| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | 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 | |
| E.1.1.1 | Medical condition in easily understood language | | relapsed acute myeloid leukaemia (AML) after intensive chemotherapy including allogeneic stem cell transplantation or primary refractory to standard induction chemotherapy | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10000886 | | E.1.2 | Term | Acute myeloid leukemia | | E.1.2 | System Organ Class | 100000004864 | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | 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.
| |
| E.2.2 | Secondary objectives of the trial | 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
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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)
• 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 < 1.5 x 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. | |
| E.4 | Principal 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 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 | |
| E.5 End points |
| E.5.1 | 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
| |
| E.5.1.1 | 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
| |
| E.5.2 | 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)
| |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | 24 months after enrollment of last patient per post-study follow up | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description | | investigate the combination of venetoclax with increasing cytarabine+mitoxantrone | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
