Clinical trial NCT00151242: Study on All-Trans Retinoic Acid, Induction and Consolidation Therapy, and Pegfilgrastim After Consolidation Therapy in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia
Official title: Randomized Phase II/III-Study on All-Trans Retinoic Acid in Combination With Induction and Consolidation Therapy as Well as Pegfilgrastim After Consolidation Therapy in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Myeloid Leukemia
Lead sponsor: University of Ulm
Sponsor class: OTHER
First posted: 2005-09-08
Enrollment: 920
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial is a study on all-trans retinoic acid in combination with induction and consolidation therapy as well as pegfilgrastim after consolidation therapy in younger patients with newly diagnosed acute myeloid leukemia (AML).

Detailed description: First Induction Therapy:

* Cytarabine 100 mg/m² cont. i.v. days 1-7
* Idarubicin 12 mg/m² i.v. days 1,3,5
* Etoposide 100 mg/m² i.v. days 1-3
* ± ATRA 45 mg/m² p.o. days 6-8
* ATRA 15 mg/m² p.o. days 9-21

Second Induction Therapy:

* Cytarabine 100 mg/m² cont. i.v. days 1-7
* Idarubicin 12 mg/m² i.v. days 1 and 3
* Etoposide 100 mg/m² i.v. days 1-3
* ± ATRA 45 mg/m² p.o. days 6-8
* ATRA 15 mg/m² p.o. days 9-21

Consolidation Therapy:

cohort 1 (\<= ID 336)

* Cytarabine 3 g/m² 2x/die i.v. Tag 1,3,5
* ± ATRA 15 mg/m² p.o. Tag 6-21
* Pegfilgrastim 6 mg s.c day 10

cohort 2 (\> ID 336)

* Cytarabine 3 g/m² 2x/die i.v. Tag 1,2,3
* ± ATRA 15 mg/m² p.o. Tag 4-21
* Pegfilgrastim 6 mg s.c day 8

Eligibility criteria: Inclusion Criteria:

* Newly diagnosed AML defined according to the World Health Organization (WHO)-classification (excluding acute promyelocytic leukemia \[APL\])
* Ages 18-60 years
* Written informed consent of each patient at study entry.
* Molecular and cytogenetical diagnostics on initial bone marrow and peripheral blood specimen at the central reference laboratories

Exclusion Criteria:

* Bleeding independent of the AML
* Acute promyelocytic leukemia
* Uncontrollable infection
* Participation in a concurrent clinical study
* Insufficiency of the kidneys (creatinine \> 1.5x upper normal serum level), of the liver (bilirubin, AST or AP \> 2x upper normal serum level), severe obstructive or restrictive ventilation disorder, heart failure New York Heart Association (NYHA) III/IV
* Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
* No consent for registration, storage and processing of the individual disease-characteristics and course.
* Performance status WHO \> 2
* Pregnancy

