Study of Chemotherapy in Combination With All-trans Retinoic Acid (ATRA) With or Without Gemtuzumab Ozogamicin in Patients With Acute Myeloid Leukemia (AML) and Mutant Nucleophosmin-1 (NPM1) Gene Mutation

NCT ID: NCT00893399

Last Updated: 2023-02-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 600 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-12
• Study Completion Date: 2021-09-01

Brief Summary

Randomized Phase-III, two-arm, open-label, multi-center study in adult patients with AML and NPM1 mutation.

Before Amendment No. 4 (December 2013):

Primary Efficacy Objective:

• Evaluation of efficacy based on event-free survival (EFS) after induction and consolidation chemotherapy plus all-trans retinoic acid (ATRA) with or without gemtuzumab ozogamicin (GO) in adult patients with acute myeloid leukemia (AML) and mutant nucleophosmin-1 (NPM1)

After Amendment No. 4 (December 2013):

Primary Efficacy Objective:

• Evaluation of efficacy based on overall survival (OS) after induction and consolidation chemotherapy plus all-trans retinoic acid (ATRA) with or without gemtuzumab ozogamicin (GO) in adult patients with acute myeloid leukemia (AML) and mutant nucleophosmin-1 (NPM1)

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

chemotherapy in combination with ATRA with gemtuzumab ozogamicin

Group Type: EXPERIMENTAL

Gemtuzumab Ozogamicin (Mylotarg)

Intervention Type: DRUG

Induction Cycle 1, 2: GO 3mg/m² by intravenous infusion (IVI) on day 1 (total dose 3 mg/m2). Start after etoposide IVI. No dose reduction is foreseen in elderly (> 60 yrs) patients.

Consolidation 1: GO 3mg/m² by intravenous infusion (IVI) on day 1 (total dose 3 mg/m2). Start after first dose of high-dose cytarabine. No dose reduction is foreseen in elderly (> 60 yrs) patients.

For all patients experiencing prolonged thrombocytopenia CTC-Grade 3/4 during the first or second induction therapy, which occurs for more than day 35 after start of the cycle, the further cycles of therapy will be administered without Gemtuzumab ozogamicin.

Consolidation 2, 3: no GO

standard chemotherapy

Intervention Type: DRUG

Idarubicin, Etoposide, Cytarabine, ATRA, Pegfilgrastim

2

chemotherapy in combination with ATRA without gemtuzumab ozogamicin

Group Type: ACTIVE_COMPARATOR

standard chemotherapy

Intervention Type: DRUG

Idarubicin, Etoposide, Cytarabine, ATRA, Pegfilgrastim

Interventions

Gemtuzumab Ozogamicin (Mylotarg)

Induction Cycle 1, 2: GO 3mg/m² by intravenous infusion (IVI) on day 1 (total dose 3 mg/m2). Start after etoposide IVI. No dose reduction is foreseen in elderly (> 60 yrs) patients.

Consolidation 1: GO 3mg/m² by intravenous infusion (IVI) on day 1 (total dose 3 mg/m2). Start after first dose of high-dose cytarabine. No dose reduction is foreseen in elderly (> 60 yrs) patients.

For all patients experiencing prolonged thrombocytopenia CTC-Grade 3/4 during the first or second induction therapy, which occurs for more than day 35 after start of the cycle, the further cycles of therapy will be administered without Gemtuzumab ozogamicin.

Consolidation 2, 3: no GO

Intervention Type: DRUG

standard chemotherapy

Idarubicin, Etoposide, Cytarabine, ATRA, Pegfilgrastim

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients with confirmed diagnosis of acute myeloid leukemia according to the World Health Organization (WHO) classification.
• Presence of NPM1 mutation as assessed in one of the central AMLSG reference laboratories.
• Age ≥ 18 years. There is no upper age limit.
• No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if needed for up to 5 days during the diagnostic screening phase.
• 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.
• Female patients in the reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and within one year after the last dose of chemotherapy.

• 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).
• "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 use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy.
• Signed written informed consent.

Exclusion Criteria

• AML with other recurrent genetic changes (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 other translocations involving RARA)
• AML with t(9;11)(p22;q23); MLLT3-MLL (or other translocations involving MLL)
• AML with t(6;9)(p23;q34); DEK-NUP214
• AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1.
• 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 about study participation.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Ulm

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. Hartmut Doehner

Prof. Dr.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hartmut Doehner, MD

Role: PRINCIPAL_INVESTIGATOR

University of Ulm

Locations

Medizinische Universitäts Graz

Graz, , Austria

Universitätsklinikum Innsbruck

Innsbruck, , Austria

Krankenhaus der Barmherzigen Schwestern Linz Betriebsgesellschaft m.b.H.

