MDM2 Inhibitor DS-3032b and Low-Dose Cytarabine in Treating Participants With Newly Diagnosed Recurrent or Refractory Acute Myeloid Leukemia

Objectives:

Primary Objectives:

The primary objectives of this study are to evaluate the safety, tolerability, and determine
the recommended phase two dose (Phase 1) and efficacy (by IWG criteria - Phase 2) of the MDM2
inhibitor, DS-3032b, in combination with LDAC in relapsed/refractory (non-TP53 mutant)
patient population.

Secondary Objectives:

Evaluation of time to response variables including overall survival (OS), event-free survival
(EFS) and duration of response (DOR) Determine biomarkers that may be predictive of DS-3032b
activity. Molecular profiling at screening, on study, and at relapse to determine genomic
predictors of response and resistance

Inclusion Criteria:

1. Subjects must have refractory or relapsed AML (salvage 1, 2, and 3).

2. TP53 wild-type status on molecular testing performed within the last 3 months.

3. Patient should be >/= 18 years old.

4. Eastern Cooperative Oncology Group (ECOG) performance status
5. Adequate renal function, defined as: creatinine clearance >/= 60 mL/min, as calculated
using the modified Cockcroft-Gault equation, ([{140 - age in years} × {actual weight
in kg}] divided by [{72 × serum creatinine in mg/dL} multiply by 0.85 if female]), OR
creatinine
6. Adequate hepatic function, defined as: AST/ALT unless resulting from hemolysis, Gilbert's disease or considered to be due to leukemic
involvement. No gastrointestinal issues to interfere with oral medication absorption.

7. No active uncontrolled infection or comorbidity that would interfere with therapy or
place patient at increased risk.

8. Subject (male and female) of childbearing/ reproductive potential must agree to use
double-barrier contraceptive measures or avoid intercourse during the study and for 90
days after the last dose of study drug.

9. Subject must sign and date 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.

10. Able and willing to provide bone marrow biopsies/aspirates as requested by the
protocol.

11. Willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at
screening.

12. A life expectancy of at least 3 months.

Exclusion Criteria:

1. Patient with t(15;17) karyotypic abnormality or a diagnosis of acute promyelocytic
leukemia.

2. Patient with other malignancy that contains a non-synonymous mutation, insertion, or
deletion in the TP53 gene determined previously or at screening.

3. Prior treatment with an MDM2 inhibitor.

4. Presence of central nervous system involvement of leukemia. History of prior
leptomeningeal leukemia / disease that has fully resolved is eligible.

5. A second concurrent primary malignancy that has required active treatment within the
previous 2 years, except for localized cancers that have apparently been cured, for
example non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of
the cervix or breast.

6. Any condition that would preclude adequate absorption of DS-3032b, including
refractory vomiting, malabsorption, biliary shunt, significant bowel resection, and/or
graft-versus-host disease (GVHD) affecting the gut.

7. Any active uncontrolled infection, known human immunodeficiency virus infection, or
active hepatitis B or C infection.

8. Any concomitant medical condition that would in the opinion of the Investigator
increase the risk of toxicity.

9. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other
than alopecia) not yet resolved to NCI-CTCAE v5, Grade chronic Grade 2 toxicities may be eligible per discretion of the Investigator and
Sponsor (eg, Grade 2 chemotherapy-induced neuropathy).

10. Patient having received Hematopoietic Stem Cell Transplantation (HSCT) within 60 days
of the first dose of DS-3032b, is on immunosuppressive therapy post-HSCT at the time
of screening, or has clinically significant GVHD (use of topical steroids for ongoing
skin GVHD will be permitted).

11. Patient receiving treatment with a strong inhibitor or inducer of CYP3A4. - Patient
receiving drugs that are strong CYP3A inhibitors within 7 days prior to the first dose
and during treatment. - Patient receiving drugs that are strong inducers of CYP3A
within 14 days prior to the first dose and during treatment.

12. Received any therapies intended to treat malignancy within 14 days of first receipt of
DS-3032b (except for hydroxyurea, which is allowed for control prior to and during the
first cycle of study treatment.

13. Prolongation of corrected QT interval by Fridericia's method (QTcF) at rest, where the
mean QTcF interval is >/= 450 ms for males or >/= 470 ms for females based on
triplicate electrocardiograms (ECGs). Patients with incomplete RBBB and QTc above
threshold will be eligible after PI review.

14. Pregnant or breastfeeding.

15. 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.