daunorubicin 29 mg / m2and cytarabine 65 mg / m2) liposome should be administered via IV infusion over 90 minutes on Days 1 and 3. Ziftomenib treatment is initiated on Cycle 1, Day 8, at a dose of 100 mg, 200 mg, 400 mg, or 600 mg, once daily, and continued Day 1 to 28 for Cycle 2 onward. If a patient is in CR, CRi, MLFS, or receives clinical benefit after induction, patients may proceed to: consolidation with ziftomenib in combination with HiDAC or IDAC, or with ziftomenib in combination with VYXEOSTMfor 1 or more consolidation cycles; or auto- or allo-HSCT followed by ziftomenib maintenance therapy.

[0183] HSCT: Patients who proceed to HSCT may receive ziftomenib treatment at a dose of100 mg, 200 mg, 400 mg, or 600 mg once daily as maintenance therapy.WSGR Reference No.47535-753.601

[0184] DS and TLS Mitigation: Patients are monitored for DS symptoms and risk asdescribed herein. TLS prophylaxis may be employed, particularly during the ven ramp-up period such as on Day 1 of ven administration or Day 1 of any ven dose adjustment, by administering a uric acid reducing agent, ensuring adequate oral and IV hydration, monitoring fluid status, and testing tumor lysis syndrome chemistry (calcium, inorganic phosphorus, potassium, uric acid, and creatinine). ^Study DataA. Study Data for the first 20 enrolled patients (as of January 11, 2024) – Part 1

[0185] Data for the first 20 patients enrolled across the four cohorts are reported below.Table 2. Patient DemographicsWSGR Reference No.47535-753.601

[0186] Safety: Continuous daily dosing of ziftomenib at 200 mg QD has been well toleratedand the safety profile consistent with features of underlying disease and / or standard-of-care therapies. No DS events of any grade, DLTs (including delayed hematologic count recovery), or evidence of QTc prolongation, drug-drug interactions, or additive myelosuppression were reported among the first 20 patients enrolled in the study across all 4 cohorts. Observed TEAEs were consistent with underlying disease and SOC combination therapies.

[0187] In comparison, in the KO-MEN-001 Phase 1 study of ziftomenib monotherapy, the rateof DS in KMT2A-r patients was similar at the 200 and 600 mg doses (46.2% and 43.8%) and was lower in NPM1-m patients (0% at 200 mg; 20.0% at 600 mg). Rates of severe DS (≥Grade 3) in KMT2A-r patients (35.7% at 200 mg; 22.2% at 600 mg) was also higher than in NPM1-m patients (0% at 200 mg; 5% at 600 mg). Specific safety data from the monotherapy study are shown in Table 3. Table 3.

[0188] Clinical Activity: Among 5 patients treated with ziftomenib (200 mg QD) incombination with daunorubicin / cytarabine in the front-line (1L) setting, the CR rate was 100% (including full count recovery) (NPM1-m (A-2; 4); KMT2A-r (B-2; 1)), compared to a reported CR / CRi rate in this population of 32-33% (Lancet et al., Blood 2014, 123(21), 3239-46; Lin et al., Blood Adv.2021, 5(6), 1719-1728).

[0189] Among 15 R / R AML patients treated with ziftomenib / ven / aza (200 mg QDziftomenib), the ORR (CR+CRh+CRi+CRc+MLFS) was 53% overall (8 / 15; NPM1-m, 71% (A- 1; 5 / 7); KMT2A-r, 38% (B-1; 3 / 8)), and the CR / CRi rate was 47% overall (7 / 15; NPM1-m, 57% (A-1; 4 / 7); KMT2A-r, 38% (B-1; 3 / 8)). The CR / CRh rate in patients who were menin inhibitor-WSGR Reference No.47535-753.601 naïve was 56% (5 / 9), including 50% (3 / 5) in patients with NPM1-m AML (A-1) and 60% (3 / 5) in patients with KMT2A-r AML (B-1).

[0190] In the KO-MEN-001 Phase 1 ziftomenib monotherapy study, in R / R NPM1-m patientstreated at 600 mg (n=20), the CR and CR / CRh rates were both 35% (40% overall on study including HSCT patients), the CRc rate was 40%, the ORR was 45%, and the MRD negativity rate among tested CR / CRh patients was 57.1%. The median duration of CRc was 6.6 months, the median durations of CR / CRh and of CR / CRh or CRc censored at HSCT were each 5.6 months, and the median OS was 5.6 months. For R / R NPM1-m patients dosed at 200 mg (n=6), the CR, CRh, and CRc rates were 16.7%, the ORR was 33.3%, and median OS was 2.7 months. For R / R KMT2A-r patients treated at 600 mg (n=18), the CR / CRh rate was 11.1%, the CRc rate was 16.7%, and the ORR was 16.7% For R / R KMT2A-r patients treated at 200 mg (n=14), 4 experienced stable disease (28.6%); no CR, CRh, CRi, MLFS, or PR responses were observed.

[0191] Bone marrow blast counts were measured at baseline and post-baseline in a sample ofpatients in cohorts A-1, A-2, and B-1 and showed significant reductions of 40 to 100% across the cohorts.

[0192] Notably, the combination of ziftomenib with ven / aza in R / R disease drove responses inpatients who had previously failed on ven. These patients typically face dismal prognosis with a median OS of 2.4 months and response rates following ven / aza about 0 to 20% including less than 10% ORR for R / R KMT2A-r AML (Zainaldin et al., Lymphoma 2022, 63(13), 3245-3248; Chan and Walker, Hematology 2023, 702-708; Maiti et al., Haematologica 2021, 106(3), 894- 898; Issa, Syndax ASH Investor Presentation (Dec.2023)). As of the data cutoff, these patients had an overall ORR of 40% (4 / 10), including 60% in NPM1-m patients (A-1; 3 / 5) and 20% in KMT2A-r patients (B-1; 1 / 5), and an overall CRc rate of 30% (3 / 10), including 40% in NPM1-m patients (A-1; 2 / 5) and 20% in KMT2A-r (B-1; 1 / 5).

