Trial for Relapsed or Refractory AML Patients Combining Cytarabine and Mitoxantrone With Venetoclax (RELAX)

This is an open-label Phase I dose-escalation study of oral venetoclax in combination with increasing cytarabine doses plus mitoxantrone to define the safety profile and MTD of cytarabine in subjects with a histologically or cytologically confirmed acute myeloid leukemia who are refractory or suffered a relapse. This study will be conducted at multiple centers in Germany.

Inclusion criteria for both escalation and expansion phase: * Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained before screening. * AML according to WHO-2016 criteria, excluding acute promyelocytic leukemia * Relapsed from first or second CR after 1-2 cycles of standard induction chemotherapy (which must have included cytarabine with an anthracycline or anthracenedione), including relapse after allogeneic stem cell transplantation (dose escalation and expansion part) * Age 18-75 years * Fit for intensive chemotherapy, defined by * ECOG 0-2, life expectancy \> 3months * Adequate hepatic function: ALAT/ASAT/Bilirubin ≤2.5 x ULN\* * unless considered due to leukemic organ involvement Note: Subjects with Gilbert's Syndrome may have a bilirubin \> 2.5 × ULN per discussion between the investigator and Coordinating investigator. * Adequate renal function assessed by serum creatinine ≤ 1.5x ULN OR creatinine clearance (by Cockcroft Gault formula) ≥ 50 mL/min * Patient is afebrile and hemodynamically stable for at least 72 hours at the time of study medication initiation. * Male subjects must agree to refrain from unprotected sex and sperm donation from time point of signing the informed consent until 30 days after the last dose of study drug. * Women must fulfill at least one of the following criteria in order to be eligible for trial inclusion: * Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH \> 40 U/ml) * Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days before the first dose of study drug. * Continuous and correct application of a contraception method with a Pearl Index of \410 mg/m2 doxorubicin equivalents * Acute GVHD ≥ grade 2, extensive chronic GVHD or requiring systemic immunosuppressive therapy within 2 weeks prior to start of study treatment * HIV infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections). * Inability to swallow oral medications * Any malabsorption condition * Cardiovascular disability status of New York Heart Association (NYHA) Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain. * Chronic respiratory disease that requires continuous oxygen use. * White blood cell count \> 25 × 109/L. Note: Hydroxyurea is permitted to meet this criterion. * AML relapse treatment with any investigational or commercial drug within 14 days before enrolment. Hydroxyurea is allowed until enrolment to control peripheral WBC counts. Toxic effects of previous investigational drug treatment have to recover to Grade \