Protocol in Acute Myeloid Leukemia With FLT3-ITD

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01477606
• Other study ID #: AMLSG 16-10
• Secondary ID: 2011-003168-63
• Status: Completed
• Phase: Phase 2
• Start date: May 2012
• Est. completion date: February 26, 2020

Study information

• Verified date: June 2020
• Source: University of Ulm
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 451
• Est. completion date: February 26, 2020
• Est. primary completion date: February 26, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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

Locations

Country	Name	City	State
Austria	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	Wien
Germany	Helios Klinikum Bad Saarow	Bad Saarow
Germany	Charité Universitätsmedizin Berlin	Berlin
Germany	Vivantes Klinikum Neukölln	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
Germany	Malteser Krankenhaus St. Franziskus Hospital Flensburg	Flensburg
Germany	Medizinische Universitätsklinik Freiburg	Freiburg
Germany	MVZ Osthessen	Fulda
Germany	Klinik der Justus-Liebig-Universität Gießen	Gießen
Germany	Wilhelm-Anton-Hospital gGmbH Goch	Goch
Germany	Universitätsmedizin Göttingen	Göttingen
Germany	Asklepios Klinik Altona	Hamburg
Germany	Universitätsklinikum Eppendorf	Hamburg
Germany	Evangelisches Krankenhaus Hamm	Hamm
Germany	Klinikum Region Hannover GmbH	Hannover
Germany	Medizinische Hochschule Hannover	Hannover
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	Klinikum rechts der Isar der TU München	München
Germany	Klinikum Schwabing	München
Germany	Stauferklinikum Mutlangen	Mutlangen
Germany	Ortenau Klinikum	Offenburg
Germany	Klinikum Oldenburg	Oldenburg
Germany	Pius Hospital Oldenburg	Oldenburg
Germany	Klinikum Passau	Passau
Germany	Universitätsklinikum Regensburg	Regensburg
Germany	Caritasklinik St. Theresia Saarbrücken	Saarbrücken
Germany	Diakonie-Klinikum Stuttgart	Stuttgart
Germany	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

Sponsors (2)

Lead Sponsor	Collaborator
University of Ulm	Novartis Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Rate of complete remission (CR)		Two months
Secondary	Relapse-free survival		8 years
Secondary	overall survival		8 years
Secondary	Cumulative incidence of relapse		8 years
Secondary	cumulative incidence of death in CR		8 years
Secondary	Target (FLT3) inhibition by measuring the FLT3 plasma inhibitory activity	Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin	8 years
Secondary	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
Secondary	Rate of early deaths and hypoplastic deaths (ED/HD)		two months
Secondary	Death in CR		8 years
Secondary	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
Secondary	Impact of allogeneic HSCT	Assessment of the relative impact of allogeneic HSCT analyzed as time-dependent variable on survival endpoints.	8 years