Acute Myeloid Leukemia (AML)
Conditions
Keywords
AML, Dasatinib, Core Binding Factor (CBF)
Brief summary
This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin \[DNR\] and cytarabine \[Ara-C\]) and consolidation therapy (high-dose cytarabine \[HDAC\]) with or without dasatinib in adult patients with newly diagnosed CBF-AML
Detailed description
This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin \[DNR\] and cytarabine \[Ara-C\]) and consolidation therapy (high-dose cytarabine \[HDAC\]) with or without dasatinib in adult patients with newly diagnosed CBF-AML; in the investigational arm, consolidation therapy is followed by a one-year maintenance therapy with dasatinib. Patients with molecular disease persistence or molecular relapse as assessed by quantitative RQ-PCR for the CBF fusion transcripts will be eligible for hematopoietic stem cell transplantation before overt hematologic relapse occurs. Primary endpoint is event-free survival. AML patients will be assessed for the CBF fusion genes in one of two AMLSG central laboratories within 48 hours of diagnosis, and only patients with CBF-AML will be enrolled.
Interventions
DRUGDasatinib
DRUGCytarabine
DRUGDaunorubicin
DRUGIdarubicin
Sponsors
University of Ulm
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Core-binding factor (CBF) AML with molecular diagnosis of RUNX1-RUNX1T1 fusion transcript resulting from t(8;21)(q22;q22.1) (or a variant form) or of CBFB-MYH11 fusion transcript resulting from inv(16)(p13.1q22)/t(16;16)(p13.1;q22) as assessed in one of the central AMLSG reference laboratories (Ulm, Hannover) * Age ≥ 18; there is no upper age limit * No prior chemotherapy for leukemia except hydroxyurea for up to 5 days during the diagnostic screening phase * Non-pregnant and non-nursing. Due to the unknown teratogenic potential of dasatinib in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL with-in 72 hours prior to registration. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control - one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least four weeks before she begins dasatinib therapy. Women of childbearing potential is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months. * Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking dasatinib and for 3 months after therapy is stopped, even if they have undergone a successful vasectomy. * Signed written informed consent.
Exclusion criteria
* Performance status WHO \>2 * Pulmonary edema and/or pleural/pericardial effusion within 14 days of day 1. If edema/effusion resolves to CTC Grade ≤1, patients can be treated with dasatinib. * Patients with ejection fraction \<50% by echocardiography within 14 days of day 1 * Organ insufficiency (creatinine \>1.5x upper normal serum level; bilirubin, AST or AP \>2.5x upper normal serum level; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder) * Uncontrolled infection * Patients with a currently active second malignancy other than non-melanoma skin cancers. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. * Severe neurological or psychiatric disorder interfering with ability of giving an informed consent * Known positive for HIV, active HBV, HCV, or Hepatitis A infection * Bleeding disorder independent of leukemia * No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation. * No consent for biobanking.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | 4 years | To assess event-free survival (EFS) after intensive induction (daunorubicin and cytarabine) and consolidation (high-dose cytarabine) chemotherapy with or without dasatinib in patients with CBF-AML |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative incidence of death (CID) | 4 years | — |
| overall survival | 4 years | — |
| Cumulative incidence of relapse (CIR) | 4 years | — |
| PIA analysis | 4 years | Pharmacodynamic inhibition of KIT as assessed by the KIT plasma inhibitory assay (PIA) |
| toxicity | 7 months (standard arm) / 19 months (investigational arm) | Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] version 4.03), timing and relatedness of non-hematologic toxicity observed during different treatment cycles. |
| relapse-free survival | 4 years | — |
Countries
Austria, Germany
Outcome results
None listed