Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Inclusion Criteria 1. Has a diagnosis of refractory or relapsed (R/R) AML or high-risk MDS: * Part 1 and 1A (Dose Escalation) * Participants with R/R AML, OR * Participants with untreated, high-risk MDS or participants who have received prior MDS treatment regimens. * Participants ≥18 years old. * Part 2 (Dose Expansion) * Cohort 1: R/R AML * Participants who have treatment failure to prior AML therapy or have relapsed after prior AML therapy. * Participants ≥18 years old. * Cohort 2: Newly diagnosed AML * Participants with newly diagnosed AML who are ineligible for intensive induction chemotherapy. Participants must have had no prior AML treatment, with the exceptions of therapy for antecedent hematologic malignancies or hydroxyurea. * Participants ≥75 years old, OR Participants between 18 and 74 years old (inclusive) with at least one of the specific protocol-defined comorbidities. * Cohort 3: High-risk MDS * Participants with untreated, high-risk MDS or who received up to 2 prior MDS treatment regimens. 2. Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. * As an exception, participants with newly diagnosed AML between 18 and 74 years old (inclusive) in Part 2 Cohort 2 with ECOG Performance Status of 3 will be eligible. 3. Has protocol-defined adequate renal, hepatic and blood clotting functions. 4. Is able to provide written informed consent (or authorized representative), comply with protocol visits and procedures, and take oral medication, and does not have any active infection or comorbidity that would interfere with therapy. 5. If female, is either postmenopausal (no menstrual period for a minimum of 12 months), surgically sterile, or, if of childbearing potential, has a negative serum pregnancy test upon entry into this study and is willing to use maximally effective birth control during the period of therapy and for 6 months following the last investigational drug dose. * If male, is surgically sterile or willing to use a maximally effective double-barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose. 6. Is fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects). 7. Signs and dates an Institutional Review Board-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study-specific procedures or tests. 8. Is able and willing to provide bone marrow biopsies/aspirates as requested by the protocol. 9. Is willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening. Exclusion Criteria 1. Has a diagnosis of acute promyelocytic leukemia. 2. Has a malignancy that is known to contain a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening. 3. Has presence of central nervous system (CNS) involvement of leukemia or a history of primary CNS leukemia. 4. Has a second concurrent primary malignancy that required active treatment within the previous 2 years, except for localized cancers that have apparently been cured, such as non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast. 5. Has any condition that would preclude adequate absorption of DS-3032b, including refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut. 6. Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection. 7. Has a concomitant medical condition that would increase the risk of toxicity. 8. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE Grade ≤ 1, or baseline. Subjects with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator and Sponsor (eg, Grade 2 chemotherapy-induced neuropathy). 9. Has received Hematopoietic Stem Cell Transplantation (HSCT) within 60 days of the first dose of study drugs or has clinically significant GVHD or GVHD requiring initiation of systemic treatment or systemic treatment escalation within 21 days prior to Screening and/or \>Grade 1 persistent or clinically significant GVHD or other non-hematologic toxicity related to HCT. 10. Is receiving concomitant treatment with a strong inhibitor or inducer of cytochrome P450 3A4/5. 11. Has received any therapies intended to treat malignancy within 7 days (small molecules) or 21 days (anti-body/immune based biologics) of first receipt of study drugs \[except for hydroxyurea, which must be discontinued at least 48 hours (Day -2) prior to study treatment\]. 12. Had major surgery within 4 weeks prior to study drug treatment. 13. Participated in a therapeutic clinical study within a washout time of 2 weeks or 5 half-lives of the drug/biologic (whichever is longer) before starting study drug treatment under this protocol, or current participation in other therapeutic investigational procedures. 14. Has prolongation of corrected QT interval using Fridericia's method (QTcF) at rest, where the mean QTcF interval is \> 480 ms based on triplicate electrocardiograms (ECGs). 15. Is pregnant or breastfeeding. 16. Has substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results. 17. Prior treatment with an MDM2 inhibitor.