Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™)
- Conditions
- Acute Myeloid Leukemia (AML)
- Interventions
- Registration Number
- NCT02013648
- Lead Sponsor
- University of Ulm
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 204
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard arm Cytarabine Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7. Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5. Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (\>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours. Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse. Standard arm Daunorubicin Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7. Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5. Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (\>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours. Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse. Standard arm Idarubicin Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7. Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5. Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (\>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours. Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse. Investigational arm Dasatinib Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21. Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (\>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse). Investigational arm Cytarabine Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21. Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (\>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse). Investigational arm Idarubicin Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21. Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (\>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse). Investigational arm Daunorubicin Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21. Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (\>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse).
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method overall survival 4 years relapse-free survival 4 years Cumulative incidence of relapse (CIR) 4 years Cumulative incidence of death (CID) 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.
Trial Locations
- Locations (54)
Hanuschkrankenhaus
🇦🇹Wien, Austria
Krankenhaus der Barmherzigen Schwestern
🇦🇹Linz, Austria
Universitätsklinik der PMU
🇦🇹Salzburg, Austria
Knappschaftskrankenhaus Bochum
🇩🇪Bochum, Germany
Universitätsklinikum Schleswig-Holstein
🇩🇪Kiel, Schleswig-Holstein, Germany
MVZ Osthessen
🇩🇪Fulda, Hessen, Germany
Helios Klinikum Bad Saarow, Klinik für Hämatologie
🇩🇪Bad Saarow, Germany
Charité Universitätsmedizin Campus Virchow Klinikum
🇩🇪Berlin, Germany
St. Johannes Hospital
🇩🇪Dortmund, Germany
Klinikum Aschaffenburg-Alzenau
🇩🇪Aschaffenburg, Germany
Klinikum am Urban
🇩🇪Berlin, Germany
Klinikum Neukölln
🇩🇪Berlin, Germany
Malteser Krankenhaus St. Franziskus-Hospital
🇩🇪Flensburg, Germany
Universitätsklinikum Medizinische Klinik und Poliklinik III
🇩🇪Bonn, Germany
Klinikum Bremen Mitte gGmbH
🇩🇪Bremen, Germany
Universitätsklinikum Medizinische Klinik und Poliklinik
🇩🇪Düsseldorf, Germany
Klinikum Darmstadt Medizinische Klinik V
🇩🇪Darmstadt, Germany
Klinikum Esslingen
🇩🇪Esslingen, Germany
Universitätsklinikum Freiburg
🇩🇪Freiburg, Germany
Wilhelm-Anton-Hospital gGmbH
🇩🇪Goch, Germany
Klinikum Region Hannover GmbH
🇩🇪Hannover, Germany
Ortenau Klinikum
🇩🇪Offenburg, Germany
Marienhospital Klinikum der Ruhr-Universität
🇩🇪Herne, Germany
Märkische Kliniken GmbH
🇩🇪Lüdenscheid, Germany
III. Medizinische Klinik und Poliklinik Universitätsmedizin der Johannes Gutenberg-Universität
🇩🇪Mainz, Germany
Johannes Wesling Klinikum
🇩🇪Minden, Germany
Klinikum Mutterhaus der Borromäerinnen gGmbH
🇩🇪Trier, Germany
Medizinische Universitätsklinik
🇩🇪Tübingen, Germany
Stauferklinikum Schwäbisch Gmünd
🇩🇪Mutlangen, Germany
PIUS Hospital
🇩🇪Oldenburg, Germany
Klinikum rechts der Isar der TU
🇩🇪München, Germany
Klinikum Oldenburg gGmbH
🇩🇪Oldenburg, Germany
Klinikum Passau
🇩🇪Passau, Germany
Caritasklinkum Saarbrücken St. Theresia
🇩🇪Saarbrücken, Germany
Schwarzwald-Baar Klinikum
🇩🇪Villingen Schwenningen, Germany
Kliniken Essen Süd
🇩🇪Werden, Germany
HELIOS Klinikum
🇩🇪Wuppertal, Germany
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
Städtisches Klinikum Braunschweig gGmbH
🇩🇪Braunschweig, Germany
Universitätsmedizin Göttingen
🇩🇪Göttingen, Germany
Universitätsklinikum des Saarlandes
🇩🇪Homburg, Germany
Städtisches Klinikum Karlsruhe gGmbH
🇩🇪Karlsruhe, Germany
Gemeinschaftspraxis Hämato-Onkologie
🇩🇪Lebach, Germany
Univ-Klinikum der Otto-von Guericke-Universität
🇩🇪Magdeburg, Germany
Universitätsklinikum Ulm Zentrum für Innere Medizin
🇩🇪Ulm, Germany
Universitätsklinik für Innere Medizin V
🇦🇹Innsbruck, Austria
Universitätsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Klinikum Hanau GmbH
🇩🇪Hanau, Germany
SLK-Kliniken GmbH
🇩🇪Heilbronn, Germany
Klinikum Lippe GmbH
🇩🇪Lemgo, Germany
Klinikum Stuttgart
🇩🇪Stuttgart, Germany
Universitätsklinikum Regensburg
🇩🇪Regensburg, Germany
Vinzenz von Paul Kliniken gGmbH Marienhospital
🇩🇪Stuttgart, Germany
Krankenhaus der Elisabethinen Linz GmbH
🇦🇹Linz, Austria