[0193] The combination of ziftomenib / ven / aza was shown to significantly reduce levels ofextramedullary disease that had been unaffected by prior ven / aza and ven / decitabine treatment in a heavily pre-treated patient. In an R / R NPM1-m AML patient with 7 prior lines of therapy (including 1stinduction 1L of 5+1 (HiDAC days 1-5 and high-dose mitoxantrone on day 2), 2ndinduction with etoposide, cytarabine, and midosaturin, aza / ven (CRi), MUD allo-HSCT followed by gilteritinib maintenance, decitabine and ven (CR), donor lymphocyte infusion (DLI) + ven (not evaluable), and 2ndDLI), treatment with ziftomenib / ven / aza induced a CRi by week 4, with rapid dissolution of extramedullary disease shortly after ziftomenib initiation, which progressed to CRh by week 8, and progression to HSCT at week 10.WSGR Reference No.47535-753.601

[0194] The ziftomenib / ven / aza combination also showed clinical activity in multiple patientswith prior ven and / or prior menin inhibitor exposure (SNDX-5613), where significant reductions in bone marrow and peripheral blasts were observed during Cycle 1. In an R / R NPM1-m AML patient with 11 prior lines of therapy (including (1) FLAG-IDA, HiDAC, (2) decitabine, MUD HSCT, (3) post-HSCT aza maintenance, (4) DLI x 2, (5) ven / aza maintenance until molecular relapse, (6) 2ndHSCT, (7) DLI, ven / aza (maintenance until molecular relapse), (8) clofarabine + cytarabine, (9) SNDX5613 (CRi), (10) 3rdHSCT), (11) SNDX5613 maintenance (3 months to progression)), ziftomenib / ven / aza showed clinical benefit with reduction in bone marrow blasts from 33% at baseline to 7-9% from Cycle 1, Day 21 through at least Cycle 2, Day 28.

[0195] Ziftomenib / ven / aza was shown to be effective in treating aggressive disease. In a 1LKMT2A-r AML patient, treatment induced a CR by week 3. The patient continued on ziftomenib monotherapy to relapse at week 10. In an R / R KMT2A-r AML patient, pre-treated by zifto / 7+3 induction and Zifto / AraC consolidation, treatment in this study with ziftomenib / ven / aza induced a CRi by week 3, with DOR of at least 9 weeks at the time of the data cut. In this patient, bone marrow and peripheral blasts were reduced from 10% and 20% at baseline to less than 5% and 0%, respectively, at Cycle 1, Day 21.

[0196] In a 1L NPM1-m AML patient ziftomenib was administered in combination withdaunorubicin and cytarabine as described above and induced a CR by week 5, remained in CR to HSCT at week 15, and continued with ziftomenib maintenance as a monotherapy thereafter. Bone marrow and peripheral blasts were reduced from 77% and 20% at baseline to below 5% and 0%, respectively, at Cycle 1, Day 21.

[0197] As of the data cutoff, 80% (16 / 20) patients remained on trial, including 100% (11 / 11)of all NPM1-m patients. B. Study Data – Part 2 1. Newly Diagnosed Patients.

[0198] Adults (age ≥18 years) with newly diagnosed (ND), KMT2A-r AML or high-riskNPM1-m were enrolled into separate dose-escalation cohorts for each genotype. High-risk disease was defined as adverse-risk cytogenetics per ELN criteria, age ≥60 years, or treatment- related AML regardless of age. Following a rule-based approach, at least six dose-limiting toxicity (DLT) evaluable patients were assigned to each cohort where ziftomenib (200, 400, or 600 mg once daily) was escalated with standard doses of cytarabine and daunorubicin (7+3). Ziftomenib was administered orally from Cycle 1 Day 8 and continuously thereafter (through induction, consolidation and continued therapy including post-transplant). Primary endpoints inWSGR Reference No.47535-753.601 phase 1a were DLTs and adverse events (AEs); key secondary endpoints included composite complete remission (CRc; defined as complete remission [CR] or CR with partial or incomplete hematological recovery) and minimal residual disease (MRD).

[0199] As of the June 21, 2024, data cutoff, for the first 34 patients with ND AML (ziftomenib200 mg, n=18; 400 mg, n=16), median age was 58 (range 28–74) years and 62% were female; 44% (15 / 34) had NPM1-m (high-risk only) and 56% (19 / 34) had KMT2A-r. At 200 mg and 400 mg, respectively, median follow-up was 33 and 18 weeks for ND pts with NPM1-m, and 22 and 12 weeks for those with KMT2A-r. The most common (≥20% of pts) grade ≥3 treatment- emergent AEs (TEAEs) were febrile neutropenia (56%), decreased platelet count (47%), decreased neutrophil count (38%), anemia (32%) and decreased white blood cell count (29%). Nine pts (26%) had grade ≥3 ziftomenib- or backbone-related AEs, including decreased platelet count (18%), decreased neutrophil count (15%), and anemia (9%). During continuous ziftomenib administration at 200 mg or 400 mg, respectively, in NPM1-m patients without persistent AML at end of Cycle 1, median time to neutrophil recovery (ANC ≥1K) was 32.5 and 28 days, and 32.5 and 26 days to platelet recovery (≥100K); in KMT2A-r patients, median time to neutrophil recovery was 31 and 24 days, and 28.5 and 28.5 days to platelet recovery. There were no cases of differentiation syndrome (DS), ziftomenib-associated QTc prolongation, or DLTs with the 200 mg or 400 mg dose levels.

