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

Eligibility Criteria

• 1. Patients with MDS must have IPSS-R risk categorization of "high" or "very high" at initial diagnosis or at study entry and have bone marrow blasts ≥ 5% (which is the definition of high-risk MDS in this study)
• 2. Patients with MDS must have relapsed or refractory disease and have exhausted available standard therapies including at least 2 cycles of treatment with HMA
• 1. 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
• 2. Have measurable disease as defined in the protocol
• 3. Meet the laboratory parameters set in the protocol
• 1. Have MLLr or NPM1m.
• 2. Have MLLr or NPM1m AND any of the following FLT3 mutations: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.
• 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, with induction chemotherapy, consolidation chemotherapy, and stem cell transplantation with 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 H assessed 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-5336 monotherapy, acute leukemia patients ≥12 years of age who weigh ≥40 kg may be enrolled.
• 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 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)
• 7. Clearance of creatinine (CLcr) level ≥ 50 ml/min, assessed by the Cockcroft-Gault formula
• 8. Total bilirubin ≤1.5 the upper limit of normal (ULN) (or ≤2.0 ULN for patients with known 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 of birth control (each partner must use one method) or use prevention of pregnancy measures (ie, agreement to refrain completely from heterosexual intercourse) during the study and for 6 months (for females and males alike) after the last dose of study drug, if male or female patient is of child-producing potential
• 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, an alternative suitable tissue (ex: peripheral blood) must be provided.
• 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 of DSP 5336
• 4. Have abnormal ECGs at screening that are clinically significant, such as (QTc \>480 msec, with QTc corrected according to Fridericia's formula (QTcF). Note: In case of bundle branch block, QT interval correction can be performed.
• 5. Has an active anduncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy. Note: Patients must be afebrile with negative blood cultures at least 72 hours prior to Cycle 1 Day 1.
• 6. Receives concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole, isavuconazole and itraconazole. Other antifungals that are used as standard of care to prevent or treat infections are permitted. If a patient is on one of the excluded azole class antifungals, he/she can be taken off or switched to a permitted azole 7 or 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 CNS leukemia involvement are excluded from Phase 2 Arms G and H.
• 10. Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336. Patients who have received \>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 of DSP-5336, or receiving immunosuppressive therapy post-HSCT at the time of screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD
• 12. Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational 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 that could 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 active infection.
• 15. Have severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit 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 the ability of the patient o receive therapy according to the protocol, or adversely affect 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 are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug
• 18. Have any history or complication of interstitial lung disease (for sites in Japan in Phase 1 dose escalation only).
• 19. Have a history of Torsades de Pointes
• 20. Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP-5336
• 21. Have plasma cell leukemia (\>2.0 x 109 /L plasma cells in blood by standard differential) (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 FLT3 inhibitor in the relapsed refractory setting (prior FLT3 inhibitor in front line therapy is allowed)
• 23. Have a known intolerance of hypersensitivity reaction to components of the investigational medicinal product
• 24. Patients with LDH \>500 U/L (\>8.3 µkat/L) are excluded from Phase 2 Arms G and H