Linz, , Austria

Krankenhaus der Barmherzigen Schwestern Linz

Linz, , Austria

Krankenhaus der Elisabethinen Linz

Linz, , Austria

Salzburger Landeskliniken

Salzburg, , Austria

Hanuschkrankenhaus Wien

Vienna, , Austria

Klinikum Aschaffenburg-Alzenau

Aschaffenburg, , Germany

Ubbo-Emmius-Klinik Aurich

Aurich, , Germany

Helios Klinikum Bad Saarow

Bad Saarow, , Germany

Vivantes Klinikum am Urban

Berlin, , Germany

Vivantes Klinikum Neukölln

Berlin, , Germany

Charité Berlin - Campus Virchow Klinikum

Berlin, , Germany

Knappschaftskrankenhaus Bochum-Langendreer

Bochum, , Germany

Universitätsklinikum Bonn

Bonn, , Germany

Städtisches Klinikum Braunschweig gGmbH

Braunschweig, , Germany

Klinikum Bremen-Mitte

Bremen, , Germany

Klinikum Darmstadt

Darmstadt, , Germany

Universitätsklinikum Düsseldorf

Düsseldorf, , Germany

Kliniken Essen Süd, Ev. Krankenhaus Essen-Werden gGmbH

Essen, , Germany

Klinikum Esslingen

Esslingen am Neckar, , Germany

St. Franziskus Hospital

Flensburg, , Germany

Klinikum Frankfurt Höchst GmbH

Frankfurt-Höchst, , Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Medizinisches Versorgungszentrum Osthessen GmbH

Fulda, , Germany

Universitätsklinikum Gießen

Giessen, , Germany

Wilhelm-Anton-Hospital gGmbH Goch

Goch, , Germany

Universitätsklinikum Göttingen

Göttingen, , Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Asklepios Klinik Altona

Hamburg, , Germany

Evangelisches Krankenhaus Hamm gGmbH

Hamm, , Germany

Klinikum Hanau

Hanau, , Germany

KRH Klinikum Hannover-Siloah

Hanover, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

SLK-Kliniken GmbH Heilbronn

Heilbronn, , Germany

Universitätskliniken des Saarlandes

Homburg, , Germany

Städtisches Klinikum Karlsruhe gGmbH

Karlsruhe, , Germany

Universitätsklinikum Kiel

Kiel, , Germany

Caritas-Krankenhaus Lebach

Lebach, , Germany

Klinikum Lippe-Lemgo

Lemgo, , Germany

Klinikum Lüdenscheid

Lüdenscheid, , Germany

Universitätsklinikum der Otto-von Guericke Universität Magdeburg

Magdeburg, , Germany

Klinikum der Johannes Gutenberg Universität Mainz

Mainz, , Germany

Johannes Wesling Klinikum Minden

Minden, , Germany

Klinikum Schwabing

München, , Germany

Klinikum rechts der Isar München

München, , Germany

Lukaskrankenhaus GmbH Neuss

Neuss, , Germany

Ortenau Klinikum Offenburg Gengenbach

Offenburg, , Germany

Klinikum Oldenburg gGmbH

Oldenburg, , Germany

Klinikum Passau

Passau, , Germany

Caritas-Klinik St. Theresia Saarbrücken

Saarbrücken, , Germany

Stauferklinikum Schwäbisch Gmünd

Schwäbisch Gmünd, , Germany

Klinikum Stuttgart - Katharinenhospital

Stuttgart, , Germany

Diakonie-Klinikum Stuttgart

Stuttgart, , Germany

Klinikum Traunstein

Traunstein, , Germany

Krankenhaus der Barmherzigen Brüder

Trier, , Germany

Universitätsklinikum Tübingen

Tübingen, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH

Villingen-Schwenningen, , Germany

Helios Klinikum Wuppertal

Wuppertal, , Germany

Countries

Austria; Germany

References

Miah K, Goeman JJ, Putter H, Kopp-Schneider A, Benner A. Variable Selection via Fused Sparse-Group Lasso Penalized Multi-state Models Incorporating Molecular Data. Biom J. 2025 Dec;67(6):e70087. doi: 10.1002/bimj.70087.

Reference Type: DERIVED

PMID: 41146443 (View on PubMed)

Dohner H, Weber D, Krzykalla J, Fiedler W, Kuhn MWM, Schroeder T, Mayer K, Lubbert M, Wattad M, Gotze K, Fransecky L, Koller E, Wulf G, Schleicher J, Ringhoffer M, Greil R, Hertenstein B, Krauter J, Martens UM, Nachbaur D, Samra MA, Machherndl-Spandl S, Basara N, Leis C, Schrade A, Kapp-Schwoerer S, Cocciardi S, Bullinger L, Thol F, Heuser M, Paschka P, Gaidzik VI, Saadati M, Benner A, Schlenk RF, Dohner K, Ganser A; German-Austrian AML Study Group. Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09-09): a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2023 Jul;10(7):e495-e509. doi: 10.1016/S2352-3026(23)00089-3. Epub 2023 May 12.

Reference Type: DERIVED

PMID: 37187198 (View on PubMed)

Other Identifiers

AMLSG 09-09

Identifier Type: -

Identifier Source: org_study_id