[0200] Thirty-three patients (15 with NPM1-m; 18 with KMT2A-r) had ≥1 responseassessment as of the data cutoff. For NPM1-m patients (A-2), CRc rates were 100% (8 / 8) at 200 mg and 86% (6 / 7) at 400 mg (overall 93%, 14 / 15), with MRD negativity among tested responders of 100% (8 / 8) and 80% (4 / 5), respectively. For KMT2A-r patients (B-2), CRc rates were 90% (9 / 10) at 200 mg and 63% (5 / 8) at 400 mg (overall 78%, 14 / 18), with MRD negativity among tested responders of 83% (5 / 6) and 100% (3 / 3), respectively. In response-evaluable ND patients, CRc rate at both dose levels was 93% (14 / 15) for NPM1-m and 78% (14 / 18) for KMT2A-r. As of the data cutoff, 100% (15 / 15) of ND NPM1-m patients (200 mg, n=8; 400 mg, n=7) and 84% (16 / 19) of ND KMT2A-r patients (200 mg, n=7; 400 mg, n=9) remained on study.

[0201] Based on preliminary data as of the June 21, 2024, data cutoff for the 600 mg dose inthe ND patient cohorts (NPM1-m, n=7; KMT2A-r, n=3), this dose in combination was well- tolerated, with no instances of DS based on IDMC / SMC review for hallmark DS features, low rates of ziftomenib-related SAEs (NPM1-m, 14.3%; KMT2A-r, 0%), and no TEAEs leading to dose reductions. The response rate was 43% (CR and CR / CRh) for NPM1-m patients; the data was not yet mature enough to evaluate the KMT2A-r group. As of the data cutoff, all patients in the NPM1-m cohort remained on study. Enrollment for these cohorts was ongoing.WSGR Reference No.47535-753.601

[0202] In summary, ziftomenib combined with 7+3 in this patient population was welltolerated, with a consistent safety profile across dose levels, and produced evidence of robust clinical activity. No DLTs, DS events, or events of ziftomenib-induced QTc prolongation were reported, and rates of ziftomenib-related cytopenias were low, with no additional myelosuppression observed with the combination.

[0203] Based on these results and the results provided below for R / R patients, the combinationof ziftomenib, venetoclax, and azacitidine is also evaluated in newly diagnosed NPM1-m or KMT2A-r AML patients, with an 8-day lead-in for ziftomenib (ven / aza start on Cycle 1, Day 1, and ziftomenib start on Cycle 1, Day 8, of the first cycle). Patients with NPM1-m may be identified as high-risk AML (adverse risk cytogenetics according to ELN criteria, age ≥ 60 years, or treatment-related AML regardless of age), or ND NPM1-m patients may be enrolled without any of these high-risk qualifiers. 2. Relapsed / Refractory Patients.

[0204] Adults (age ≥18 years) with R / R NPM1-m or KMT2A-r AML were enrolled intoseparate dose escalation cohorts for each genotype. Following a rule-based approach, at least six dose-limiting toxicity (DLT)-evaluable patients were assigned to each cohort where ziftomenib (200, 400, or 600 mg once daily) was escalated with standard doses of venetoclax and azacitidine (Ven / Aza). Ziftomenib was administered orally from Cycle 1 Day 8 and continuously thereafter. Primary endpoints in phase 1a were DLTs and adverse events (AEs); key secondary endpoints included composite complete remission rates (CRc; defined as complete remission [CR] or CR with partial or incomplete hematological recovery).

[0205] As of the June 21, 2024, data cutoff, for the first 34 patients treated in the R / R cohorts(ziftomenib 200 mg, n=18; 400 mg, n=16), median age was 56 (range 23–86) years, and 50% were female; 41% (14 / 34) had NPM1-m and 59% (20 / 34) had KMT2A-r. Median follow-up was 35 and 14 weeks at 200 mg and 400 mg, respectively, for R / R pts with NPM1-m; and 15 and 14 weeks for those with KMT2A-r. Median number of prior therapies was 2 (range 1–8); 32% (11 / 34) had prior transplant; and 74% (25 / 34) were menin inhibitor-naive, including 68% (17 / 25) who had prior Ven exposure. No DLTs or ziftomenib-induced QTc prolongation were reported. The most common (≥20% of patients) grade (Gr) ≥3 treatment-emergent AEs (TEAEs) were febrile neutropenia (35%), decreased platelet count (35%), anemia (26%), decreased neutrophil count (24%), and pneumonia (24%). Gr≥3 ziftomenib- and / or backbone- related AEs occurred in 44% of patients, including decreased platelet count (18%), decreased neutrophil count (15%), and anemia (12%). On-target differentiation syndrome (DS) occurredWSGR Reference No.47535-753.601 in 12% (4 / 34) of R / R patients (1 NPM1-m [400 mg, Gr3] and 3 KMT2A-r [200 mg, 1-Gr3; 400 mg, 1-Gr2 and 1-Gr3]), and all cases were manageable per the DS guidance.

