Clinical trial NCT02013648: Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™)
Official title: Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™) in Adult Patients With Newly Diagnosed Core-Binding Factor Acute Myeloid Leukemia (CBF-AML)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia (AML)
Keywords: AML
Dasatinib
Core Binding Factor (CBF)
Lead sponsor: University of Ulm
Sponsor class: OTHER
First posted: 2013-12-17
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Event-free Survival
timeFrame: 4 years
Secondary outcomes:
measure: Cumulative incidence of relapse (CIR)
timeFrame: 4 years
measure: Cumulative incidence of death (CID)
timeFrame: 4 years
measure: overall survival
timeFrame: 4 years
measure: relapse-free survival
timeFrame: 4 years
measure: PIA analysis
timeFrame: 4 years
measure: toxicity
timeFrame: 7 months (standard arm) / 19 months (investigational arm)
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Universitätsklinik für Innere Medizin V
city: Linz
country: Austria
facility: Krankenhaus der Barmherzigen Schwestern
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen Linz GmbH
city: Salzburg
country: Austria
facility: Universitätsklinik der PMU
city: Wien
country: Austria
facility: Hanuschkrankenhaus
city: Fulda
country: Germany
facility: MVZ Osthessen
state: Hessen
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
state: Schleswig-Holstein
city: Aschaffenburg
country: Germany
facility: Klinikum Aschaffenburg-Alzenau
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow, Klinik für Hämatologie
city: Berlin
country: Germany
facility: Klinikum am Urban
city: Berlin
country: Germany
facility: Klinikum Neukölln
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Campus Virchow Klinikum
city: Bochum
country: Germany
facility: Knappschaftskrankenhaus Bochum
city: Bonn
country: Germany
facility: Universitätsklinikum Medizinische Klinik und Poliklinik III
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig gGmbH
city: Bremen
country: Germany
facility: Klinikum Bremen Mitte gGmbH
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt Medizinische Klinik V
city: Dortmund
country: Germany
facility: St. Johannes Hospital
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Medizinische Klinik und Poliklinik
city: Esslingen
country: Germany
facility: Klinikum Esslingen
city: Flensburg
country: Germany
facility: Malteser Krankenhaus St. Franziskus-Hospital
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Goch
country: Germany
facility: Wilhelm-Anton-Hospital gGmbH
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hanau
country: Germany
facility: Klinikum Hanau GmbH
city: Hannover
country: Germany
facility: Klinikum Region Hannover GmbH
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heilbronn
country: Germany
facility: SLK-Kliniken GmbH
city: Herne
country: Germany
facility: Marienhospital Klinikum der Ruhr-Universität
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe gGmbH
city: Lebach
country: Germany
facility: Gemeinschaftspraxis Hämato-Onkologie
city: Lemgo
country: Germany
facility: Klinikum Lippe GmbH
city: Lüdenscheid
country: Germany
facility: Märkische Kliniken GmbH
city: Magdeburg
country: Germany
facility: Univ-Klinikum der Otto-von Guericke-Universität
city: Mainz
country: Germany
facility: III. Medizinische Klinik und Poliklinik Universitätsmedizin der Johannes Gutenberg-Universität
city: Minden
country: Germany
facility: Johannes Wesling Klinikum
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd
city: München
country: Germany
facility: Klinikum rechts der Isar der TU
city: Offenburg
country: Germany
facility: Ortenau Klinikum
city: Oldenburg
country: Germany
facility: PIUS Hospital
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg gGmbH
city: Passau
country: Germany
facility: Klinikum Passau
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Saarbrücken
country: Germany
facility: Caritasklinkum Saarbrücken St. Theresia
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Stuttgart
country: Germany
facility: Vinzenz von Paul Kliniken gGmbH Marienhospital
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen gGmbH
city: Tübingen
country: Germany
facility: Medizinische Universitätsklinik
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Zentrum für Innere Medizin
city: Villingen Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum
city: Werden
country: Germany
facility: Kliniken Essen Süd
city: Wuppertal
country: Germany
facility: HELIOS Klinikum
Study officials:
affiliation: University of Ulm
name: Hartmut Doehner, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Paschka P, Schlenk RF, Weber D, Benner A, Bullinger L, Heuser M, Gaidzik VI, Thol F, Agrawal M, Teleanu V, Lubbert M, Fiedler W, Radsak M, Krauter J, Horst HA, Greil R, Mayer K, Kundgen A, Martens U, Heil G, Salih HR, Hertenstein B, Schwanen C, Wulf G, Lange E, Pfreundschuh M, Ringhoffer M, Girschikofsky M, Heinicke T, Kraemer D, Gohring G, Ganser A, Dohner K, Dohner H. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial. Leukemia. 2018 Jul;32(7):1621-1630. doi: 10.1038/s41375-018-0129-6. Epub 2018 Apr 17.