Phase III Study of Induction and Consolidation Chemotherapy with Venetoclax in Patients with Newly Diagnosed AML or MDS-EB-2

A Randomized, Placebo-Controlled Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2

Prospective, multicenter, double-blind, randomized, placebo-controlled phase 3 clinical study. The randomized phase of the study will be preceded by a feasibility run-in dose-escalation phase in patients with AML in which the venetoclax dose for the phase 3 part will be established.

After the feasibility run-in phase, eligible patients will be randomized to intensive chemotherapy with venetoclax or placebo. Patients will receive two cycles of induction chemotherapy; patients achieving CR or CRi after two cycles will continue with consolidation treatment according to initial randomization, and according to Cooperative Group-specific consolidation regimens or investigator choice. Patients achieving morphologic leukemia-free state (MLFS) only, may also continue consolidation treatment on protocol. Assignment to either allogeneic hematopoietic cell transplantation (HCT), conventional chemotherapy or autologous HCT will be done according to institutional standards, and based on (prognostic) disease characteristics, individual patient assessment, and established comorbidity risk scores (e.g., HCT-CI score).

Eligibility Criteria:
Inclusion Criteria:

1. Patients with newly diagnosed acute myeloid leukemia (AML), or myelodysplastic syndrome with excess blasts-2 (MDS-EB2) according to World Health Organization (WHO) classification.
2. Age ≥ 18 years, no upper age limit.
3. Patient considered eligible for intensive chemotherapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at randomization.
5. Molecular analysis centrally performed in AMLSG and HOVON laboratories.
6. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance \>40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
7. Adequate hepatic function as evidenced by:

   * Serum total bilirubin ≤ 2.5 × ULN unless considered due to Gilbert's disease, or leukemic involvement following approval by the Coordinating Investigator or Trial Coordinator
   * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Coordinating Investigator or Trial Coordinator
8. No prior chemotherapy for AML except hydroxyurea for up to 14 days during the diagnostic screening phase for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell \[WBC\] counts \> 25x109/L); patients may have had previous treatment with erythroid stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS; ESA and HMAs have to be stopped at least four weeks before enrolment.
9. Subjects must not have received a known strong or moderate CYP3A inducer 7 days before enrolment. Subjects must have no known medical conditions requiring chronic therapy with moderate or strong CYP3A inducers.
10. Female patient must either:

    * Be of nonchildbearing potential:

      * Postmenopausal (defined as at least 1 year without any menses)
      * Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
    * Or, if of childbearing potential (not surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) and not postmenopausal)

      * Not planning to become pregnant during the study and for 6 months after the final study drug administration
      * And have a negative urine or serum pregnancy test at screening
      * And, if heterosexually active, agree to consistently apply one highly effective\* in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration

        \*Highly effective forms of birth control include
      * Consistent and correct usage of established hormonal contraceptives that inhibit ovulation (hormonal contraception is only a highly effective method of birth control, if a combined \[estrogen and progestogen containing\] hormonal contraception or a progestogen-only hormonal contraception - both associated with inhibition of ovulation - is used.
      * Established intrauterine device (IUD) or intrauterine system (IUS)
      * Bilateral tubal occlusion
      * Vasectomy - a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
      * Male is sterile due to a bilateral orchiectomy.
      * Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.

        \*List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period.
      * Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.
      * Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
11. Men must use a latex condom during any sexual contact with WOCBP, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential have to use a highly effective method of birth control.
12. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
13. Able to understand and willing to sign an informed consent form (ICF).

Exclusion Criteria:

1. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.
2. AML with BCR-ABL1; or myeloid blast crisis of CML.
3. Patients with AML and activating FLT3 mutations who have access (including reimbursement) to treatment with a FLT3 inhibitor approved for first-line therapy of AML.
4. Prior treatment of MDS with intensive chemotherapy or allogeneic hematopoietic cell transplantation (HCT) with a curative intent.
5. Significant active cardiac disease within 6 months prior to the start of study treatment, including:

   * New York Heart Association (NYHA) class III or IV congestive heart failure;
   * Myocardial infarction;
   * Unstable angina and/or stroke;
   * Severe cardiac arrhythmias
   * Left ventricular ejection fraction (LVEF) \<40% by ultrasound obtained within 28 days prior to the start of study treatment
6. Severe obstructive or restrictive ventilation disorder.
7. Co-administration of moderate/strong CYP inhibitors during the DLT observation period for subjects in the dose-finding part of the study.
8. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required, if there is a clinical suspicion of CNS involvement by leukemia during screening.
9. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled at randomization and may interfere with the study objectives or which could expose the subject to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed.
10. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
11. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
12. Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at \< 30% risk of relapse within one year. However, subjects with the following history/concurrent conditions are allowed:

    * Basal or squamous cell carcinoma of the skin;
    * Carcinoma in situ of the cervix;
    * Carcinoma in situ of the breast;
    * Incidental histologic finding of prostate cancer.
13. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: subjects, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
14. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
15. Known or suspected hypersensitivity to any of the chemotherapeutic agents used.
16. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician about study participation.
17. No consent for biobanking of patient's biological specimens.
18. Participation in other prospective studies with anti-leukemic and/or investigational agents.
19. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.