Acute Lymphoblastic Leukemia (ALL) Clinical Trials

• For patients in Phase I:

• Have a diagnosis of relapsed or refractory AML, ALL or acute leukemia of ambiguous lineage according to World Health Organization (WHO) 2022 classification, or, in selected sites and regions, a diagnosis of MDS or MM as determined by pathology review at the treating institution, and whose disease has progressed after available standard therapies known to be active for their AML, ALL, or acute leukemia of ambiguous lineage or, in selected sites and regions, for MM or MDS. If acute leukemia patients are transformation from MDS or other hematologic malignancies, patients need to receive available standard therapies as acute leukemia after AML transformation and before enrolling this trial. In regions or countries where required by regulatory authorities, participants must have a documented KMT2A (MLL) fusion or NPM1 mutation, including those with coexisting FLT3 genomic alterations and/or IDH1/2 mutation. Participants who are candidates for stem cell transplantation must have been offered this therapeutic option.

• For patients with MDS (selected sites and regions):

‣ Patients with MDS must have bone marrow blasts ≥ 5%

‣ Patients with MDS must have relapsed or refractory disease and have exhausted available standard therapies including at least 2 cycles of treatment with HMA

∙ For patients with MM (selected sites and regions):

‣ Have a confirmed diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) 2016 classification (Kumar, 2016) and whose disease has progressed after treatment with a minimum of 3 prior anti-myeloma regimens including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb); patients must not be candidates for available therapies with established clinical benefit

‣ Have measurable disease as defined in the protocol

‣ Meet the laboratory parameters set in the protocol

∙ For patients with relapsed/refractory AML in the venetoclax and azacitidine combination cohort (in countries and sites where permitted):

‣ Have MLLr or NPM1m.

∙ For patients with relapsed/refractory AML in the gilteritinib combination cohort (in countries and sites where permitted):

‣ Have MLLr or NPM1m AND any of the following FLT3 mutations: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.

∙ For patients with relapsed/refractory AML with NPM1 enrolled in the RP2D confirmation cohort:

‣ Must have ≥5% blasts in bone marrow by morphologic assessment

‣ Must not have received prior treatment with a menin inhibitor

∙ For patients with newly diagnosed AML:

∙ Must have AML as defined by WHO 2022 criteria with a documented MLLr or NPM1m (patients with AML characterized by MLL partial tandem duplications, MLL deletions, or trisomy 11 are not eligible)

∙ Must not have received treatment for AML with the exception of hydroxyurea for control of white blood cell counts.

• For patients in Phase 2:

• Have a confirmed diagnosis of relapsed AML or ALL according to WHO 2022 classification, as determined by pathology review at the treating institution, and who have ≥5% blasts by morphologic assessment in the bone marrow. Patients with extramedullary disease or peripheral blasts as the only manifestation of relapse are not eligible. Patients must have received clinically applicable standard therapies with confirmed survival benefit. Patients must not have had prior exposure to a menin inhibitor.

• Have a documented KMT2A (MLL)-fusion assessed at relapse or immediately prior to the determination of refractory status. KMT2A genetic alterations other than fusions (eg, KMT2A-PTD, amplification, point mutation) are not permitted.

• For all patients:

• Be \> 18 years of age. For countries and sites where approved, for DSP-5336 monotherapy, acute leukemia patients ≥12 years of age who weigh ≥40 kg may be enrolled.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

• For monotherapy, WBC below 30,000/μ at enrollment. For the combination arms, WBC count must be below 25,000/uL at enrollment and prior to starting treatment. (Hydroxyurea and steroids for cytoreduction purposes are allowed prior to enrollment and during study treatment)

• Clearance of creatinine level ≥ 50 ml/min, assessed by the CPK-EPI formula (2021 version and Cystatin C not required)

• Total bilirubin ≤1.5 the upper limit of normal (ULN) (or ≤2.0 ULN for patients with known Gilbert's syndrome)

• Aspartate aminotransferase (AST) ≤3.0 times ULN

⁃ Alanine aminotransferase (ALT) ≤3.0 times ULN

⁃ Any prior treatment-related toxicities resolved to Grade ≤1 prior to enrollment, with the exception of Grade ≤2 alopecia or neuropathy

⁃ Be willing to attend study visits as required by the protocol

⁃ Have an estimated life expectancy ≥3 months, based on the investigator's assessment

⁃ Females of childbearing potential must have a negative serum pregnancy test. Females of childbearing potential are defined as women who have (1) experienced menarche and have not undergone sterilization procedures (hysterectomy, or bilateral oophorectomy), or have (2) not experienced menopause as defined in the protocol.

⁃ All men and all women of childbearing potential and male patients' partners who are women of childbearing potential are required to use a highly effective method of contraception during the study and for 6 months (for females and males alike) after the last dose of study drug. Further guidelines noted in protocol.

⁃ Have AML/ALL/MDS/MM bone marrow material suitable for genomic analysis of AML,ALL, MDS, or MM genetic alterations. Note: If a bone marrow material is insufficient, an alternative suitable tissue (ex: peripheral blood) must be provided.