[0206] Twenty-four menin inhibitor-naive patients (NPM1-m, n=11; KMT2A-r, n=13) had ≥1response assessment as of the data cutoff. Among R / R NPM1-m patients (A-1), the overall response rate (ORR) was 100% (5 / 5) at 200 mg and 67% (4 / 6) at 400 mg; CRc rates were 80% (4 / 5) at 200 mg and 50% (3 / 6) at 400 mg. In NPM1-m patients who received prior Ven, ORR was 100% (3 / 3) at 200 mg and 50% (2 / 4) at 400 mg. For R / R KMT2A-r patients (B-1), ORR was 43% (3 / 7) at 200 mg and 33% (2 / 6) at 400 mg; CRc rates were 29% (2 / 7) at 200 mg and 17% (1 / 6) at 400 mg. In KMT2A-r patients who received prior Ven, ORR was 40% (2 / 5) at 200 mg and 25% (1 / 4) at 400 mg. The study was ongoing at the data cutoff, with 50% (7 / 14) of R / R NPM1-m patients (200 mg, n=4; 400 mg, n=3) and 30% (6 / 20) of R / R KMT2A-r patients (200 mg, n=3; 400 mg, n=3) remaining on study.

[0207] Ziftomenib combined with Ven / Aza was well tolerated at the dose levels tested to dateand continued to demonstrate promising clinical activity in R / R pts. No DLTs or ziftomenib- induced QTc prolongation were reported. Clinical activity was also demonstrated in previously Ven-exposed NPM1-m and KMT2A-r patients. Data from the 400 mg cohorts continued to mature and 600 mg cohorts were enrolling as of the data cutoff. An additional cohort of R / R NPM1-m AML is enrolled to receive the combination of ziftomenib and venetoclax, starting administration at Cycle 1, Day 1, for both agents. C. Study Data – Part 3 1. Newly Diagnosed Patients.

[0208] As of an October 1, 2024, cutoff, out of 51 patients across Cohorts A-2 and B-2, 45(88%) remained on study (24 NPM1-m, 21 KMT2A-r). Baseline patient characteristics are shown in Table 4. Table 4.WSGR Reference No.47535-753.601aPatients on treatment or in long-term follow-up

[0209] Ziftomenib in combination was well tolerated, with the incidence of treatment-emergent adverse events (graded according to CTCAE v.5.0) that occurred at greater than or equal to 25% across all patients shown in Table 5. Table 5.WSGR Reference No.47535-753.601The safety profile of ziftomenib in combination with intensive chemotherapy was similar to that reported for newly diagnosed AML patients treated with 7+3 alone (Lin et al., Blood Adv.2021, 5(6), 1719-1728). The rate of TEAEs was consistent across escalating doses of ziftomenib.

[0210] Grade 3 or above treatment-emergent adverse events occurring in at least 10% of allpatients are shown in Table 6. One case (1 / 51 overall, 2%) of Grade 3 DS (NPM1-m, 600 mg) occurred, and it was successfully managed according to the DS guidance and the patient remained on treatment. No ziftomenib-associated QTc prolongation was observed, and no dose- limiting toxicities (DLTs) occurred at any dose level. Table 6.WSGR Reference No.47535-753.601

[0211] Clinical activity for all response-evaluable patients (defined as patients who had atleast one response assessment or who had died) is shown in Table 7. Historically, only 33% of 7+3 treated newly diagnosed adverse-risk AML patients achieve CRc, with a median overall survival of about 6 months (Lin et al., supra; Lancet et al., Blood 2014, 123(21), 3239-3246). MRD negativity is reported for CRc responders tested for MRD per local assay (NGS, RT- qPCR, FISH, flow cytometry). Table 7.bN = CRc responders tested for MRS per local assay (NGS, RT-qPCR, FISH, flow cytometry)

[0212] As of the October 1, 2024, cutoff date, the median duration of CRc and median OS forNPM1-m and KMT2A-r patients had not been reached, but after a median follow-up time of 31 weeks (range 17-63), 100% (24 / 24) NPM1-m patients were still alive, and 5 NPM1-m patients received HSCT (200 mg n=3; 400 mg n=2), and 2 then went onto ziftomenib maintenance, and after a median follow up of 19 weeks (range 2-43), 96% (26 / 27) KMT2A-r patients were stillWSGR Reference No.47535-753.601 alive, and 10 KMT2A-r patients received HSCT (200 mg n=6; 400 mg n=3; 600 mg n=1), and 5 then went onto ziftomenib maintenance.

[0213] Absolute neutrophil count (ANC) and platelet recovery data for CRc responders areshown in Table 8. Higher ziftomenib doses did not impact or delay neutrophil or platelet count recoveries. Table 8.

[0214] In the Phase 1a portion of the KOMET-007 study, ziftomenib combined withcytarabine and daunorubicin (7+3) was well tolerated across dose levels in patients with newly diagnosed NPM1-m and KMT2A-r AML. No DLTs or ziftomenib-associated QTc prolongation were reported. On-target DS occurred in 4% (n=1, Gr3), and was successfully managed and the patient remained on treatment. For clinical activity in newly diagnosed patients, CRc rates were 100% for NPM1-m patients and 83% for KMT2A-r patients. MRD negativity rates were 76% for NPM1-m patients and 75% for KMT2A-r patients. All (100%, 24 / 24) NPM1-m patients and 96% (26 / 27) KMT2A-r patients remained alive as of the cutoff date (median follow-up of 31 and 19 weeks, respectively).

[0215] Cohort A-4 for newly diagnosed NPM1-m AML patients (ziftomenib + venetoclax +azacitidine) is also conducted, each dosing with ziftomenib (at 200, 400, or 600 mg QD, or at 600 mg QD) starting at Cycle 1, Day 8 of the induction cycle and continuing QD thereafter. As of an October 28, 2024, data cutoff (n=6), during the initial treatment period, no patients experienced DS of Grade 3 or higher and no TEAEs leading to permanent ziftomenib dose reduction or discontinuation were reported. 2. Relapsed / Refractory Patients.

