Protocol in Acute Myeloid Leukemia With FLT3-ITD

Sponsor

University of Ulm (Other)

Overall Status

Completed

CT.gov ID

NCT01477606

Collaborator

Novartis Pharmaceuticals (Industry)

451

Enrollment

Locations

Arm

93.9

Duration (Months)

8.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Midostaurin Drug: Cytarabine Drug: Daunorubicin	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

451 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

May 1, 2012

Actual Primary Completion Date :

Feb 26, 2020

Actual Study Completion Date :

Feb 26, 2020

Arms and Interventions

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)

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)

Outcome Measures

Primary Outcome Measures

Event-free Survival [8years]
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.

Secondary Outcome Measures

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 [8 years]
Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin
Quality of life [5 years]
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.
Rate of early deaths and hypoplastic deaths (ED/HD) [two months]
Death in CR [8 years]
Toxicities [between 18 and 24 months]
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
Impact of allogeneic HSCT [8 years]
Assessment of the relative impact of allogeneic HSCT analyzed as time-dependent variable on survival endpoints.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Medizinische Universität Innsbruck	Innsbruck	Austria	3020
2	Krankenhaus der Barmherzigen Schwestern Linz	Linz	Austria	4010
3	Krankenhaus der Elisabethinen Linz GmbH	Linz	Austria	4020
4	Universitätsklinik für Innere Medizin III Salzburg	Salzburg	Austria	5020
5	Hanuschkrankenhaus Wien	Wien	Austria	1140
6	Helios Klinikum Bad Saarow	Bad Saarow	Germany	15526
7	Vivantes Klinikum Neukölln	Berlin	Germany	12351
8	Charité Universitätsmedizin Berlin	Berlin	Germany	13353
9	Marienhospital Bochum-Herne	Bochum	Germany	44625
10	Medizinische Universitätsklinik Bochum	Bochum	Germany	44892
11	Universitätsklinikum Bonn	Bonn	Germany	53105
12	Städtisches Klinikum Braunschweig gGmbH	Braunschweig	Germany	38114
13	Klinikum Bremen-Mitte gGmbH	Bremen	Germany	64276
14	Klinikum Darmstadt	Darmstadt	Germany	64276
15	Universitätsklinkum Düsseldorf	Düsseldorf	Germany	40225
16	Kliniken Essen-Süd	Essen	Germany	45239
17	Klinik für Onkologie, Gastroenterologie und Allg. Innere Medizin Esslingen	Esslingen	Germany	73730
18	Malteser Krankenhaus St. Franziskus Hospital Flensburg	Flensburg	Germany	24939
19	Medizinische Universitätsklinik Freiburg	Freiburg	Germany	79106
20	MVZ Osthessen	Fulda	Germany	36043
21	Klinik der Justus-Liebig-Universität Gießen	Gießen	Germany	35385
22	Wilhelm-Anton-Hospital gGmbH Goch	Goch	Germany	47574
23	Universitätsmedizin Göttingen	Göttingen	Germany	37075
24	Universitätsklinikum Eppendorf	Hamburg	Germany	20246
25	Asklepios Klinik Altona	Hamburg	Germany	22763
26	Evangelisches Krankenhaus Hamm	Hamm	Germany	59063
27	Klinikum Region Hannover GmbH	Hannover	Germany	30449
28	Medizinische Hochschule Hannover	Hannover	Germany	30625
29	SLK Kliniken Heilbronn GmbH	Heilbronn	Germany	74078
30	Universitätskliniken des Saarlandes	Homburg/Saar	Germany	66421
31	Städtisches Klinikum Karlsruhe	Karlsruhe	Germany	76133
32	Städtisches Krankenhaus Kiel GmbH	Kiel	Germany	24116
33	Caritas Krankenhaus Lebach	Lebach	Germany	66822
34	Klinikum Lippe-Lemgo	Lemgo	Germany	32657
35	Märkische Kliniken GmbH Lüdenscheid	Lüdenscheid	Germany	58515
36	Universitätsklinikum der Otto-von-Guericke Universität Magdeburg	Magdeburg	Germany	39120
37	Universitätsklinikum der Johannes Gutenberg-Universität Mainz	Mainz	Germany	55131
38	Johannes Wesling Klinikum Minden	Minden	Germany	32429
39	Stauferklinikum Mutlangen	Mutlangen	Germany	73557
40	Klinikum Schwabing	München	Germany	80804
41	Klinikum rechts der Isar der TU München	München	Germany	81675
42	Ortenau Klinikum	Offenburg	Germany	77654
43	Pius Hospital Oldenburg	Oldenburg	Germany	26121
44	Klinikum Oldenburg	Oldenburg	Germany	26133
45	Klinikum Passau	Passau	Germany	94032
46	Universitätsklinikum Regensburg	Regensburg	Germany	93053
47	Caritasklinik St. Theresia Saarbrücken	Saarbrücken	Germany	66113
48	Klinikum Stuttgart	Stuttgart	Germany	70174
49	Diakonie-Klinikum Stuttgart	Stuttgart	Germany	70176
50	Klinikum Mutterhaus der Borromäerinnen gGmbH Trier	Trier	Germany	54290
51	Krankenhaus der Barmherzigen Brüder Trier	Trier	Germany	54292
52	Medizinische Universitätsklinik Tübingen	Tübingen	Germany	72076
53	University Hospital of Ulm	Ulm	Germany	89081
54	Schwarzwald-Baar Klinikum Villingen-Schwenningen	Villingen-Schwenningen	Germany	78050
55	Helios Klinikum Wuppertal	Wuppertal	Germany	42283