Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™)

Sponsor

University of Ulm (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02013648

Collaborator

(none)

203

Enrollment

Locations

Arms

115.1

Duration (Months)

3.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia (AML)	Drug: Dasatinib Drug: Cytarabine Drug: Daunorubicin Drug: Idarubicin	Phase 3

Detailed Description

This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin [DNR] and cytarabine [Ara-C]) and consolidation therapy (high-dose cytarabine [HDAC]) with or without dasatinib in adult patients with newly diagnosed CBF-AML; in the investigational arm, consolidation therapy is followed by a one-year maintenance therapy with dasatinib. Patients with molecular disease persistence or molecular relapse as assessed by quantitative RQ-PCR for the CBF fusion transcripts will be eligible for hematopoietic stem cell transplantation before overt hematologic relapse occurs. Primary endpoint is event-free survival.

AML patients will be assessed for the CBF fusion genes in one of two AMLSG central laboratories within 48 hours of diagnosis, and only patients with CBF-AML will be enrolled.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

203 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™) in Adult Patients With Newly Diagnosed Core-Binding Factor Acute Myeloid Leukemia (CBF-AML)

Study Start Date :

Jul 1, 2014

Anticipated Primary Completion Date :

Feb 1, 2024

Anticipated Study Completion Date :

Feb 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard arm Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7. Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5. Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours. Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse.	Drug: Cytarabine Other Names: ARA-cell Drug: Daunorubicin Other Names: Daunoblastin Drug: Idarubicin
Experimental: Investigational arm Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21. Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse).	Drug: Dasatinib Other Names: Sprycel Drug: Cytarabine Other Names: ARA-cell Drug: Daunorubicin Other Names: Daunoblastin Drug: Idarubicin

Arm

Intervention/Treatment

Active Comparator: Standard arm

Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7. Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5. Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours. Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse.

Drug: Cytarabine

Other Names:

ARA-cell

Drug: Daunorubicin

Other Names:

Daunoblastin

Drug: Idarubicin

Experimental: Investigational arm

Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21. Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse).

Drug: Dasatinib

Other Names:

Sprycel

Drug: Cytarabine

Other Names:

ARA-cell

Drug: Daunorubicin

Other Names:

Daunoblastin

Drug: Idarubicin

Outcome Measures

Primary Outcome Measures

Event-free Survival [4 years]
To assess event-free survival (EFS) after intensive induction (daunorubicin and cytarabine) and consolidation (high-dose cytarabine) chemotherapy with or without dasatinib in patients with CBF-AML

Secondary Outcome Measures

Cumulative incidence of relapse (CIR) [4 years]
Cumulative incidence of death (CID) [4 years]
overall survival [4 years]
relapse-free survival [4 years]
PIA analysis [4 years]
Pharmacodynamic inhibition of KIT as assessed by the KIT plasma inhibitory assay (PIA)
toxicity [7 months (standard arm) / 19 months (investigational arm)]
Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03), timing and relatedness of non-hematologic toxicity observed during different treatment cycles.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Core-binding factor (CBF) AML with molecular diagnosis of RUNX1-RUNX1T1 fusion transcript resulting from t(8;21)(q22;q22.1) (or a variant form) or of CBFB-MYH11 fusion transcript resulting from inv(16)(p13.1q22)/t(16;16)(p13.1;q22) as assessed in one of the central AMLSG reference laboratories (Ulm, Hannover)
Age ≥ 18; there is no upper age limit
No prior chemotherapy for leukemia except hydroxyurea for up to 5 days during the diagnostic screening phase
Non-pregnant and non-nursing. Due to the unknown teratogenic potential of dasatinib in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL with-in 72 hours prior to registration. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control - one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least four weeks before she begins dasatinib therapy. "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.
Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking dasatinib and for 3 months after therapy is stopped, even if they have undergone a successful vasectomy.
Signed written informed consent.

