DSP-5336-101

R/R AML/ALL (± MLLr or NPM1m) with required disease/genomic confirmation; age >=18 (site exceptions), ECOG <=2, WBC below protocol threshold, adequate renal/hepatic function, life expectancy >=3 months, contraception/pregnancy requirements met.

- For Phase 1: confirmed refractory or relapsed AML, ALL, or acute leukemia of ambiguous lineage (WHO 2022), or in US MDS/MM, with progression after available standard active therapies. If in transformation from MDS/other hematologic malignancy, standard AML therapy after transformation is required before enrollment. In regions/countries where required, documented KMT2A (MLL) fusion or NPM1 mutation (coexisting FLT3 and/or IDH1/2 allowed). Candidates for stem-cell transplantation must have been offered this option. - Acute leukemia definitions: - Refractory: no CR/CRi after initial intensive therapy, or no CR/CRi/MLFS/PR after sufficient HMA/LDAC-based therapy (>=4 cycles HMA/LDAC or >=2 cycles combination with venetoclax or glasdegib; rare 1-cycle exception if clear progression and further cycle unethical). - Relapse: relapse by bone marrow assessment, peripheral blasts, or extramedullary disease after prior CR/CRi (with or without consolidation/maintenance and with or without HSCT). - MDS (US): bone marrow blasts >=5%; relapsed/refractory disease; exhausted available standard therapies including >=2 HMA cycles. - MM (US): IMWG 2016 diagnosis; progression after >=3 prior regimens including PI + IMiD + anti-CD38 mAb; not candidates for established-benefit options; measurable disease by protocol M-protein/free-light-chain thresholds; protocol-specified calcium/ANC/Hb/platelet criteria. - Venetoclax/azacitidine combination cohort (R/R AML): must have MLLr or NPM1m. - Gilteritinib combination cohort (R/R AML): must have MLLr or NPM1m AND FLT3-ITD or FLT3-TKD (D835 or I836). - RP2D confirmation cohort (R/R AML with NPM1): bone marrow blasts >=5%; no prior menin inhibitor. - For Phase 2: confirmed refractory/relapsed AML or ALL (WHO 2022) with >=5% marrow blasts by morphology; extramedullary-only or peripheral-blast-only relapse not eligible; no prior menin inhibitor; documented KMT2A fusion or NPM1 mutation at relapse/immediately before refractory determination (KMT2A alterations other than fusions not allowed). - For all patients: - Age >=18 years (or local adult age; South Korea >=19). At permitted countries/sites, monotherapy acute-leukemia patients >=12 years and >=40 kg may enroll. - ECOG <=2. - WBC: <30,000/uL for monotherapy; <25,000/uL for combination arms at enrollment and before treatment start (hydroxyurea/steroid cytoreduction allowed). - Prior treatment toxicities resolved to <=Grade 1 except <=Grade 2 alopecia/neuropathy. - Adequate organ function: CLcr >=50 mL/min (Cockcroft-Gault), bilirubin <=1.5x ULN (<=2.0x if Gilbert syndrome), AST <=3x ULN, ALT <=3x ULN. - Willingness for protocol visits; estimated life expectancy >=3 months. - Negative pregnancy test (if applicable) and required contraception/pregnancy prevention during treatment and for 6 months after last dose (UK-specific highly effective contraception requirement applies). - Bone marrow material suitable for genomic analysis (or alternative such as peripheral blood if marrow insufficient).

APL; recent HSCT/CAR-T or ongoing significant GVHD/immunosuppression; recent anti-cancer/investigational therapy; active CNS leukemia; significant cardiac/QTc risk; uncontrolled active infection/viral replication; prohibited strong CYP3A4/5 modulators; pregnancy/breastfeeding; major GI absorption issues.

- Histologic acute promyelocytic leukemia. - HSCT or CAR-T/modified T-cell therapy within 60 days before first dose (UK: CAR-T/modified T-cell within 6 months). - Donor lymphocyte infusion within 28 days; active post-HSCT immunosuppression at screening; clinically active GVHD or GVHD needing active intervention beyond topical steroids for cutaneous GVHD. - Antineoplastic agents (except defined hormonal maintenance and hydroxyurea for blast control) or other investigational treatment within 14 days or 5 half-lives (whichever is shorter). - Systemic calcineurin inhibitors within 2 weeks before first dose. - Major surgery within 28 days before first dose. - Active CNS leukemia (prophylactic intrathecal chemotherapy allowed). - Clinically significant screening ECG abnormalities, including prolonged QTc per protocol thresholds (general QTcF >480 ms; UK sex-specific QTcF thresholds), history of prolonged QT syndrome, or need for QT-prolonging therapies. - LVEF <50% by ECHO. - History of Torsades de Pointes. - Concurrent conditions that may pose undue hazard or interfere with interpretation, including but not limited to NYHA class III/IV heart failure, unstable angina, treatment-requiring arrhythmia (except asymptomatic AF), recent MI/acute coronary syndrome, significant pulmonary disease, uncontrolled hypertension, or poorly controlled diabetes with recurrent ketoacidosis. - Active infection markers: known detectable HIV or HCV viral load, or HBsAg positivity indicating active infection (with region-specific HBV testing follow-up where required). - Active uncontrolled bacterial/viral/fungal infection requiring parenteral therapy; must be afebrile with negative blood cultures >=72 hours before Cycle 1 Day 1. - Severe dysphagia, short-gut syndrome, gastroparesis, or other oral absorption-limiting conditions; inability to swallow oral medication. - Cognitive/psychological/psychosocial impediment compromising consent/compliance. - Concurrent sensitive narrow-therapeutic-index CYP3A substrates or strong CYP3A4/5 inhibitors/inducers; specifically excluded azoles include ketoconazole, itraconazole, and isavuconazole (switching to permitted azole with required washout may allow Arm B entry). - Pregnant, breastfeeding, or planning pregnancy (breastfeeding interruption rules apply). - Interstitial lung disease exclusions per region (eg, Japan Phase 1 dose-escalation; EU Grade >=2 drug-induced ILD or non-infectious pneumonitis within 6 months). - Plasma cell leukemia for MM patients (>2.0 x 10^9/L plasma cells in blood). - For gilteritinib-combination intent: must be gilteritinib-naive or gilteritinib-sensitive and have no FLT3 inhibitor in relapsed/refractory setting (frontline FLT3 inhibitor allowed). - Known intolerance/hypersensitivity to investigational product components. - UK Arm E only: live vaccine within 30 days before first DSP-5336 dose.