A Study of DSP-5336 in Relapsed/Refractory AML/ ALL With or Without MLL Rearrangement or NPM1 Mutation

Inclusion Criteria:

Patients in the Phase 1 dose-escalation portion must 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 the US only, 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 the US, for MM or MDS.

For patients with MDS (US only):

1. Patients with MDS must have IPSS-R risk categorization of "high" or "very high" atinitial diagnosis or at study entry and have bone marrow blasts ≥ 5% (which is thedefinition of high-risk MDS in this study)

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

For patients with MM (US only):

1. Have a confirmed diagnosis of multiple myeloma according to International MyelomaWorking Group (IMWG) 2016 classification (Kumar, 2016) and whose disease hasprogressed after treatment with a minimum of 3 prior anti-myeloma regimens includinga proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38monoclonal antibody (mAb); patients must not be candidates for available therapieswith established clinical benefit

2. Have measurable disease as defined in the protocol

3. 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):

1. Have MLLr or NPM1m. For patients with relapsed/refractory AML in the gilteritinib combination cohort (incountries and sites where permitted):

2. Have MLLr or NPM1m AND any of the following FLT3 mutations: FLT3-ITD, FLT3-TKD/D835or FLT3-TKD/I836.

Patients in the Phase 2 dose expansion portion of the study must have a confirmed diagnosis of relapsed AML or ALL as determined by pathology review at the treating institution, and who have ≥5% blasts by morphologic assessment in the bone marrow and failed available standard therapies known to be active for their AML (Arm G and H) or ALL (Arm I). If the primary disease is a transformation from MDS or other hematologic malignancies, patients need to receive available standard therapies for acute leukemia before enrolling this trial. Participants who are candidates for stem cell transplantation must have been offered this therapeutic option. Patients with extramedullary disease or peripheral blasts as the only manifestation of relapse are not eligible.

1. Patients must not have had prior exposure to a menin inhibitor

2. Patients for Arms G and H are limited to a total of 3 prior lines of therapy, withinduction chemotherapy, consolidation chemotherapy, and stem cell transplantationwith or without subsequent maintenance treatment considered to be 1 line.

3. Have a documented KMT2A (MLL)-fusion for Arm G and I or NPM1 mutation for Arm Hassessed at relapse or immediately prior to the determination of refractory status.For Arms G and I, KMT2A genetic alterations other than fusions (eg, KMT2A-PTD,amplification, point mutation) are not permitted.

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

5. ECOG < 2; For Phase 2 only, patients must have an ECOG performance status 0 or 1.

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

7. Clearance of creatinine (CLcr) level ≥ 50 ml/min, assessed by the Cockcroft-Gaultformula

8. Total bilirubin ≤1.5 the upper limit of normal (ULN) (or ≤2.0 ULN for patients withknown Gilbert's syndrome)

9. Aspartate aminotransferase (AST) ≤3.0 times ULN

10. Alanine aminotransferase (ALT) ≤3.0 times ULN

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

12. Be willing to attend study visits as required by the protocol

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

14. Females of childbearing potential must have a negative serum pregnancy test.

15. Must agree to use a highly effective contraception method or 2 acceptable methods ofbirth control (each partner must use one method) or use prevention of pregnancymeasures (ie, agreement to refrain completely from heterosexual intercourse) duringthe study and for 6 months (for females and males alike) after the last dose ofstudy drug, if male or female patient is of child-producing potential For sites in Japan only: Implantable hormonal contraceptives, a diaphragm withspermicide, cervical cap with spermicide and contraceptive sponge (spermicide isalready in the contraceptive sponge) included in the barrier contraceptive methodare not approved and cannot be used in Japan.

16. 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, analternative suitable tissue (ex: peripheral blood) must be provided.

Exclusion Criteria:

1. Has a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO

2. Histological diagnosis of acute promyelocytic leukemia

3. Received systemic calcineurin inhibitors within 2 weeks prior to the first dose ofDSP 5336

4. Have abnormal ECGs at screening that are clinically significant, such as (QTc >480msec, with QTc corrected according to Fridericia's formula (QTcF). Note: In case ofbundle branch block, QT interval correction can be performed.