Exclusion Criteria:

Performance status WHO >2
Pulmonary edema and/or pleural/pericardial effusion within 14 days of day 1. If edema/effusion resolves to CTC Grade ≤1, patients can be treated with dasatinib.
Patients with ejection fraction <50% by echocardiography within 14 days of day 1
Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or AP

2.5x upper normal serum level; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)

Uncontrolled infection
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.
Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
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	State	Country	Postal Code
1	Universitätsklinik für Innere Medizin V	Innsbruck		Austria	6020
2	Krankenhaus der Barmherzigen Schwestern	Linz		Austria	4010
3	Krankenhaus der Elisabethinen Linz GmbH	Linz		Austria	4020
4	Universitätsklinik der PMU	Salzburg		Austria	5020
5	Hanuschkrankenhaus	Wien		Austria	1140
6	MVZ Osthessen	Fulda	Hessen	Germany	36043
7	Universitätsklinikum Schleswig-Holstein	Kiel	Schleswig-Holstein	Germany	24116
8	Klinikum Aschaffenburg-Alzenau	Aschaffenburg		Germany	63739
9	Helios Klinikum Bad Saarow, Klinik für Hämatologie	Bad Saarow		Germany	15526
10	Klinikum am Urban	Berlin		Germany	10967
11	Klinikum Neukölln	Berlin		Germany	12351
12	Charité Universitätsmedizin Campus Virchow Klinikum	Berlin		Germany	13353
13	Knappschaftskrankenhaus Bochum	Bochum		Germany
14	Universitätsklinikum Medizinische Klinik und Poliklinik III	Bonn		Germany	53105
15	Städtisches Klinikum Braunschweig gGmbH	Braunschweig		Germany	38114
16	Klinikum Bremen Mitte gGmbH	Bremen		Germany	28117
17	Klinikum Darmstadt Medizinische Klinik V	Darmstadt		Germany	64276
18	St. Johannes Hospital	Dortmund		Germany	44137
19	Universitätsklinikum Medizinische Klinik und Poliklinik	Düsseldorf		Germany	40001
20	Klinikum Esslingen	Esslingen		Germany	73730
21	Malteser Krankenhaus St. Franziskus-Hospital	Flensburg		Germany	24939
22	Universitätsklinikum Freiburg	Freiburg		Germany	79106
23	Wilhelm-Anton-Hospital gGmbH	Goch		Germany	47574
24	Universitätsmedizin Göttingen	Göttingen		Germany	37075
25	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
26	Klinikum Hanau GmbH	Hanau		Germany	63450
27	Klinikum Region Hannover GmbH	Hannover		Germany	30449
28	Medizinische Hochschule Hannover	Hannover		Germany	30625
29	SLK-Kliniken GmbH	Heilbronn		Germany	74078
30	Marienhospital Klinikum der Ruhr-Universität	Herne		Germany	44625
31	Universitätsklinikum des Saarlandes	Homburg		Germany	66421
32	Städtisches Klinikum Karlsruhe gGmbH	Karlsruhe		Germany	76133
33	Gemeinschaftspraxis Hämato-Onkologie	Lebach		Germany	66822
34	Klinikum Lippe GmbH	Lemgo		Germany	32657
35	Märkische Kliniken GmbH	Lüdenscheid		Germany	58515
36	Univ-Klinikum der Otto-von Guericke-Universität	Magdeburg		Germany	39120
37	III. Medizinische Klinik und Poliklinik Universitätsmedizin der Johannes Gutenberg-Universität	Mainz		Germany	55131
38	Johannes Wesling Klinikum	Minden		Germany	32429
39	Stauferklinikum Schwäbisch Gmünd	Mutlangen		Germany	73557
40	Klinikum rechts der Isar der TU	München		Germany	81675
41	Ortenau Klinikum	Offenburg		Germany	77654
42	PIUS Hospital	Oldenburg		Germany	26121
43	Klinikum Oldenburg gGmbH	Oldenburg		Germany	26133
44	Klinikum Passau	Passau		Germany	94032
45	Universitätsklinikum Regensburg	Regensburg		Germany	93053
46	Caritasklinkum Saarbrücken St. Theresia	Saarbrücken		Germany	66113
47	Klinikum Stuttgart	Stuttgart		Germany	70174
48	Vinzenz von Paul Kliniken gGmbH Marienhospital	Stuttgart		Germany	70199
49	Klinikum Mutterhaus der Borromäerinnen gGmbH	Trier		Germany	54290
50	Medizinische Universitätsklinik	Tübingen		Germany	72076
51	Universitätsklinikum Ulm Zentrum für Innere Medizin	Ulm		Germany	89081
52	Schwarzwald-Baar Klinikum	Villingen Schwenningen		Germany	78052
53	Kliniken Essen Süd	Werden		Germany	45239
54	HELIOS Klinikum	Wuppertal		Germany	42283