AML or MDS-EB2
Conditions
Sponsors
University Hospital Ulm
Eligibility
Sex/Gender
All
Inclusion 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. Patients considered eligible for intensive chemotherapy. 4. Eastern Cooperative Oncology Group (ECOG) performance status = 2. 5. Molecular analysis centrally performed in AMLSG and HOVON laboratories. 6. Adequate renal function as evidenced by serum creatinine = 2.0 × upper limit of normal (ULN) or creatinine clearance >40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR). 7. Adequate hepatic function as evidenced by: o Serum total bilirubin = 2.5 × ULN unless considered due to Gilbert’s disease, or leukemic involvement following approval by the Principal Investigator or Trial Coordinator o Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) = 3.0 × ULN, unless considered due to leukemic involvement following approval by the Principal 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 start of study treatment. 9. Patients must not have received a known strong or moderate CYP3A inducer 7 days before start of study treatment. Patients must have no known medical conditions requiring chronic therapy of moderate or strong CYP3A inducers. 10. Female patient must either: o Be of nonchildbearing potential: • Postmenopausal (defined as at least 1 year without any menses) • Documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) or status posthysterectomy (at least 1 month prior to screening) o Or, if of childbearing potential (not surgically 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* method of birth control in combination to a barrier method for the duration of the study and for 27 weeks after the final study drug administration. *Highly effective forms of birth control include ? Consistent and correct usage of established hormonal contraceptives that inhibit ovulation, for at least 1 month prior to taking study drug. (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 a 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 durin
Exclusion criteria
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: o New York Heart Association (NYHA) class III or IV congestive heart failure; o Myocardial infarction; o Unstable angina and/or stroke; o Severe cardiac arrhythmias o 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. 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. 8. Active infection, including hepatitis B or hepatitis C antibody or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient 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. 9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation. 10. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs. 11. 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, patients with the following history/concurrent conditions are allowed: o Basal or squamous cell carcinoma of the skin; o Carcinoma in situ of the cervix; o Carcinoma in situ of the breast; o Incidental histologic finding of prostate cancer. 12. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patients, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy). 13. Severe neurological or psychiatric disorder interfering with ability to give an informed consent. 14. Known or suspected hypersensitivity to any of the chemotherapeutic agents used. 15. 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. 16. No consent for biobanking of patient’s biological specimens. 17. Participation in other prospective studies with anti-leukemic and/or investigational agents. 18. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess if treatment with venetoclax, as compared to placebo, in combination with induction and consolidation therapy prolongs event-free survival (EFS) in adult patients with newly diagnosed AML.;Secondary Objective: -To assess if treatment with venetoclax, as compared to placebo, in combination with induction and consolidation therapy prolongs overall survival (OS) of adult patients with newly diagnosed AML. -To assess the impact of venetoclax on CR/CRi rate by the end of induction chemotherapy in newly diagnosed AML patients. -To assess the impact of venetoclax on CR rates by the end of induction chemotherapy in newly diagnosed AML patients. -To assess the impact of venetoclax on the rate of CR/CRi without measurable residual disease (CR/CRiMRD-) by the end of induction chemotherapy in newly diagnosed AML patients. -To assess the impact of venetoclax on the rates of CR without measurable residual disease (CRMRD-) by the end of induction chemotherapy in newly diagnosed AML patients. -To evaluate the impact of venetoclax on relapse-free survival (RFS) in newly diagnosed AML patients. -To evaluate cumulative incidence of relapse (CIR) and death (CID) in newly diagnosed AML patients. ;Primary end point(s): Event-free survival (EFS);Timepoint(s) of evaluation of this end point: EFS is defined as the time from randomization to treatment failure, death from any cause, relapse after achieving CR or CRi, or start of new (non-study) therapy due to confirmed molecular progression or relapse whichever occurs first. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Overall survival (OS) - Complete remission (CR) - Rates of CR/CRi without measurable residual disease (CR/CRiMRD-) - Rates of CR without measurable residual disease (CRMRD-) - Relapse-free survival (RFS) - Cumulative incidence of relapse (CIR) - Cumulative incidence of death (CID) ;Timepoint(s) of evaluation of this end point: Endpoint will be evaluated when the data of all eligible patients are available. | — |
Countries
Austria, Belgium, Denmark, Estonia, Finland, Germany, Ireland, Israel, Lithuania, Luxembourg, Netherlands, Norway, Sweden, Switzerland
Contacts
Public ContactHartmut Döhner
University Hospital Ulm
Outcome results
None listed