5. Has an active anduncontrolled, bacterial, viral, or fungal infection requiringparenteral therapy. Note: Patients must be afebrile with negative blood cultures atleast 72 hours prior to Cycle 1 Day 1.

6. Receives concurrent sensitive substrates with a narrow safety window or stronginhibitors or inducers of CYP3A4/5, including specifically: ketoconazole,isavuconazole and itraconazole. Other antifungals that are used as standard of careto prevent or treat infections are permitted. If a patient is on one of the excludedazole class antifungals, he/she can be taken off or switched to a permitted azole 7or more days prior to first dose, then the patient could be allowed on study (Arm B)with approval of the medical monitor.

7. Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within 42 days prior to the first dose of DSP-5336

8. Had major surgery within 28 days prior to the first dose of DSP-5336

9. Has active central nervous system leukemia. Patients with a history of any CNSleukemia involvement are excluded from Phase 2 Arms G and H.

10. Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modifiedT-cell therapy within 60 days prior to the first dose of DSP-5336. Patients who havereceived >1 prior HSCT are excluded from Phase 2 Arms G and H.

11. Received a donor lymphocyte infusion within 28 days prior to the first dose ofDSP-5336, or receiving immunosuppressive therapy post-HSCT at the time of screening,or with clinically active GVHD or GVHD requiring active medical intervention otherthan the use of topical steroids for ongoing cutaneous GVHD

12. Received antineoplastic agents (except hormonal therapies as adjuvant maintenancefor breast or prostate cancers if a patient is taking before starting studytreatment, and hydroxyurea given for controlling blast cells) or otherinvestigational treatment within 14 days or 5 half-lives, whichever is shortest,prior to the first dose of DSP-5336

13. In the opinion of the treating investigator, have any concurrent conditions thatcould pose an undue medical hazard or interfere with interpretation of study results

14. Have a known detectable viral load for human immunodeficiency virus or hepatitis C,or evidence of hepatitis B surface antigen, all being indicative of activeinfection. For sites in Japan, Taiwan, and Korea only: Hepatitis B core (HBc) antibody orhepatitis B surface (HBs) antibody test should be performed if HBsAg is negative. IfHBc antibody or HBs antibody test is positive, HBV DNA quantification test should beperformed to confirm that HBV DNA is negative.

15. Have severe dysphagia, short-gut syndrome, gastroparesis, or other conditions thatlimit the ingestion or gastrointestinal absorption of drugs administered orally,including the inability to swallow oral medication

16. Have cognitive, psychologic, or psychosocial impediment that would impair theability of the patient o receive therapy according to the protocol, or adverselyaffect the ability of the patient to comply with the informed consent process,protocol, or protocol-required visits and procedures

17. Are pregnant or breastfeeding or planning to become pregnant. Note: Patients who arebreastfeeding may be enrolled if they interrupt breastfeeding prior to the firstdose of any study drugs and do not feed the baby with breast milk expressed afterreceiving the first dose of any study drugs. Breastfeeding should not be resumed forat least 6 months after the last dose of study drug

18. Have any history or complication of interstitial lung disease (for sites in Japan inPhase 1 dose escalation only). For clinical sites in the EU, have a history of Grade ≥ 2 drug-induced interstitiallung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of startingstudy treatment.

19. Have a history of Torsades de Pointes

20. Received systemic calcineurin inhibitors within 4 weeks prior to the first dose ofDSP-5336

21. Have plasma cell leukemia (>2.0 x 109 /L plasma cells in blood by standarddifferential) (for patients with MM only)

22. For patients intending to enroll into the combination cohort with gilteritinib:Patients must be gilteritinib-naïve or sensitive and have not received a FLT3inhibitor in the relapsed refractory setting (prior FLT3 inhibitor in front linetherapy is allowed)

23. Have a known intolerance of hypersensitivity reaction to components of theinvestigational medicinal product

24. Patients with LDH >500 U/L (>8.3 µkat/L) are excluded from Phase 2 Arms G and H