[0216] As of an October 1, 2024, cutoff, out of 54 patients across Cohorts A-1 and B-1(including one patient who did not receive a dose of ziftomenib), 13 (24%) remained on study (10 NPM1-m, 3 KMT2A-r). Baseline patient characteristics are shown in Table 9, including the numbers (%) of patients who received prior hematopoietic stem cell transplant (HSCT), venetoclax, or other menin inhibitors.WSGR Reference No.47535-753.601 Table 9.aIncludes 1 pt who did not receive a dose of ziftomenib

[0217] Ziftomenib in combination was well tolerated, with the incidence of treatment-emergent adverse events (graded according to CTCAE v.5.0) that occurred at greater than or equal to 20% across all patients shown in Table 10. There were four cases (4 / 54, 7% overall, or 4 / 53, 8% of patients who received at least one dose of ziftomenib) of DS (1 Gr3, NPM1-m, 400 mg; 1 Gr3, KMT2A-r, 200 mg, 1 Gr2, KMT2A-r, 400 mg, and 1 Gr3, KMT2A-r, 400 mg), but allWSGR Reference No.47535-753.601 instances were manageable according to the DS guidance and no discontinuations were required due to DS (0% rate of >Gr3 DS; any grade DS: NPM1-m, 1 / 26, 4%; KMT2A-r, 3 / 27, 11%). No ziftomenib-associated QTc prolongation was observed and there were no dose-limiting toxicities (DLTs) at any dose level. Table 10.aIncludes 1 pt who did not receive a dose of ziftomenibWSGR Reference No.47535-753.601

[0218] Clinical activity (per ELN 2022) in all response-evaluable patients (defined as patientswho had at least one response assessment or had died) is shown in Table 11 (total n for KMT2A-r patients includes one patient who did not receive a dose of ziftomenib). CR = complete remission; CRc = composite complete remission; CRh = complete remission with partial hematological recovery; CRi = complete remission with incomplete hematological recovery; MLFS = morphologic leukemia-free state; NE = not evaluable; NR = no response; PR = partial remission. Patients in the 600 mg cohorts listed as NR or NE remained on treatment as of the cutoff date. Table 11.

[0219] Clinical activity in menin inhibitor-naïve patients is shown in Table 12. Among 11menin inhibitor-experienced patients (3 NPM1-m; 8 KMT2A-r), there were two responders (MLFS for one 200 mg KMT2A-r patient and one 400 mg KMT2A-r patient). Table 12.WSGR Reference No.47535-753.601

[0220] Clinical activity in patients with and without prior venetoclax therapy is shown inTable 13. Patients with prior venetoclax exposure achieved responses with ziftomenib combination therapy (ORR: 50% in NPM1-m patients; 30% in KMT2A-r patients). Table 13.

[0221] For NPM1-m patients and overall, median duration of CRc was 23.4 weeks (95%confidence interval 8.7-NE), and 6 NPM1-m patients received HSCT (3 at 200 mg; 1 at 400 mg; 2 at 600 mg) and one went onto ziftomenib maintenance therapy. For KMT2A-r patients, duration of CRc was not yet reached, and 3 patients received HSCT (2 at 200 mg; 1 at 400 mg), and one went onto ziftomenib maintenance.

[0222] Absolute neutrophil count (ANC) and platelet recovery data for CRc responders areshown in Table 14. Table 14.a Includes 4 NPM1-m patients (1 at 200 mg, 1 at 400 mg, 2 at 600 mg) with platelet counts that were never below 50 x 109 / L.

[0223] In the Phase 1a portion of the KOMET-007 study, ziftomenib combined with standarddoses of venetoclax / azacitidine was well tolerated at all dose levels tested and continued to demonstrate promising clinical activity in R / R NPM1-m and KMT2A-r AML. Ziftomenib combination therapy was well tolerated. No DLTs or ziftomenib-induced QTc prolongationWSGR Reference No.47535-753.601 were reported. On-target DS occurred in 8% (n=4) of patients receiving ziftomenib (all Grade 2 or 3), including in 3 KMT2A-r and 1 NPM1-m patients; all patients had resolution of DS with appropriate management. Clinical activity was demonstrated in NPM1-m and KMT2A-r R / R AML, including VEN-experienced patients. In the NPM1-m efficacy-evaluable population, ORR was 68% and CRc was 50%. In NPM1-m patients with VEN exposure, ORR was 50% and CRc was 36%. For KMT2A-r patients, ORR was 33%.

[0224] As of an October 28, 2024, for Cohort A-3 (R / R NPM1-m AML patients who havefailed at least one prior line of therapy, patients received ziftomenib and venetoclax), where ziftomenib was dosed at 200, 400, or 600 mg QD, or at 600 mg QD, starting at Cycle 1, Day 8 of an induction cycle, and QD thereafter, there were no reports of ≥ Grade 3 ziftomenib-related TEAEs, ziftomenib-related serious TEAEs, ziftomenib-related TEAEs leading to ziftomenib dose interruption / reduction, or differentiation syndrome.

[0225] Overall, ziftomenib was well tolerated in patients with R / R or ND NPM1-m orKMT2A-r AML when administered in combination with ven, ven / aza, or 7+3 (e.g., daunorubicin / cytarabine). Further, DS was mitigated by administering a 7-day lead-in of the standard-of-care backbone therapy of standard induction therapy with 7+3 (e.g., daunorubicin / cytarabine) or with ven or ven / aza prior to initiating ziftomenib dosing, as evidenced by the low rates of DS and low rates of > Grade 3 DS reported by patients across cohorts. Example 3 – Phase 1 Study of Safety and Tolerability of Ziftomenib Combinations with FLAG-IDA or LDAC in NPM1-m or KMT2A-r R / R AML

[0226] A two-part, multi-center Phase 1 dose escalation and expansion / validation study toassess the safety, tolerability, pharmacokinetics and preliminary clinical activity of ziftomenib when combined with standard of care (SOC) therapies in adults with relapse or refractory (R / R) NPM1-m or KMT2A-r AML is conducted. Patients with NPM1-m or KMT2A-r AML are enrolled into separate arms to receive one of the following treatment combinations.

