1. Patients aged ≥18 years at time of screening.
2. Written informed consent by the patient (or their legal representative) prior to
admission to this study. In addition, any locally required authorization (Health
Insurance Portability and Accountability Act in the US), must be obtained from the
patient prior to performing any protocol-related procedures, including screening
3. Adequate renal and hepatic function defined as:
1. Total bilirubin within 1.5 x upper limit of normal (ULN), except those with
Gilberts syndrome for whom this must be ≤3 x ULN
2. AST and ALT ≤2.5 x ULN
3. Calculated creatinine clearance ≥45 mL/min
4. Serum albumin ≥2.5 g/dL For any patient with laboratory values outside the ranges
outlined above that are considered due to the patient's underlying disease (AML
or MDS), the patient may be enrolled into the study following consultation
between the Investigator and the Sponsor's Medical Officer, if the patient is
likely to benefit from receiving ONO-7475 (based on the Investigator's
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 as assessed during
the screening period and then again anytime during the 2-day period immediately
preceding the start of dosing in Parts A and D.
5. Life expectancy of at least 3 months
6. Sexually active female patients of childbearing potential and sexually active male
patients must agree to use an effective method of birth control (e.g., barrier methods
with spermicides, oral or parenteral contraceptives and/or intrauterine devices)
during the entire duration of the study and for 4 months after final administration of
study drug. Note that sterility in female patients must be confirmed in the patients'
medical records and be defined as any of the following: surgical hysterectomy with
bilateral oophorectomy, bilateral tubular ligation, natural menopause with last menses
>1 year ago, radiation-induced oophorectomy with last menses >1 year ago,
chemotherapy-induced menopause with last menses >1 year ago.
7. Diagnosis of AML or MDS according to WHO criteria 2016 (Part A only).
8. Either criterion is met (Part A only):
1. Patients with R/R AML with at least 5% blasts by BM biopsy or aspirate, or at
least 1% blasts in peripheral blood, not likely to benefit from standard salvage
2. Patients with R/R MDS who are either not eligible for (or unlikely to benefit
from) other forms of therapy, including HSCT, according to the treating
9. All patients must have received at least one previous line of therapy (Part A only).
10. Diagnosis of AML according to WHO criteria (2016) (Part D only).
11. Patients with R/R AML who have no standard-of-care options known to provide clinical
benefit in patients with R/R AML (Part D only)
1. Refractory AML: Patients who have not achieved complete remission after two
cycles of induction chemotherapy (i.e., anthracycline containing regimen), four
cycles of hypomethylating agents, or two cycles of other AML therapy
2. Relapsed AML: Patients who have ≥5% BM blasts in BM, or reappearance of blasts in
the peripheral blood not attributable to another cause (e.g., recovery of normal
cells following chemotherapy-induced aplasia) or (re)appearance of extramedullary
disease after CR of prior AML therapy.
12. All patients must have measured BM aspirate blast counts at Screening. Where the
aspirate is hypo cellular or inaspirable a biopsy would be considered (Part D only).
13. All patients must have received 1 to 3 (inclusive) prior AML therapies after first
diagnosis of AML (Part D).
1. Patients with active central nervous system leukemia.
2. QT interval corrected according to Fredericia's formula (QTcF) prolongation defined as
a QTcF interval >470 msec or other significant ECG abnormalities including second
degree (type II) or third degree atrioventricular block or bradycardia (ventricular
rate <50 beats/min).
3. Clinically significant liver disease, including active viral or other hepatitis,
current alcohol abuse, or severe cirrhosis.
4. Human immunodeficiency virus (HIV), active hepatitis B (HBV) or C (HCV) infection.
5. Retinal disease (e.g., retinitis pigmentosa including Mertk mutations), retinal
hemorrhage or any disorder which may inhibit follow up for retinal toxicity.
6. Serious intercurrent medical or psychiatric illness that will prevent participation or
compliance with study procedures, including serious active infection (including
7. Acute promyelocytic leukemia (the French-American-British M3 classification).
8. Patients not recovered to Grade 1 or stabilized from the effects (excluding alopecia)
of any prior therapy for their malignancies.
9. Concurrent treatment with other investigational drugs.
10. Daily requirement of ≥10 mg/day of prednisone or equivalent dose of other
11. Prior HSCT within 12 weeks of the first dose of study treatment or ongoing
immunosuppressive therapy for graft-versus-host disease.
12. Participation in another clinical trial with any investigational drug within 14 days
or with any licensed drug within five half-lives, prior to the first ONO-7475 dosing
(for Part A) or prior to the first venetoclax dosing (for Part D).
13. Prior AML or MDS therapy (non-experimental) within 14 days or 5 half-lives, whichever
is longer, prior to the first dose of ONO-7475 (for Part A) or prior to the first
venetoclax dosing (for Part D) (except those permitted in Section 7.1) and no residual
toxicity from the prior therapy hindering of the ONO-7475 dosing (for Part A) or
ONO-7475 plus venetoclax dosing (for Part D).
14. Prior radiotherapy within 21 days of screening, with the exception of localized
15. Patients undergoing current treatments for other cancers.
16. Pregnant or lactating women.
17. Proliferative disease (white blood cell [WBC] counts >30 x 10e9/L) confirmed prior to
the first dose of ONO-7475 (for Part A) or WBC >25 x 10e9/L in Part D.
18. Active malignancy, other than AML (Parts A and D) or MDS (Part A), requiring systemic
therapy except for those patients who have been diagnosed with either prostate or
breast cancer and who have received a stable dose of hormone therapy for a minimum of
6 months prior to entering this study.
19. Known hypersensitivity to venetoclax (Part D only).