Summary

[Updated]: To assess the safety and tolerability of ONO-7475 monotherapy in patients with
relapsed or refractory acute myeloid leukemia or relapsed or refractory myelodysplastic
syndromes and to assess: i) safety and tolerability and ii) preliminary efficacy of the
combination of ONO-7475 and venetoclax in patients with relapsed or refractory acute myeloid
leukemia.

Eligibility

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 evaluations.
3. Adequate renal and hepatic function defined as:
4. Total bilirubin within 1.5 x upper limit of normal (ULN), except those with Gilberts syndrome for whom this must be =3 x ULN
5. AST and ALT =2.5 x ULN
6. Calculated creatinine clearance =45 mL/min
7. 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 assessment).
8. 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.
9. Life expectancy of at least 3 months
10. 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.
11. Diagnosis of AML or MDS according to WHO criteria 2016 (Part A only).
12. Either criterion is met (Part A only):
13. 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 chemotherapy
14. 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 Physician/Investigator .
15. All patients must have received at least one previous line of therapy (Part A only).
16. Diagnosis of AML according to WHO criteria (2016) (Part D only).
17. 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)
18. 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
19. 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.
20. Patients must have measured BM aspirate blast counts at Screening. Where the aspirate is hypo cellular or inaspirable a biopsy would be considered.
21. Patients who were refractory to or relapsed after their 1st line treatment for AML must have received 2 or less additional lines of intensive / aggressive chemotherapy, which also includes a venetoclax-based regimen, as per the latest National Comprehensive Cancer Network (NCCN) Guidelines.