[0227] NPM1-m R / R AML: Cohort A-1: Zifto / FLAG-IDA (intensive chemotherapy); CohortA-2: Zifto / LDAC (nonintensive chemotherapy).

[0228] KMT2A-r R / R AML: Cohort B-1: Zifto / FLAG-IDA (intensive chemotherapy); CohortB-2: Zifto / LDAC (nonintensive chemotherapy).

[0229] Relapsed is defined as reappearance of ≥5% blasts in the bone marrow (BM) orreappearance of blasts in the blood in ≥2 peripheral blood samples ≥1 week apart; orWSGR Reference No.47535-753.601 development of new extramedullary disease. Refractory is defined as patients who have failed at least 1 prior line of therapy.

[0230] Inclusion Criteria include: Adults 18 years and older diagnosed with AML whorelapsed or were refractory to at least 1 prior line of therapy with documented NPM1-m or KMT2A-r (excluding PTD); adequate liver, renal, and cardiac function; ECOG status less than or equal to 2; no clinical signs / symptoms of leukocytosis or white blood count > 25x109L.

[0231] Dosing regimens for each of the combinations are outlined below. All SOC backboneagents within the respective cohorts, in addition to any associated premedication, are administered per institutional SOC and according to the respective manufacturer’s prescribing information.

[0232] Ziftomenib: Oral administration of ziftomenib should be given at 100 mg, 200 mg, 400mg, or 600 mg QD, or at 600 mg QD, starting at Cycle 1, Day 8.

[0233] FLAG-IDA (Cohorts A-1 and B-1): The components of FLAG-IDA (fludarabine +cytarabine + G-CSF + idarubicin) should be administered according to the details outlined in their respective prescribing information during induction (1 or 2 induction cycles). Fludarabine should be administered 30 mg / m2 / day IV on Days 1 to 4, idarubicin should be administered 6 to 10 mg / m2 / day intravenously (IV) on Days 1 to 3, cytarabine should be administered 1500 to 2000 mg / m2 / day IV on Days 1 to 5, and G-CSF should be administered 300 mcg / m2 / day SC from Days 1 to 5. Additional G-CSF may be administered starting Day 6 following completion of chemotherapy until ANC > 1000 / μL. G-CSF should be discontinued for at least 7 days prior to obtaining bone marrow to document remission. As noted above, ziftomenib is dosed beginning on Day 8 of Cycle 1 (induction cycle) and once daily thereafter; consolidation cycles may include ziftomenib dosed on Days 1 to 28 in combination with HiDAC (3000 mg / m2dose of cytarabine by IV over 3 hours every 12 hours on Days 1, 3, and 5 (total dose 18,000 mg / m2)) or IDAC (1500 mg / m2dose of cytarabine by IV over 3 hours every 12 hours on Days 1, 3, and 5 (total dose 9000 mg / m2)) per consolidation cycle.

[0234] Low-dose cytarabine (LDAC; Cohorts A-2 and B-2): patients indicated to receiveLDAC in combination with ziftomenib should be administered a 20 mg dose of cytarabine twice a day (BID) subcutaneously (SC) on Days 1 to 10 of each 28-day cycle. Ziftomenib should begin on Day 8 of Cycle 1 (induction cycle) and should be administered on Days 1 to 28 of Cycle 2 and beyond (consolidation cycles or continued therapy).

[0235] Patients who progress to HSCT may receive ziftomenib monotherapy at a dose of 100mg, 200 mg, 400 mg, or 600 mg QD as maintenance therapy.WSGR Reference No.47535-753.601

[0236] DS and TLS Mitigation: Patients are monitored for DS symptoms and risk asdescribed herein. TLS prophylaxis may be employed as described herein.

[0237] As of an October 28, 2024, data cutoff, preliminary safety data for patients during theinitial treatment period (e.g., prior to HSCT) indicated ziftomenib is well tolerated in patients with R / R NPM1-m or KMT2A-r AML when administered in combination with FLAG-IDA or LDAC. Differentiation syndrome incidence and severity is mitigated by initiating ziftomenib following a 7-day lead-in with the standard-of-care chemotherapy backbone agents (FLAG-IDA or LDAC). In Cohorts A-1 (n=3) and A-2 (n=2), there were no reports of differentiation syndrome, and in Cohort B-1 (n=8), 1 patient with DS (12.5%; Grade 3), and in Cohort B-2 (n=2), 1 patient experienced differentiation syndrome (< Grade 3). Across these cohorots, there were no reports of > Grade 3 DS. Example 4 – Drug-Drug Interaction between Ziftomenib and CYP Inhibitors or Substrates

[0238] Ziftomenib was administered as a monotherapy in subjects with relapsed / refractoryAML, at doses ranging from 50 mg to 1000 mg once daily, with or without co-administration of azoles, which are typically CYP3A4 inhibitors. FIG.1 shows ziftomenib pharmacokinetics (PK) in patients without CYP3A4 inhibitors (n=10), on moderate CYP3A4 inhibitors (fluconazole, isavuconazole and isavuconazonium, n=12), and on strong CYP3A4 inhibitors (posaconazole and voriconazole, n=33).

