Oral Azacitidine Combined with Venetoclax in Previously Untreated Higher-risk Myelodysplastic Syndromes

Inclusion Criteria:

1. Subjects must understand and voluntarily sign and date an ICF indicating theinvestigational nature of the study, approved by an independent EC/IRB, prior to theinitiation of any screening or study-specific procedures.

2. Age ≥ 18 years at the date of signing the ICF.

3. Diagnosis of MDS according to the 2016 WHO classification (13) (Appendix 1), withpresence of < 20% bone marrow blasts per bone marrow aspirate at screening,confirmed by local investigator with HR-MDS, based on the revised InternationalPrognostic Scoring System (IPSS-R) >3 (intermediate, high or very high) (14) (Appendix 2) and a blast percentage of 5 or more.

4. Previously untreated HR-MDS: no prior therapy for MDS with any hypomethylatingagents (azacitidine or decitabine), chemotherapy, allo-Hematopoietic Stem CellTransplantation (HSCT) or experimental agent. All other treatments are notconsidered prior therapy.

5. Not immediately eligible for allo-HSCT or intensive chemotherapy at the time ofscreening due to individual clinical factors such as age, comorbidities andperformance status, donor availability.

6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

7. Total white blood cell (WBC) count ≤ 10 G/L; Treatment with hydroxyurea is permittedto lower the WBC to reach this inclusion criterion and will be stopped at least 48hours before treatment initiation.

8. Adequate liver functions as demonstrated by:

• Serum alanine transaminase (ALT) < 3.0 × upper limit of normal [ULN];

• Serum aspartate transaminase (AST) < 3.0 × ULN;

• Serum total bilirubin ≤ 2.0 × ULN (except in the setting of isolated Gilbertsyndrome, where participants may only be included with total bilirubin ≤ 3.0 xULN)

9. Adequate renal function with calculated creatinine clearance ≥ 40 mL/min/1.73 m² (estimation based on Modification of Diet in Renal Disease (MDRD) formula orCKD-EPI, by local laboratory).

10. Participant is able to communicate with the investigator, and has the ability tocomply with the requirements of the study procedures, available for regular bloodsampling, study related assessments, including bone marrow aspirates and appropriateclinical management at the treating institution for the duration of the study.

11. Females of childbearing potential (FCBP) is a female who: 1) has achieved menarcheat some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3)has not been naturally postmenopausal (amenorrhea following cancer therapy does notrule out childbearing potential) for at least 24 consecutive months (ie, has hadmenses at any time in the preceding 24 consecutive months). FCBP must agree toundergo medically supervised pregnancy test prior to starting study drug, during thecourse of the study, and after end of study therapy:

• Have one negative pregnancy test as verified by the Investigator prior tostarting study therapy. The first pregnancy test will be performed at screening (within 3 days prior to first study drug administration), and a negativeurinary test before starting all subsequent cycles. This applies even if theparticipant practices true abstinence from heterosexual contact or agree touse, and be able to comply with highly effective contraception withoutinterruption, 28 days prior to starting investigational product, during thestudy therapy (including dose interruptions), and for 6 months after last doseof Onureg, or at least 1 month after the last dose of venetoclax, whichever islater or longer if required by local regulations.

• Female patients are either post-menopausal, free from menses for > 2 years,surgically sterilized or willing to use 2 adequate barrier methods ofcontraception to prevent pregnancy or agree to abstain from becoming pregnantthroughout the study, starting with Visit 1. Females of reproductive potentialas well as fertile men and their partners who are female of reproductivepotential must agree to abstain from sexual intercourse or to use two highlyeffective forms of contraception from the time of giving informed consent,during the study and for 6 months (females and males) following the last doseof treatment.

12. Male participants must practice true abstinence (which must be reviewed on a monthlybasis) or agree to use an adequate method of contraception for the duration of thestudy. Men should be advised not to father a child while receiving treatment and for 3 months post study. Men must agree to learn about the procedures for preservationof sperm before starting treatment.

Exclusion Criteria:

1. Previous treatment for MDS, any approved or investigational antineoplastic agents orradiotherapy.

2. Previous diagnosis of:

• MDS evolving from a pre-existing myeloproliferative neoplasm (MPN)

• MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronicmyeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) andunclassifiable MDS/MPN.

3. Participant has an active, uncontrolled systemic fungal, bacterial, or viralinfection. The participant should be afebrile and off antibiotics for at least 72hours and off antifungals for 7 days. In the case of prior SARS-CoV-2 infection,symptoms must have completely resolved and based on Investigator assessment inconsultation with the Medical Monitor, there are no sequelae that would place thepatient at a higher risk of receiving investigational treatment.

4. History of clinically significant medical conditions, laboratory abnormality,psychiatric illness or any other reason that the investigator determines wouldinterfere with the subject's participation in this study, would make the subject anunsuitable candidate to receive study drug or predisposes the participant to highrisk of noncompliance with the protocol.

5. History of active malignancy within the past year prior to screening, with theexception of:

• Adequately treated carcinoma in situ of the uterine cervix

• Adequately treated basal cell carcinoma or localized squamous cell carcinoma ofthe skin

• Asymptomatic prostate cancer without known metastatic disease and with norequirement for therapy. Patients with ongoing horomonotherapy could be included.

6. Participant has received strong or moderate CYP3A inhibitors or inducers or p-gpinhibitors within 7 days prior to initiation of study treatment with prolongedtreatment required without therapeutic alternatives. Azols are the only exceptionand may be permitted after cycle 1 at investigator's discretion and will result invenetoclax dose reduction.

7. Consumption of grapefruit products, Seville oranges or starfruit within 3 days priorto first dose of venetoclax.

8. Received live attenuated vaccines prior to initiation of study treatment.

9. History of clinically significant (per investigator's judgment) drug or alcoholabuse within the last 6 months.

10. Conditions that could interfere with drug absorption including short gut syndrome,dysphagia, gastroparesis, or other conditions that limit the ingestion orgastrointestinal absorption of drugs administered orally.

11. Participant has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHgor diastolic BP > 100 mmHg) or has not been stable for at least 1 month prior totreatment.

12. Significant active cardiac disease within the previous 6 months prior to signing theICF, including:

• New York Heart Association (NYHA) Class III or IV congestive heart failure

• Unstable angina or angina requiring surgical or medical intervention

• Significant cardiac arrhythmia

• And/or myocardial infarction

13. Participant is a pregnant or lactating female.

14. Participant has known or suspected to have hypersensitivity to any of the componentsof the assigned study treatments.

15. Positive test result(s) for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Subjects with serologic evidence of priorvaccination to hepatitis B virus (i.e., hepatitis B surface antigen [HBsAg]negative, anti-hepatitis B surface [HBs] antibody positive and anti-hepatitis B core [HBc] antibody negative) may participate.

16. Absence of social security affiliation.