Protocol in Acute Myeloid Leukemia With FLT3-ITD

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

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

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Midostaurin; Drug: Cytarabine; Drug: Daunorubicin

• Study Type: Interventional
• Enrollment (Actual): 451
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 3020
    • Medizinische Universität Innsbruck
  • Linz, Austria, 4010
    • Krankenhaus der Barmherzigen Schwestern Linz
  • Linz, Austria, 4020
    • Krankenhaus der Elisabethinen Linz GmbH
  • Salzburg, Austria, 5020
    • Universitätsklinik für Innere Medizin III Salzburg
  • Wien, Austria, 1140
    • Hanuschkrankenhaus Wien
• Germany
  • Bad Saarow, Germany, 15526
    • HELIOS Klinikum Bad Saarow
  • Berlin, Germany, 13353
    • Charite Universitatsmedizin Berlin
  • Berlin, Germany, 12351
    • Vivantes Klinikum Neukölln
  • Bochum, Germany, 44625
    • Marienhospital Bochum-Herne
  • Bochum, Germany, 44892
    • Medizinische Universitätsklinik Bochum
  • Bonn, Germany, 53105
    • Universitatsklinikum Bonn
  • Braunschweig, Germany, 38114
    • Städtisches Klinikum Braunschweig gGmbH
  • Bremen, Germany, 64276
    • Klinikum Bremen-Mitte gGmbH
  • Darmstadt, Germany, 64276
    • Klinikum Darmstadt
  • Düsseldorf, Germany, 40225
    • Universitätsklinkum Düsseldorf
  • Essen, Germany, 45239
    • Kliniken Essen-Süd
  • Esslingen, Germany, 73730
    • Klinik für Onkologie, Gastroenterologie und Allg. Innere Medizin Esslingen
  • Flensburg, Germany, 24939
    • Malteser Krankenhaus St. Franziskus Hospital Flensburg
  • Freiburg, Germany, 79106
    • Medizinische Universitätsklinik Freiburg
  • Fulda, Germany, 36043
    • MVZ Osthessen
  • Gießen, Germany, 35385
    • Klinik der Justus-Liebig-Universität Gießen
  • Goch, Germany, 47574
    • Wilhelm-Anton-Hospital gGmbH Goch
  • Göttingen, Germany, 37075
    • Universitatsmedizin Gottingen
  • Hamburg, Germany, 22763
    • Asklepios Klinik Altona
  • Hamburg, Germany, 20246
    • Universitätsklinikum Eppendorf
  • Hamm, Germany, 59063
    • Evangelisches Krankenhaus Hamm
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Hannover, Germany, 30449
    • Klinikum Region Hannover GmbH
  • Heilbronn, Germany, 74078
    • SLK Kliniken Heilbronn GmbH
  • Homburg/Saar, Germany, 66421
    • Universitätskliniken des Saarlandes
  • Karlsruhe, Germany, 76133
    • Städtisches Klinikum Karlsruhe
  • Kiel, Germany, 24116
    • Städtisches Krankenhaus Kiel GmbH
  • Lebach, Germany, 66822
    • Caritas Krankenhaus Lebach
  • Lemgo, Germany, 32657
    • Klinikum Lippe-Lemgo
  • Lüdenscheid, Germany, 58515
    • Märkische Kliniken GmbH Lüdenscheid
  • Magdeburg, Germany, 39120
    • Universitätsklinikum der Otto-von-Guericke Universität Magdeburg
  • Mainz, Germany, 55131
    • Universitätsklinikum der Johannes Gutenberg-Universität Mainz
  • Minden, Germany, 32429
    • Johannes Wesling Klinikum Minden
  • Mutlangen, Germany, 73557
    • Stauferklinikum Mutlangen
  • München, Germany, 80804
    • Klinikum Schwabing
  • München, Germany, 81675
    • Klinikum rechts der Isar der TU Munchen
  • Offenburg, Germany, 77654
    • Ortenau Klinikum
  • Oldenburg, Germany, 26121
    • Pius Hospital Oldenburg
  • Oldenburg, Germany, 26133
    • Klinikum Oldenburg
  • Passau, Germany, 94032
    • Klinikum Passau
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
  • Saarbrücken, Germany, 66113
    • Caritasklinik St. Theresia Saarbrücken
  • Stuttgart, Germany, 70176
    • Diakonie-Klinikum Stuttgart
  • Stuttgart, Germany, 70174
    • Klinikum Stuttgart
  • Trier, Germany, 54292
    • Krankenhaus der Barmherzigen Brüder Trier
  • Trier, Germany, 54290
    • Klinikum Mutterhaus der Borromäerinnen gGmbH Trier
  • Tübingen, Germany, 72076
    • Medizinische Universitätsklinik Tübingen
  • Ulm, Germany, 89081
    • University Hospital of Ulm
  • Villingen-Schwenningen, Germany, 78050
    • Schwarzwald-Baar Klinikum Villingen-Schwenningen
  • Wuppertal, Germany, 42283
    • Helios Klinikum Wuppertal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Midostaurin

Drug: 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.; Other Names: PKC412; 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).; Drug: Daunorubicin; Induction therapy: 60 mg/m², by 1-hour i.v. infusion, day 1-3 (total dose 180 mg/m²)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Target (FLT3) inhibition by measuring the FLT3 plasma inhibitory activity	Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin	8 years
Quality of life	Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics initially, in first CR, after one year,3 and 5 years after initial diagnosis.	5 years
Rate of early deaths and hypoplastic deaths (ED/HD)		two months
Death in CR		8 years
Toxicities	Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0), timing and relatedness of hematological and non-hematological toxicities observed during the different treatment cycles	between 18 and 24 months
Impact of allogeneic HSCT	Assessment of the relative impact of allogeneic HSCT analyzed as time-dependent variable on survival endpoints.	8 years

Collaborators and Investigators

• Sponsor: University of Ulm
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Hartmut Doehner, MD, University Hospital of Ulm

Publications and helpful links

General Publications

• Döhner H, Weber D, Krzykalla J, Fiedler W, Wulf G, Salih H, Lübbert M, Kühn MWM, Schroeder T, Salwender H, Götze 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, Döhner 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): February 26, 2020
• Study Completion (Actual): February 26, 2020

Study Registration Dates

• First Submitted: November 17, 2011
• First Submitted That Met QC Criteria: November 21, 2011
• First Posted (Estimate): November 22, 2011

Study Record Updates

• Last Update Posted (Actual): June 4, 2020
• Last Update Submitted That Met QC Criteria: June 3, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Acute myeloid leukemia; FLT3-ITD; midostaurin (PKC412)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Cytarabine; Daunorubicin; Midostaurin
• Other Study ID Numbers: AMLSG 16-10; 2011-003168-63 (EudraCT Number)