[0239] Physiologically based pharmacokinetic (PBPK) modeling of this PK data wasconducted. Based on this analysis, the ziftomenib fraction metabolized by CYP3A4 was estimated to be 40%, and 30% each by CYP2D6 and CYP1A2, compared to estimates based on in vitro metabolism of 94.8%, 2.8%, and 2.4%, respectively. PBPK modeling further demonstrated that strong (e.g., itraconazole) and moderate (e.g., fluconazole or erythromycin) CYP3A4 inhibitors increased ziftomenib exposure by 1.7-fold and approximately 1.4-fold, respectively, and other CYP inhibitors (e.g., CYP2D6 and CYP1A2 inhibitors) increased ziftomenib exposure approximately 1.4- to 1.5-fold (Table 15). These results are characterized as weak DDI and not clinically relevant. Based on these results, ziftomenib can be co- administered with CYP inhibitors, including moderate or strong CYPA4 inhibitors, without the need to reduce the dose of ziftomenib. Table 15. Effect of CYP Inhibitors on PK of ZiftomenibWSGR Reference No.47535-753.601

[0240] Additionally, PBPK modeling also predicted a weak interaction with CYP3A4inducers (e.g., dexamethasone), and predicted no interaction between ziftomenib and CYP3A4 substrates such as midazolam and venetoclax with an increased exposure of these agents by only 5-6% (Table 16). Based on these results, ziftomenib can be co-administered with CYP3A4 substrates, without the need for dose adjustment of the substrate drug. Table 16. Effect of Ziftomenib on PK of CYP3A4 Substrates

[0241] Population PK modeling of the ziftomenib monotherapy clinical data alsodemonstrated that hepatic and renal impairment did not change ziftomenib clearance compared to patients with normal hepatic and renal function.

[0242] In sum, these modeling data demonstrate that ziftomenib does not require doseadjustment when co-administered with CYP3A inhibitors or in patients with hepatic or renal insufficiency. The projected lack of effect of ziftomenib on exposure of sensitive CYP3A4 substrates supports study of combination therapy of ziftomenib with such agents, e.g., venetoclax, without dose adjustment of either drug.

[0243] The low risk of clinically meaningful drug-drug interactions, no evidence to date ofQTc prolongation, and once daily dosing profile demonstrate that ziftomenib is suitable for combination with other therapeutic agents for treatment of patients. DDI classifications are listed as per FDA guidance (Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry.2020).

[0244] While some embodiments of the present invention have been shown and describedherein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutionsWSGR Reference No.47535-753.601 will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations, or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Reference No.47535-753.601 CLAIMS Listing of Claims1. A method of treating acute leukemia in an individual comprising administering to theindividual a standard-of-care therapy and a menin inhibitor.

2. A method of reducing the risk of a differentiation syndrome-suspect adverse event in anindividual with acute leukemia comprising administering to the individual a menin inhibitor and a standard-of-care therapy.

3. The method of claim 1 or claim 2, comprising administering to the individual thestandard-of-care therapy without the menin inhibitor during a lead-in period of an induction cycle; and administering to the individual the menin inhibitor for the remainder of the induction cycle, optionally in combination with the standard-of-care therapy or a component thereof.

4. The method of any of claims 1 to 3, wherein the acute leukemia is menin-dependent.

5. The method of any one of claims 1 to 4, wherein the acute leukemia comprises amutation selected from an NPM1 mutation, a KMT2A rearrangement, a KMT2A-PTD mutation, a SETD2 mutation, a RUNX1 mutation, a FLT3-ITD mutation, a FLT3-TKD mutation, an IDH mutation (such as an IDH1 mutation or an IDH2 mutation), a TERT mutation, a BRAF mutation, or a NUP98 rearrangement, or any combination thereof, optionally wherein the acute leukemia comprises an NPM1 mutation or a KMT2A rearrangement.

6. The method of any one of claims 1 to 5, wherein the acute leukemia comprises an NPM1mutation.

7. The method of any one of claims 1 to 5, wherein the acute leukemia comprises a KMT2Arearrangement.

8. The method of any one of claims 1 to 7, wherein the acute leukemia is acute myeloidleukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndrome (MDS).

9. The method of any one of claims 1 to 8, wherein the acute leukemia is AML.WSGR Reference No.47535-753.60110. The method of claim 9, wherein the AML is refractory AML, relapsed AML, relapsedand refractory AML, or newly diagnosed AML, optionally wherein the AML is relapsed or refractory AML, optionally wherein the individual has been treated with at least one prior line of therapy, optionally wherein the individual has failed at least one prior line of therapy.

11. The method of any one of claims 1 to 8, wherein the acute leukemia is ALL, optionallywherein the ALL is refractory ALL, relapsed ALL, relapsed and refractory ALL, or newly diagnosed ALL, optionally wherein the ALL is relapsed or refractory ALL, optionally wherein the individual has been treated with at least one prior line of therapy, optionally wherein the individual has failed at least one prior line of therapy.

12. The method of claim 10 or claim 11, wherein the at least one prior line of therapycomprises a BCL-2 inhibitor, a hypomethylating agent, a nucleoside metabolic inhibitor (such as a cytosine arabinoside), a topoisomerase inhibitor, a DNA synthesis inhibitor, a granulocyte colony-stimulating factor, a menin inhibitor, HSCT, donor lymphocyte infusion (DLI), or any combination thereof.

13. The method of any one of the preceding claims, wherein the standard-of-care therapycomprises a BCL-2 inhibitor, a hypomethylating agent, a nucleoside metabolic inhibitor (such as a cytosine arabinoside), a topoisomerase inhibitor, a DNA synthesis inhibitor, or a granulocyte colony-stimulating factor, or any combination thereof.

