Patients 18-75 years with acute myeloid leukaemia (AML) at first or second relapse after intensive chemotherapy including allogeneic stem cell transplantation or primary refractory to standard induction chemotherapy who are eligible for intensive salvage treatment MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: venetoclax
Product Code: ABT-199
Pharmaceutical Form: Coated tablet
INN or Proposed INN: VENETOCLAX
CAS Number: 1257044-40-8
Concentration unit: mg milligram(s)
Concentration type: equal
Sponsors
Technische Universität Dresden
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Signed Informed consent • AML according to WHO criteria, excluding APL • Relapsed after first or second CR, including relapse after allogeneic stem cell transplantation (dose escalation and expansion phase) • Only expansion phase: Primary refractory after 1-2 cycles of standard induction chemotherapy (100 to 200 mg/m2 cytarabine over 7-10 days plus anthracycline or mitoxantrone over 3 days) or equivalent treatment (e.g. CPX351) Note: Primary refractory disease is defined by either = 20% myeloid blasts on early response assessment around day 15 after start of the most recent induction, or by = 5% myeloid blasts after blood count recovery after start of the most recent induction, respectively. • Age 18-75 years • Fit for intensive chemotherapy, defined by - ECOG 0-2, life expectancy > 3 months - Adequate hepatic function (ALAT/ASAT/Bilirubin =2.5 x ULN ) - Adequate renal function assessed by creatinine =65 years) yes F.1.3.1 Number of subjects for this age range 54
Exclusion criteria
Exclusion criteria: • Acute promyelocytic leukemia • CNS involvement or subjects with extramedullary disease only • Known hypersensitivity to any agent given in association with this study including cytarabine or mitoxantrone • relapse within 90 days after last cytarabine dose • Intended hematopoietic stem cell transplantation planned as early conditioning from aplasia without previous blood count recovery • Cumulative previous exposure to anthracyclines of >410 mg/m2 doxorubicin equivalents • Acute GVHD = grade 2, extensive chronic GVHD or requiring systemic immunosuppressive therapy • 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 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 10 days before enrolment. Hydroxyurea is allowed until enrolment to control peripheral WBC counts. • Substance abuse, medical, psychological, or social conditions that may interfere with the subject’s cooperation with the requirements of the trial or evaluation of the study results • Acute non-hematologic toxicities from any prior anti-leukemia therapy or from previous investigational drugs that have not resolved to Grade <2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 • History of active or chronic infectious hepatitis unless serology demonstrates clearance of infection (Occult or prior hepatitis B virus (HBV) infection (defined as negative hepatitis B surface antigen and positive total hepatitis B core antibody) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody after vaccination or prior but cured hepatitis B are eligible. Patients positive for hepatitis C virus antibody are eligible provided PCR is negative for HCV RNA) • History of clinically significant liver cirrhosis (e.g., Child-Pugh class B and C). • Pregnant or breastfeeding patients
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine safety, tolerability, maximum tolerated dose, and recommended phase II dose of venetoclax in combination with increasing cytarabine doses plus fixed dose mitoxantrone in subjects with a relapsed or refractory AML considered fit for intensive salvage therapy. ;Secondary Objective: To assess the preliminary efficacy of venetoclax in combination with increasing cytarabine doses plus fixed dose mitoxantrone in subjects with a relapsed or refractory AML considered fit for intensive salvage therapy. Exploratory objectives (ancillary research) of this study are to • Identification of biological factors predicting CR/CRi achievement • Changes in clonal architecture of hematopoiesis during therapy Goals of the ancillary research project are: 1) To determine biomarkers for response and mechanisms of resistance to the combination of venetoclax plus ARAC-based chemotherapy 2) To display the course of minimal residual disease 3) To test if changes the clonal composition of hematopoiesis of patients occur during maintenance therapy ;Primary end point(s): Primary endpoint phase I (dose escalation): Maximum tolerated dose of cytarabine in combination with venetoclax plus mitoxantrone in the framework of a 3+3 design Primary endpoint phase II (expansion): CR/CRi rate ;Timepoint(s) of evaluation of this end point: Phase I: day 28 - 45 after start of venetoclax = DLT evaluation period/cohort; 3 cohorts and 1 cohort as fall back option are planned Phase II: day 28 - 45 after start of venetoclax treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Duration of remission - Cumulative incidence of relapse - Depth of remission (MRD) - Relapse-free survival - Overall survival - Early mortality (within 14 and 30 days) - Proportion of allogeneic stem cell transplantation following response - Tolerability (incidence and grade of adverse events) ;Timepoint(s) of evaluation of this end point: 24 months after enrollment of last patient per post-study follow up | — |
Countries
Germany
Contacts
Public ContactCoordinating Investigator
Medizinische Fakultät Carl Gustav Carus der TU Dresden; Medizinische Klinik und Poliklinik I
Outcome results
None listed