Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™)

NCT ID: NCT02013648

Last Updated: 2024-02-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 204 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-31
• Study Completion Date: 2024-02-29

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.

Conditions

Acute Myeloid Leukemia (AML)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard arm

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.

Group Type: ACTIVE_COMPARATOR

Cytarabine

Intervention Type: DRUG

Daunorubicin

Intervention Type: DRUG

Idarubicin

Intervention Type: DRUG

Investigational arm

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).

Group Type: EXPERIMENTAL

Dasatinib

Intervention Type: DRUG

Cytarabine

Intervention Type: DRUG

Daunorubicin

Intervention Type: DRUG

Idarubicin

Intervention Type: DRUG

Interventions

Dasatinib

Intervention Type: DRUG

Cytarabine

Intervention Type: DRUG

Daunorubicin

Intervention Type: DRUG

Idarubicin

Intervention Type: DRUG

Other Intervention Names

Sprycel; ARA-cell; Daunoblastin

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Ulm

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. Hartmut Doehner

Prof. Dr.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hartmut Doehner, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

University of Ulm

Locations

Universitätsklinik für Innere Medizin V

Innsbruck, , Austria

Krankenhaus der Barmherzigen Schwestern

Linz, , Austria

Krankenhaus der Elisabethinen Linz GmbH

Linz, , Austria

Universitätsklinik der PMU

Salzburg, , Austria

Hanuschkrankenhaus

Vienna, , Austria

MVZ Osthessen

Fulda, Hesse, Germany

Universitätsklinikum Schleswig-Holstein

Kiel, Schleswig-Holstein, Germany

Klinikum Aschaffenburg-Alzenau

Aschaffenburg, , Germany

Helios Klinikum Bad Saarow, Klinik für Hämatologie

Bad Saarow, , Germany

Klinikum am Urban

Berlin, , Germany

Klinikum Neukölln

Berlin, , Germany

Charité Universitätsmedizin Campus Virchow Klinikum

Berlin, , Germany

Knappschaftskrankenhaus Bochum

Bochum, , Germany

Universitätsklinikum Medizinische Klinik und Poliklinik III

Bonn, , Germany

Städtisches Klinikum Braunschweig gGmbH

Braunschweig, , Germany

Klinikum Bremen Mitte gGmbH

Bremen, , Germany

Klinikum Darmstadt Medizinische Klinik V

Darmstadt, , Germany

St. Johannes Hospital

Dortmund, , Germany

Universitätsklinikum Medizinische Klinik und Poliklinik

Düsseldorf, , Germany

Klinikum Esslingen

Esslingen am Neckar, , Germany

Malteser Krankenhaus St. Franziskus-Hospital

Flensburg, , Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Wilhelm-Anton-Hospital gGmbH

Goch, , Germany

Universitätsmedizin Göttingen

Göttingen, , Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Klinikum Hanau GmbH

Hanau, , Germany

Klinikum Region Hannover GmbH

Hanover, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

SLK-Kliniken GmbH

Heilbronn, , Germany

Marienhospital Klinikum der Ruhr-Universität

Herne, , Germany

Universitätsklinikum des Saarlandes

Homburg, , Germany

Städtisches Klinikum Karlsruhe gGmbH

Karlsruhe, , Germany

Gemeinschaftspraxis Hämato-Onkologie

Lebach, , Germany

Klinikum Lippe GmbH

Lemgo, , Germany

Märkische Kliniken GmbH

Lüdenscheid, , Germany

Univ-Klinikum der Otto-von Guericke-Universität

Magdeburg, , Germany

III. Medizinische Klinik und Poliklinik Universitätsmedizin der Johannes Gutenberg-Universität

Mainz, , Germany

Johannes Wesling Klinikum

Minden, , Germany

Stauferklinikum Schwäbisch Gmünd

Mutlangen, , Germany

Klinikum rechts der Isar der TU

München, , Germany

Ortenau Klinikum

Offenburg, , Germany

PIUS Hospital

Oldenburg, , Germany

Klinikum Oldenburg gGmbH

Oldenburg, , Germany

Klinikum Passau

Passau, , Germany

Universitätsklinikum Regensburg

Regensburg, , Germany

Caritasklinkum Saarbrücken St. Theresia

Saarbrücken, , Germany

Klinikum Stuttgart

Stuttgart, , Germany

Vinzenz von Paul Kliniken gGmbH Marienhospital

Stuttgart, , Germany

Klinikum Mutterhaus der Borromäerinnen gGmbH

Trier, , Germany

Medizinische Universitätsklinik

Tübingen, , Germany

Universitätsklinikum Ulm Zentrum für Innere Medizin

Ulm, , Germany

Schwarzwald-Baar Klinikum

Villingen-Schwenningen, , Germany

Kliniken Essen Süd

Werden, , Germany

HELIOS Klinikum

Wuppertal, , Germany

Countries

Austria; Germany

References

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.

Reference Type: DERIVED

PMID: 29720733 (View on PubMed)

Other Identifiers

AMLSG 21-13

Identifier Type: -

Identifier Source: org_study_id