A Study of ONO-7475 in Patients With Acute Leukemias

\[Updated\]: 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.

Part A is a dose escalation study of ONO-7475 in patients with acute myeloid leukemia or relapsed or refractory myelodysplastic syndromes.

Part D is a dose escalation study of ONO-7475 in combination with venetoclax. ONO-7475 starting dose is selected following safety and tolerability outcome of Part A.

Eligibility Criteria:
Inclusion Criteria:

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:

   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 assessment).
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 chemotherapy
   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 Physician/Investigator .
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. Patients must have measured BM aspirate blast counts at Screening. Where the aspirate is hypo cellular or inaspirable a biopsy would be considered.
13. 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.

Exclusion Criteria:

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 COVID-19).
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 corticosteroids.
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 palliative radiotherapy.
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).
20. Calculated creatinine clearance \<45 mL/min