Protocol in Acute Myeloid Leukemia With FLT3-ITD

NCT01477606 | Completed Phase 2 DMC

• 2 other identifiers: AMLSG 16-102011-003168-63
• Study Type: interventional
• Target: 451
• Locations: 2 countries
• Sites: 55

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

Keywords

Acute myeloid leukemia; FLT3-ITD; midostaurin (PKC412)

Outcome Measures

Primary Outcomes (1)

• Event-free Survival

  To perform two predefined subgroup analyses in the age-groups 18-60 years and 61-70 years evaluating 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.

  8years

Secondary Outcomes (11)

• Rate of complete remission (CR)

  Two months

• Relapse-free survival

  8 years

• overall survival

  8 years

• Cumulative incidence of relapse

  8 years

• cumulative incidence of death in CR

  8 years

Study Arms (1)

Midostaurin

EXPERIMENTAL

Drug: Midostaurin; Drug: Cytarabine; Drug: Daunorubicin

Interventions

Midostaurin 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.

Also known as: PKC412

Midostaurin

Cytarabine 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).

Midostaurin

Daunorubicin DRUG

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

Midostaurin

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Ulm: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (55)

Medizinische Universität Innsbruck

Innsbruck, 3020, Austria

Location

Krankenhaus der Barmherzigen Schwestern Linz

Linz, 4010, Austria

Location

Krankenhaus der Elisabethinen Linz GmbH

Linz, 4020, Austria

Location

Universitätsklinik für Innere Medizin III Salzburg

Salzburg, 5020, Austria

Location

Hanuschkrankenhaus Wien

Vienna, 1140, Austria

Location

Helios Klinikum Bad Saarow

Bad Saarow, 15526, Germany

Location

Vivantes Klinikum Neukölln

Berlin, 12351, Germany

Location

Charité Universitätsmedizin Berlin

Berlin, 13353, Germany

Location

Marienhospital Bochum-Herne

Bochum, 44625, Germany

Location

Medizinische Universitätsklinik Bochum

Bochum, 44892, Germany

Location

Universitätsklinikum Bonn

Bonn, 53105, Germany

Location

Städtisches Klinikum Braunschweig gGmbH

Braunschweig, 38114, Germany

Location

Klinikum Bremen-Mitte gGmbH

Bremen, 64276, Germany

Location

Klinikum Darmstadt

Darmstadt, 64276, Germany

Location

Universitätsklinkum Düsseldorf

Düsseldorf, 40225, Germany

Location

Kliniken Essen-Süd

Essen, 45239, Germany

Location

Klinik für Onkologie, Gastroenterologie und Allg. Innere Medizin Esslingen

Esslingen am Neckar, 73730, Germany

Location

Malteser Krankenhaus St. Franziskus Hospital Flensburg

Flensburg, 24939, Germany

Location

Medizinische Universitätsklinik Freiburg

Freiburg im Breisgau, 79106, Germany

Location

MVZ Osthessen

Fulda, 36043, Germany

Location

Klinik der Justus-Liebig-Universität Gießen

Giessen, 35385, Germany

Location

Wilhelm-Anton-Hospital gGmbH Goch

Goch, 47574, Germany

Location

Universitätsmedizin Göttingen

Göttingen, 37075, Germany

Location

Universitätsklinikum Eppendorf

Hamburg, 20246, Germany

Location

Asklepios Klinik Altona

Hamburg, 22763, Germany

Location

Evangelisches Krankenhaus Hamm

Hamm, 59063, Germany

Location

Klinikum Region Hannover GmbH

Hanover, 30449, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

SLK Kliniken Heilbronn GmbH

Heilbronn, 74078, Germany

Location

Universitätskliniken des Saarlandes

Homburg/Saar, 66421, Germany

Location

Städtisches Klinikum Karlsruhe

Karlsruhe, 76133, Germany

Location

Städtisches Krankenhaus Kiel GmbH

Kiel, 24116, Germany

Location

Caritas Krankenhaus Lebach

Lebach, 66822, Germany

Location

Klinikum Lippe-Lemgo

Lemgo, 32657, Germany

Location

Märkische Kliniken GmbH Lüdenscheid

Lüdenscheid, 58515, Germany

Location

Universitätsklinikum der Otto-von-Guericke Universität Magdeburg

Magdeburg, 39120, Germany

Location

Universitätsklinikum der Johannes Gutenberg-Universität Mainz

Mainz, 55131, Germany

Location

Johannes Wesling Klinikum Minden

Minden, 32429, Germany

Location

Stauferklinikum Mutlangen

Mutlangen, 73557, Germany

Location

Klinikum Schwabing

München, 80804, Germany

Location

Klinikum rechts der Isar der TU München

München, 81675, Germany

Location

Ortenau Klinikum

Offenburg, 77654, Germany

Location

Pius Hospital Oldenburg

Oldenburg, 26121, Germany

Location

Klinikum Oldenburg

Oldenburg, 26133, Germany

Location

Klinikum Passau

Passau, 94032, Germany

Location

Universitätsklinikum Regensburg

Regensburg, 93053, Germany

Location

Caritasklinik St. Theresia Saarbrücken

Saarbrücken, 66113, Germany

Location

Klinikum Stuttgart

Stuttgart, 70174, Germany

Location

Diakonie-Klinikum Stuttgart

Stuttgart, 70176, Germany

Location

Klinikum Mutterhaus der Borromäerinnen gGmbH Trier

Trier, 54290, Germany

Location

Krankenhaus der Barmherzigen Brüder Trier

Trier, 54292, Germany

Location

Medizinische Universitätsklinik Tübingen

Tübingen, 72076, Germany

Location

University Hospital of Ulm

Ulm, 89081, Germany

Location

Schwarzwald-Baar Klinikum Villingen-Schwenningen

Villingen-Schwenningen, 78050, Germany

Location

Helios Klinikum Wuppertal

Wuppertal, 42283, Germany

Location

Related Publications (2)

• 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.

  PMID: 35486475 DERIVED

• 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.

  PMID: 30563875 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

midostaurin; Cytarabine; Daunorubicin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Hartmut Doehner, MD

  University Hospital of Ulm

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Hartmut Doehner

Study Record Dates

• First Submitted: November 17, 2011
• First Posted: November 22, 2011
• Study Start: May 1, 2012
• Primary Completion: February 26, 2020
• Study Completion: February 26, 2020
• Last Updated: June 4, 2020

Record last verified: 2020-06

Locations

AU (5); DE (50)