Clinical trial NCT01477606: Protocol in Acute Myeloid Leukemia With FLT3-ITD
Official title: Phase-II Study Evaluating Midostaurin in Induction, Consolidation and Maintenance Therapy Also After Allogeneic Blood Stem Cell Transplantation in Patients With Newly Diagnosed Acute Myeloid Leukemia Exhibiting a FLT3 Internal Tandem Duplication
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: Acute myeloid leukemia
FLT3-ITD
midostaurin (PKC412)
Lead sponsor: University of Ulm
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2011-11-22
Enrollment: 451
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


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.

Primary outcomes:
measure: Event-free Survival
timeFrame: 8years
Secondary outcomes:
measure: Rate of complete remission (CR)
timeFrame: Two months
measure: Relapse-free survival
timeFrame: 8 years
measure: overall survival
timeFrame: 8 years
measure: Cumulative incidence of relapse
timeFrame: 8 years
measure: cumulative incidence of death in CR
timeFrame: 8 years
measure: Target (FLT3) inhibition by measuring the FLT3 plasma inhibitory activity
timeFrame: 8 years
measure: Quality of life
timeFrame: 5 years
measure: Rate of early deaths and hypoplastic deaths (ED/HD)
timeFrame: two months
measure: Death in CR
timeFrame: 8 years
measure: Toxicities
timeFrame: between 18 and 24 months
measure: Impact of allogeneic HSCT
timeFrame: 8 years
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Linz
country: Austria
facility: Krankenhaus der Barmherzigen Schwestern Linz
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen Linz GmbH
city: Salzburg
country: Austria
facility: Universitätsklinik für Innere Medizin III Salzburg
city: Wien
country: Austria
facility: Hanuschkrankenhaus Wien
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Bochum
country: Germany
facility: Marienhospital Bochum-Herne
city: Bochum
country: Germany
facility: Medizinische Universitätsklinik Bochum
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
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
city: Düsseldorf
country: Germany
facility: Universitätsklinkum Düsseldorf
city: Essen
country: Germany
facility: Kliniken Essen-Süd
city: Esslingen
country: Germany
facility: Klinik für Onkologie, Gastroenterologie und Allg. Innere Medizin Esslingen
city: Flensburg
country: Germany
facility: Malteser Krankenhaus St. Franziskus Hospital Flensburg
city: Freiburg
country: Germany
facility: Medizinische Universitätsklinik Freiburg
city: Fulda
country: Germany
facility: MVZ Osthessen
city: Gießen
country: Germany
facility: Klinik der Justus-Liebig-Universität Gießen
city: Goch
country: Germany
facility: Wilhelm-Anton-Hospital gGmbH Goch
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Hamburg
country: Germany
facility: Universitätsklinikum Eppendorf
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona
city: Hamm
country: Germany
facility: Evangelisches Krankenhaus Hamm
city: Hannover
country: Germany
facility: Klinikum Region Hannover GmbH
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heilbronn
country: Germany
facility: SLK Kliniken Heilbronn GmbH
city: Homburg/Saar
country: Germany
facility: Universitätskliniken des Saarlandes
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Kiel
country: Germany
facility: Städtisches Krankenhaus Kiel GmbH
city: Lebach
country: Germany
facility: Caritas Krankenhaus Lebach
city: Lemgo
country: Germany
facility: Klinikum Lippe-Lemgo
city: Lüdenscheid
country: Germany
facility: Märkische Kliniken GmbH Lüdenscheid
city: Magdeburg
country: Germany
facility: Universitätsklinikum der Otto-von-Guericke Universität Magdeburg
city: Mainz
country: Germany
facility: Universitätsklinikum der Johannes Gutenberg-Universität Mainz
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: Mutlangen
country: Germany
facility: Stauferklinikum Mutlangen
city: München
country: Germany
facility: Klinikum Schwabing
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Offenburg
country: Germany
facility: Ortenau Klinikum
city: Oldenburg
country: Germany
facility: Pius Hospital Oldenburg
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Passau
country: Germany
facility: Klinikum Passau
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Saarbrücken
country: Germany
facility: Caritasklinik St. Theresia Saarbrücken
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Stuttgart
country: Germany
facility: Diakonie-Klinikum Stuttgart
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen gGmbH Trier
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder Trier
city: Tübingen
country: Germany
facility: Medizinische Universitätsklinik Tübingen
city: Ulm
country: Germany
facility: University Hospital of Ulm
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum Villingen-Schwenningen
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal
Study officials:
affiliation: University Hospital of Ulm
name: Hartmut Doehner, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.