Protocol in Acute Myeloid Leukemia With FLT3-ITD

NCT ID: NCT01477606

Last Updated: 2020-06-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 451 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-05-31
• Study Completion Date: 2020-02-26

Brief Summary

This is a phase II, single-arm, open-label, multi-center study in adult patients with Acute Myeloid Leukemia (AML) and FLT3-ITD as defined in inclusion/exclusion criteria.

The primary efficacy object is to evaluate the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on event-free survival (EFS) in adult patients with AML exhibiting a FLT3-ITD.

Sample size: 440 patients

The treatment duration of an individual patient is between 18 and 24 months. Duration of the study for an individual patient including treatment (induction, consolidation [chemotherapy or allogeneic SCT], maintenance and follow-up period: Maximum 8 years

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Midostaurin

Group Type: EXPERIMENTAL

Midostaurin

Intervention Type: DRUG

Induction therapy: 50 mg, oral, twice daily, starting on day 8, thereafter continuous dosing until 48h before start of subsequent chemotherapy cycle.

Consolidation therapy: 50 mg, oral twice daily, starting on day 6, thereafter continuous dosing until 48h before start of conditioning therapy for allogeneic HSCT or 48h before start of subsequent consolidation chemotherapy.

Maintenance therapy:

50 mg oral twice daily over one year.

Cytarabine

Intervention Type: DRUG

Induction therapy:

200 mg/m2/day by continuous i.v. infusion on days 1-7 (total dose 1400 mg/m²)

Consolidation therapy:

Younger adult patients (18 to 65 yrs): 3 g/m2 by i.v infusion over 3 hours every 12 hours on days 1, 3, and 5 (total dose 18 g/m2).

Older patients (>65 yrs): 1 g/m2 by i.v. infusion over 3 hours every 12 hours on days 1, 3, and 5 (total dose 6 g/m2).

Daunorubicin

Intervention Type: DRUG

Induction therapy:

60 mg/m², by 1-hour i.v. infusion, day 1-3 (total dose 180 mg/m²)

Interventions

Midostaurin

Induction therapy: 50 mg, oral, twice daily, starting on day 8, thereafter continuous dosing until 48h before start of subsequent chemotherapy cycle.

Consolidation therapy: 50 mg, oral twice daily, starting on day 6, thereafter continuous dosing until 48h before start of conditioning therapy for allogeneic HSCT or 48h before start of subsequent consolidation chemotherapy.

Maintenance therapy:

50 mg oral twice daily over one year.

Intervention Type: DRUG

Cytarabine

Induction therapy:

200 mg/m2/day by continuous i.v. infusion on days 1-7 (total dose 1400 mg/m²)

Consolidation therapy:

Younger adult patients (18 to 65 yrs): 3 g/m2 by i.v infusion over 3 hours every 12 hours on days 1, 3, and 5 (total dose 18 g/m2).

Older patients (>65 yrs): 1 g/m2 by i.v. infusion over 3 hours every 12 hours on days 1, 3, and 5 (total dose 6 g/m2).

Intervention Type: DRUG

Daunorubicin

Induction therapy:

60 mg/m², by 1-hour i.v. infusion, day 1-3 (total dose 180 mg/m²)

Intervention Type: DRUG

Other Intervention Names

PKC412

Eligibility Criteria

Inclusion Criteria

• Patients with suspected diagnosis of AML or related precursor neoplasm, or acute leukemia of ambiguous lineage (classified according to the World Health Organization (WHO) 2008 classification)
• Presence of FLT3-ITD assessed in the central AMLSG reference laboratories
• Patients considered eligible for intensive chemotherapy
• WHO performance status of ≤ 2
• Age ≥ 18 years and ≤ 70 years
• No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis (≤ 7 days)
• Non-pregnant and non-nursing. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration ("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)
• Female patients in the reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and for 5 months after the last dose of chemotherapy
• Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner's vasectomy). Hormonal contraception is an inadequate method of birth control
• Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy (while on therapy and for 5 months after the last dose of chemotherapy)
• Signed written informed consent.

Exclusion Criteria

•AML with the following recurrent genetic abnormalities (according to WHO 2008): AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 AML with t(15;17)(q22;q12); PML-RARA (or variant translocations with other RARA gene fusions)

• Performance status WHO >2
• Patients with ejection fraction < 50% by MUGA or ECHO scan within 14 days of day 1
• Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or ALP >2.5x upper normal serum level, not attributable to AML; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)
• Uncontrolled infection
• Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
• 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
• 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
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

University of Ulm

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. Hartmut Doehner

Prof. Dr. Hartmut Doehner

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hartmut Doehner, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Ulm