14. The method of claim 13, wherein the standard-of-care therapy comprises the BCL-2inhibitor, the hypomethylating agent, or the BCL-2 inhibitor and the hypomethylating agent.

15. The method of claim 13 or claim 14, wherein the BCL-2 inhibitor is venetoclax,navitoclax, obatoclax, oblimersen sodium, or ABT-737, optionally wherein the BCL-2 inhibitor is venetoclax.

16. The method of any one of claims 13 to 15, wherein the hypomethylating agent isazacitidine or decitabine, optionally wherein the hypomethylating agent is azacitidine.

17. The method of claim 13, wherein the standard-of-care therapy comprises the nucleosidemetabolic inhibitor (such as a cytosine arabinoside), the topoisomerase inhibitor, or theWSGR Reference No.47535-753.601 nucleoside metabolic inhibitor (such as the cytosine arabinoside) and the topoisomerase inhibitor.

18. The method of claim 13 or claim 17, wherein the nucleoside metabolic inhibitor iscytarabine or cytarabine arabinoside.

19. The method of any one of claims 13, 17, or 18, wherein the topoisomerase inhibitor is ananthracycline agent, optionally wherein the anthracycline agent is daunorubicin, idarubicin, doxorubicin, or mitoxantrone, optionally wherein the anthracycline agent is daunorubicin.

20. The method of any one of claims 13 or 17 to 19, wherein the standard-of-care therapycomprises administering a 7+3 or VYXEOSTMregimen.

21. The method of claim 13, wherein the standard-of-care therapy comprises the DNAsynthesis inhibitor, the nucleoside metabolic inhibitor (such as the cytosine arabinoside), the granulocyte colony-stimulating factor, or the topoisomerase inhibitor, or a combination thereof.

22. The method of claim 21, wherein the standard-of-care therapy comprises the DNAsynthesis inhibitor, the nucleoside metabolic inhibitor (such as the cytosine arabinoside), the granulocyte-colony stimulating factor, and the topoisomerase inhibitor.

23. The method of claim 13, 21, or 22, wherein:^ the DNA synthesis inhibitor is fludarabine;^ the cytosine arabinoside is cytarabine or Ara C;^ the granulocyte colony-stimulating factor is G-CSF;^ the topoisomerase inhibitor is an anthracycline, optionally selected from daunorubicin,idarubicin, doxorubicin, and mitoxantrone, optionally wherein the topoisomerase inhibitor is daunorubicin or idarubicin; or ^a combination thereof.

24. The method of any one of claims 3 to 23, wherein the lead-in period is the first at least 3days, or at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days, or 3 to 21 days, or 3 to 14 days, or 3 to 10 days, or 3 to 7 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days,WSGR Reference No.47535-753.601 or 8 days, or 9 days, or 10 days of the induction cycle, e.g., a 28-day induction cycle, for example, on Days 1 to 14, Days 1 to 10, Days 1 to 9, Days 1 to 8, Days 1 to 7, Days 1 to 6, Days 1 to 5, Days 1 to 4, or Days 1 to 3 of a 28-day induction cycle; and administering the menin inhibitor for the remainder of the induction cycle, optionally in combination with the standard- of-care therapy or a component thereof.

25. The method of any one of claims 3 to 24, comprising administering the menin inhibitorto the individual for N additional induction cycles, wherein N is 1, 2, 3, 4, 5, or 6, or is 1, or is 2, optionally and independently for each cycle in combination with the standard-of-care therapy or a component thereof.

26. The method of any one of claims 3 to 25, comprising administering the menin inhibitorduring P consolidation cycles, wherein P is at least 1, or is 1, 2, 3, or 4, or is 1 to 4, or is 1 to 2, optionally wherein each consolidation cycle comprises 28 days, optionally and independently for each consolidation cycle in combination with the standard-of-care therapy or a component thereof.

27. The method of any of the preceding claims, comprising administering to the individualan HSCT following the one or more induction cycles, and optionally following the one or more consolidation cycles, and administering to the individual the menin inhibitor following the HSCT.

28. The method of any one of the preceding claims, wherein the administering does notproduce any one or more of a significant toxicity or a significant risk of myelosuppression, neutropenia, thrombocytopenia, QTc prolongation, adverse cardiovascular event, differentiation syndrome-suspect event, differentiation syndrome, tumor lysis syndrome, or drug-drug interaction.

29. The method of any one of claims 1 to 28, comprising administering the menin inhibitordaily, once daily, or twice daily, or comprising administering the menin inhibitor without a CYP3A inhibitor or a CYP3A4 inhibitor.

30. The method of any one of claims 1 to 29, wherein the menin inhibitor is ziftomenib,SNDX-5613 (revumenib), VTP-50469, JNJ-75276617, DS-1594, DS-1594a, DS-1594b, DSP-WSGR Reference No.47535-753.601 5336, MI-3454, M-808, A300-105A, BN104, Compound A, Compound B1, Compound B2, or Compound C, or a pharmaceutically acceptable form thereof.

31. The method of any one of claims 1 to 30, wherein the menin inhibitor is a compound ofFormula (I-A), (I-B), (II-A), (III-A), (IV-A), or (IV-B), or a pharmaceutically acceptable form thereof.

32. The method of any one of claims 1 to 31, wherein the menin inhibitor is ziftomenib or apharmaceutically acceptable form thereof, optionally comprising administering ziftomenib or the pharmaceutically acceptable form thereof at a dose of 50 to 2000 mg daily, or 50, 100, 200, 400, or 600 mg once daily.

33. A pharmaceutical composition for use according to the method of any one of claims 1 to32, comprising a menin inhibitor.

Images