This study will take place in parts:
- Dose Escalation (Part 1): Participants receive milademetan alone with different dose
- Dose Escalation (Part 1A): Participants receive milademetan in combination with AZA,
with different dose schedules
The recommended dose for Part 2 will be selected.
- Dose Expansion (Part 2): After Part 1A, participants will receive the recommended Part 2
dose schedule. There will be three groups - those with:
1. refractory or relapsed AML
2. newly diagnosed AML unfit for intensive chemotherapy
3. high-risk MDS
- End-of-Study Follow-Up: Safety information will be collected until 30 days after the
last treatment. This is the end of the study.
The recommended dose for the next study will be selected.
1. Has a diagnosis of refractory or relapsed AML or high risk MDS for inclusion in Part
1, Part 1A, and Part 2 (Cohorts 1 and 3).
2. Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
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.
6. 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.
7. Is fully informed about their illness and the investigational nature of the study
protocol (including foreseeable risks and possible side effects).
8. 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.
9. Is able and willing to provide bone marrow biopsies/aspirates as requested by the
10. Is willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion
11. Has a life expectancy of at least 3 months.
Other criteria for Part 2, Cohort 2 (newly diagnosed AML unfit for intensive
chemotherapy) The following criteria should be met by participants in Dose Expansion
Cohort 2 who never received prior treatment for AML. These participants need not meet
inclusion criteria 1 and 2 (above).
12. Participant is ineligible for intensive induction chemotherapy by meeting at least 1
(a or b) of the following criteria:
1. Is ≥ 75 years of age with ECOG performance status 0 to 2.
2. Is 18 to 74 years old and has any of the following comorbidities:
- Known congestive heart failure (New York Heart Association class 3) or
ejection fraction ≤ 50%
- ECOG performance status 3 not related to leukemia
- Any other comorbidity that the physician judges to be incompatible with
conventional intensive chemotherapy, but meets all the inclusion criteria
except 1 and 2.
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 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). Has a washout period of ≥ 2 weeks or at least 4
half-lives (whichever is longer) from their last systemic immunosuppressive treatment
10. Is receiving concomitant treatment with a strong inhibitor or inducer of cytochrome
11. Has received any therapies intended to treat malignancy within 14 days of first
receipt of DS-3032b [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
14. Has prolongation of corrected QT interval using 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).
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.