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

This phase I/II open-label, dose-finding, multi-center study will assess safety and primary efficacy of Onureg and Venetoclax combination, to define the optimal biological dose and optimal treatment duration of Onureg to be used along with Venetoclax for further studies in previously untreated patients with higher-risk myelodysplastic syndromes (HR-MDS) not eligible to transplant.

During phase I, three dose features of Onureg will be tested in combination with a fixed dose of Venetoclax to define the optimal biological dose for phase II.

The phase II will assess safety and primary efficacy of Onureg and Venetoclax combination, to define the optimal biological dose and optimal treatment duration of Onureg to be used along with Venetoclax for further studies in previously untreated patients with HR-MDS not eligible to transplant.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must understand and voluntarily sign and date an ICF indicating the investigational nature of the study, approved by an independent EC/IRB, prior to the initiation 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), with presence of \< 20% bone marrow blasts per bone marrow aspirate at screening, confirmed by local investigator with HR-MDS, based on the revised International Prognostic 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 hypomethylating agents (azacitidine or decitabine), chemotherapy, allo-Hematopoietic Stem Cell Transplantation (HSCT) or experimental agent. All other treatments are not considered prior therapy.
5. Not immediately eligible for allo-HSCT or intensive chemotherapy at the time of screening due to individual clinical factors such as age, comorbidities and performance 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 permitted to lower the WBC to reach this inclusion criterion and will be stopped at least 48 hours 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 Gilbert syndrome, where participants may only be included with total bilirubin ≤ 3.0 x ULN)
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 or CKD-EPI, by local laboratory).
10. Participant is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures, available for regular blood sampling, study related assessments, including bone marrow aspirates and appropriate clinical management at the treating institution for the duration of the study.
11. Females of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). FCBP must agree to undergo medically supervised pregnancy test prior to starting study drug, during the course of the study, and after end of study therapy:

    * Have one negative pregnancy test as verified by the Investigator prior to starting study therapy. The first pregnancy test will be performed at screening (within 3 days prior to first study drug administration), and a negative urinary test before starting all subsequent cycles. This applies even if the participant practices true abstinence from heterosexual contact or agree to use, and be able to comply with highly effective contraception without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 6 months after last dose of Onureg, or at least 1 month after the last dose of venetoclax, whichever is later 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 of contraception to prevent pregnancy or agree to abstain from becoming pregnant throughout the study, starting with Visit 1. Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 6 months (females and males) following the last dose of treatment.
12. Male participants must practice true abstinence (which must be reviewed on a monthly basis) or agree to use an adequate method of contraception for the duration of the study. 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 preservation of sperm before starting treatment.

Exclusion Criteria:

1. Previous treatment for MDS, any approved or investigational antineoplastic agents or radiotherapy.
2. Previous diagnosis of:

   * MDS evolving from a pre-existing myeloproliferative neoplasm (MPN)
   * MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.
3. Participant has an active, uncontrolled systemic fungal, bacterial, or viral infection. The participant should be afebrile and off antibiotics for at least 72 hours 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 in consultation with the Medical Monitor, there are no sequelae that would place the patient 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 would interfere with the subject's participation in this study, would make the subject an unsuitable candidate to receive study drug or predisposes the participant to high risk of noncompliance with the protocol.
5. History of active malignancy within the past year prior to screening, with the exception of:

   * Adequately treated carcinoma in situ of the uterine cervix
   * Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
   * Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy.

   Patients with ongoing horomonotherapy could be included.
6. Participant has received strong or moderate CYP3A inhibitors or inducers or p-gp inhibitors within 7 days prior to initiation of study treatment with prolonged treatment required without therapeutic alternatives. Azols are the only exception and may be permitted after cycle 1 at investigator's discretion and will result in venetoclax dose reduction.
7. Consumption of grapefruit products, Seville oranges or starfruit within 3 days prior to 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 alcohol abuse 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 or gastrointestinal absorption of drugs administered orally.
11. Participant has uncontrolled hypertension (systolic blood pressure \[BP\] \> 180 mmHg or diastolic BP \> 100 mmHg) or has not been stable for at least 1 month prior to treatment.
12. Significant active cardiac disease within the previous 6 months prior to signing the ICF, 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 components of 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 prior vaccination 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.