A Phase 1/2 Study of Enzomenib (DSP-5336) in Patients With Acute Leukemia (Horizen-1)

Inclusion Criteria:

For patients in Phase I:

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

2. Patients with MDS must have bone marrow blasts ≥ 5%

3. Patients with MDS must have relapsed or refractory disease and have exhaustedavailable standard therapies including at least 2 cycles of treatment with HMAFor patients with MM (selected sites and regions):

4. Have a confirmed diagnosis of multiple myeloma according to InternationalMyeloma Working Group (IMWG) 2016 classification (Kumar, 2016) and whosedisease has progressed after treatment with a minimum of 3 prior anti-myelomaregimens including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb); patients must not becandidates for available therapies with established clinical benefit

5. Have measurable disease as defined in the protocol

6. Meet the laboratory parameters set in the protocolFor patients with relapsed/refractory AML in the venetoclax and azacitidinecombination cohort (in countries and sites where permitted):

7. Have MLLr or NPM1m.For patients with relapsed/refractory AML in the gilteritinib combinationcohort (in countries and sites where permitted):

8. 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 RP2Dconfirmation cohort:

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

10. Must not have received prior treatment with a menin inhibitorFor patients with newly diagnosed AML:

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

12. Must not have received treatment for AML with the exception of hydroxyurea forcontrol of white blood cell counts. For patients in Phase 2:

13. Have a confirmed diagnosis of relapsed AML or ALL according to WHO 2022classification, as determined by pathology review at the treating institution, andwho have ≥5% blasts by morphologic assessment in the bone marrow. Patients withextramedullary disease or peripheral blasts as the only manifestation of relapse arenot eligible. Patients must have received clinically applicable standard therapieswith confirmed survival benefit. Patients must not have had prior exposure to amenin inhibitor.

14. Have a documented KMT2A (MLL)-fusion assessed at relapse or immediately prior to thedetermination of refractory status. KMT2A genetic alterations other than fusions (eg, KMT2A-PTD, amplification, point mutation) are not permitted. For all patients:

15. 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.

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

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

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

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

20. Aspartate aminotransferase (AST) ≤3.0 times ULN

21. Alanine aminotransferase (ALT) ≤3.0 times ULN

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

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

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

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

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

27. 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). For clinicalsites in the UK, have abnormal ECGs at screening that are clinically significant,such as QTc ≥470 msec and ≥450 msec with QTc corrected according to Fridericia'sformula (QTcF), for females and males, respectively. In addition, patients with ahistory of prolonged QT syndrome or who are required to take therapies associatedwith QT-interval prolongation are excluded. Note: In case of bundle branch block, QT interval correction can be performed.

5. Has an active and uncontrolled, 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. Had major surgery within 28 days prior to the first dose of DSP-5336

8. Has active central nervous system leukemia (prophylactic intrathecal chemotherapy isallowed).

9. 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. For clinicalsites in the UK, underwent CAR-T therapy or other modified T-cell therapy within 6months prior to the first dose of DSP-5336.

10. 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

11. 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 7 days or 5 half-lives, whichever is shortest,prior to the first dose of DSP-5336

12. In the opinion of the treating investigator, have any concurrent conditions thatcould pose an undue medical hazard or interfere with interpretation of studyresults; these conditions include, but are not limited to: clinically significantnon-healing or healing wounds; concurrent congestive heart failure (New York HeartAssociation Functional Classification Class III or IV; see Section 21.2); concurrentunstable angina; concurrent cardiac arrhythmia requiring treatment (excludingasymptomatic atrial fibrillation); recent (within the prior 6 months) myocardialinfarction; acute coronary syndrome within the previous 6 months; significantpulmonary disease (shortness of breath at rest or on mild exertion), eg, due toconcurrent severe obstructive pulmonary disease, concurrent hypertension notcontrolled with concomitant medication, or diabetes mellitus with more than 2episodes of ketoacidosis in the prior 6 months

13. 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.

14. 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

15. Have cognitive, psychological, or psychosocial impediment that would impair theability of the patient to 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

16. 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

17. Have any history or complication of interstitial lung disease (for sites in Japan inPhase 1 dose escalation). 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.

18. Have a history of Torsades de Pointes

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

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

21. 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)

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

23. For clinical sites in the UK: In Arm E (DSP-5336 + venetoclax/azacitidine), havereceived a live vaccine within 30 days prior to the first dose of DSP-5336