Primary outcomes:
measure: Complete remission (CR)-rate after induction therapy
timeFrame: after the second induction cycle
measure: Relapse-free survival, one year after consolidation therapy with high-dose cytarabine considering different temporal sequences (1-3-5 versus 1-2-3) of the consolidation therapy
timeFrame: One year after consolidation therapy
measure: Event-free survival
timeFrame: two years
Secondary outcomes:
measure: Kind, incidence, severity, temporal sequence and correlation of side effects of the study-drugs
timeFrame: during therapy
measure: Cumulative incidence of relapse
timeFrame: two years
measure: Cumulative incidence of death
timeFrame: two years
measure: Overall survival
timeFrame: two years
measure: Hematological recovery as well as incidence and duration of infections during neutropenia after each consolidation cycle
timeFrame: during consolidation therapy
measure: Timely sequence of the pegfilgrastim-concentration in correlation to the absolute neutrophil counts after each consolidation cycle
timeFrame: during consolidation therapy
measure: Hematologic and non-hematologic toxicity after consolidation therapy with high-dose cytarabine considering the different consolidation schemes (day 1-3-5 versus day 1-2-3)
timeFrame: during consolidation therapy
measure: Days in hospital after each consolidation cycle
timeFrame: after consolidation therapy
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Department of Hematology/Oncology, University Hospital Innsbruck
city: Linz
country: Austria
facility: Department of Internal Medicine I, Krankenhaus der Barmherzigen Schwestern
city: Salzburg
country: Austria
facility: Medical Department III, St. Johann-Hospital
city: Wien
country: Austria
facility: Center of Hematology and Oncology, Hanusch-Hospital
city: Bonn
country: Germany
facility: Department of General Internal Medicine, University Hospital of Bonn
city: Bremen
country: Germany
facility: Medical Department I, Hospital Bremen-Mitte
city: Düsseldorf
country: Germany
facility: Clinical Center of Hematology and Oncology, University Hospital of Düsseldorf
city: Essen
country: Germany
facility: Department of Hematology and Oncology, Hospital Essen Süd, Ev. Hospital of Essen-Werden
city: Frankfurt
country: Germany
facility: Medical Department III, Hematology/Oncology, University of Frankfurt
city: Frankfurt
country: Germany
facility: Department of Internal Medicine III, City Hospital Frankfurt am Main - Höchst
city: Freiburg
country: Germany
facility: Internal Medicine I, University of Freiburg
city: Giessen
country: Germany
facility: Medical Department IV, University Hospital of Giessen
city: Goch
country: Germany
facility: Department of Internal Medicine, Wilhelm-Anton-Hospital gGmbH
city: Göttingen
country: Germany
facility: Centre of Internal Medicine, University Hospital Göttingen
city: Hamburg
country: Germany
facility: Department of Oncology and Hematology, University Hospital Eppendorf
city: Hamburg
country: Germany
facility: Medical Department II, Hematology and Oncology, General Hospital Altona
city: Hanau
country: Germany
facility: Medical Department III, Clinical Center Hanau
city: Hannover
country: Germany
facility: Medical Department III, Hospital Hannover-Siloah
city: Hannover
country: Germany
facility: Department of Hematology, Hematology and Oncology, Medizinische Hochschule Hannover
city: Homburg
country: Germany
facility: Department of Internal Medicine I, University Hospital of Saarland
city: Karlsruhe
country: Germany
facility: Medical Department II, City Hospital Karlsruhe gGmbH
city: Kiel
country: Germany
facility: Medical Department II, University Hospital of Kiel
city: Lebach
country: Germany
facility: Department of Internal Medicine/Hematology and Oncology, Cartias Hospital Lebach
city: Lüdenscheid
country: Germany
facility: Department of Hematology and Oncology, Hospital of Lüdenscheid
city: Mainz
country: Germany
facility: Department of Hematology and Internal Oncology, University Hospital of Mainz
city: München
country: Germany
facility: Medical Department III, Clinical Center Rechts der Isar
city: Oldenburg
country: Germany
facility: Department of Hematology and Oncology, Clinical Center of Oldenburg gGmbH
city: Saarbrücken
country: Germany
facility: Department of Hematology and Oncology, Caritas Hospital St. Theresia
city: Stuttgart
country: Germany
facility: Department of Oncology, Clinical Center of Stuttgart
city: Stuttgart
country: Germany
facility: Medical Department II, Diakonie Hospital
city: Trier
country: Germany
facility: Medical Department I, Hospital of Barmherzige Brüder
city: Tübingen
country: Germany
facility: Department of Internal Medicine II, University Hospital of Tübingen
city: Villingen-Schwenningen
country: Germany
facility: Medical Clinic II-Hematology/Oncology, Hospital Villingen-Schwenningen
city: Wuppertal
country: Germany
facility: Medical Department I, Helios Hospital Wuppertal
Study officials:
affiliation: University of Ulm
name: Richard F Schlenk, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schlenk RF, Lubbert M, Benner A, Lamparter A, Krauter J, Herr W, Martin H, Salih HR, Kundgen A, Horst HA, Brossart P, Gotze K, Nachbaur D, Wattad M, Kohne CH, Fiedler W, Bentz M, Wulf G, Held G, Hertenstein B, Salwender H, Gaidzik VI, Schlegelberger B, Weber D, Dohner K, Ganser A, Dohner H; German-Austrian Acute Myeloid Leukemia Study Group. All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-04 study. Ann Hematol. 2016 Dec;95(12):1931-1942. doi: 10.1007/s00277-016-2810-z. Epub 2016 Oct 3.
citation: Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, Held G, Brossart P, Lubbert M, Salih HR, Kindler T, Horst HA, Wulf G, Nachbaur D, Gotze K, Lamparter A, Paschka P, Gaidzik VI, Teleanu V, Spath D, Benner A, Krauter J, Ganser A, Dohner H, Dohner K; German-Austrian AML Study Group. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014 Nov 27;124(23):3441-9. doi: 10.1182/blood-2014-05-578070. Epub 2014 Sep 30.
citation: Gaidzik VI, Bullinger L, Schlenk RF, Zimmermann AS, Rock J, Paschka P, Corbacioglu A, Krauter J, Schlegelberger B, Ganser A, Spath D, Kundgen A, Schmidt-Wolf IG, Gotze K, Nachbaur D, Pfreundschuh M, Horst HA, Dohner H, Dohner K. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol. 2011 Apr 1;29(10):1364-72. doi: 10.1200/JCO.2010.30.7926. Epub 2011 Feb 22.
citation: Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Wittke K, Du J, Groner S, Spath D, Krauter J, Ganser A, Dohner H, Fischer T, Dohner K; German-Austrian AML Study Group (AMLSG). Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009 Sep 17;114(12):2386-92. doi: 10.1182/blood-2009-03-209999. Epub 2009 Jul 14.
citation: Schlenk RF, Dohner K, Kneba M, Gotze K, Hartmann F, Del Valle F, Kirchen H, Koller E, Fischer JT, Bullinger L, Habdank M, Spath D, Groner S, Krebs B, Kayser S, Corbacioglu A, Anhalt A, Benner A, Frohling S, Dohner H; German-Austrian AML Study Group (AMLSG). Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica. 2009 Jan;94(1):54-60. doi: 10.3324/haematol.13378. Epub 2008 Dec 4.