Locations

Medizinische Universität Innsbruck

Innsbruck, , Austria

Krankenhaus der Barmherzigen Schwestern Linz

Linz, , Austria

Krankenhaus der Elisabethinen Linz GmbH

Linz, , Austria

Universitätsklinik für Innere Medizin III Salzburg

Salzburg, , Austria

Hanuschkrankenhaus Wien

Vienna, , Austria

Helios Klinikum Bad Saarow

Bad Saarow, , Germany

Vivantes Klinikum Neukölln

Berlin, , Germany

Charité Universitätsmedizin Berlin

Berlin, , Germany

Marienhospital Bochum-Herne

Bochum, , Germany

Medizinische Universitätsklinik Bochum

Bochum, , Germany

Universitätsklinikum Bonn

Bonn, , Germany

Städtisches Klinikum Braunschweig gGmbH

Braunschweig, , Germany

Klinikum Bremen-Mitte gGmbH

Bremen, , Germany

Klinikum Darmstadt

Darmstadt, , Germany

Universitätsklinkum Düsseldorf

Düsseldorf, , Germany

Kliniken Essen-Süd

Essen, , Germany

Klinik für Onkologie, Gastroenterologie und Allg. Innere Medizin Esslingen

Esslingen am Neckar, , Germany

Malteser Krankenhaus St. Franziskus Hospital Flensburg

Flensburg, , Germany

Medizinische Universitätsklinik Freiburg

Freiburg im Breisgau, , Germany

MVZ Osthessen

Fulda, , Germany

Klinik der Justus-Liebig-Universität Gießen

Giessen, , Germany

Wilhelm-Anton-Hospital gGmbH Goch

Goch, , Germany

Universitätsmedizin Göttingen

Göttingen, , Germany

Universitätsklinikum Eppendorf

Hamburg, , Germany

Asklepios Klinik Altona

Hamburg, , Germany

Evangelisches Krankenhaus Hamm

Hamm, , Germany

Klinikum Region Hannover GmbH

Hanover, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

SLK Kliniken Heilbronn GmbH

Heilbronn, , Germany

Universitätskliniken des Saarlandes

Homburg/Saar, , Germany

Städtisches Klinikum Karlsruhe

Karlsruhe, , Germany

Städtisches Krankenhaus Kiel GmbH

Kiel, , Germany

Caritas Krankenhaus Lebach

Lebach, , Germany

Klinikum Lippe-Lemgo

Lemgo, , Germany

Märkische Kliniken GmbH Lüdenscheid

Lüdenscheid, , Germany

Universitätsklinikum der Otto-von-Guericke Universität Magdeburg

Magdeburg, , Germany

Universitätsklinikum der Johannes Gutenberg-Universität Mainz

Mainz, , Germany

Johannes Wesling Klinikum Minden

Minden, , Germany

Stauferklinikum Mutlangen

Mutlangen, , Germany

Klinikum Schwabing

München, , Germany

Klinikum rechts der Isar der TU München

München, , Germany

Ortenau Klinikum

Offenburg, , Germany

Pius Hospital Oldenburg

Oldenburg, , Germany

Klinikum Oldenburg

Oldenburg, , Germany

Klinikum Passau

Passau, , Germany

Universitätsklinikum Regensburg

Regensburg, , Germany

Caritasklinik St. Theresia Saarbrücken

Saarbrücken, , Germany

Klinikum Stuttgart

Stuttgart, , Germany

Diakonie-Klinikum Stuttgart

Stuttgart, , Germany

Klinikum Mutterhaus der Borromäerinnen gGmbH Trier

Trier, , Germany

Krankenhaus der Barmherzigen Brüder Trier

Trier, , Germany

Medizinische Universitätsklinik Tübingen

Tübingen, , Germany

University Hospital of Ulm

Ulm, , Germany

Schwarzwald-Baar Klinikum Villingen-Schwenningen

Villingen-Schwenningen, , Germany

Helios Klinikum Wuppertal

Wuppertal, , Germany

Countries

Austria; Germany

References

Dohner H, Weber D, Krzykalla J, Fiedler W, Wulf G, Salih H, Lubbert M, Kuhn MWM, Schroeder T, Salwender H, Gotze K, Westermann J, Fransecky L, Mayer K, Hertenstein B, Ringhoffer M, Tischler HJ, Machherndl-Spandl S, Schrade A, Paschka P, Gaidzik VI, Theis F, Thol F, Heuser M, Schlenk RF, Bullinger L, Saadati M, Benner A, Larson R, Stone R, Dohner K, Ganser A. Midostaurin plus intensive chemotherapy for younger and older patients with AML and FLT3 internal tandem duplications. Blood Adv. 2022 Sep 27;6(18):5345-5355. doi: 10.1182/bloodadvances.2022007223.

Reference Type: DERIVED

PMID: 35486475 (View on PubMed)

Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, Schroeder T, Kindler T, Lubbert M, Wolf D, Westermann J, Kraemer D, Gotze KS, Horst HA, Krauter J, Girschikofsky M, Ringhoffer M, Sudhoff T, Held G, Derigs HG, Schroers R, Greil R, Griesshammer M, Lange E, Burchardt A, Martens U, Hertenstein B, Marretta L, Heuser M, Thol F, Gaidzik VI, Herr W, Krzykalla J, Benner A, Dohner K, Ganser A, Paschka P, Dohner H; German-Austrian AML Study Group. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019 Feb 21;133(8):840-851. doi: 10.1182/blood-2018-08-869453. Epub 2018 Dec 18.

Reference Type: DERIVED

PMID: 30563875 (View on PubMed)

Other Identifiers

2011-003168-63

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

AMLSG 16-10

Identifier Type: -

Identifier Source: org_study_id