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

Acute Myeloid Leukemia Clinical Trial

Official title:

Phase III Study of Chemotherapy in Combination With ATRA With or Without Gemtuzumab Ozogamicin in Patients With Acute Myeloid Leukemia and NPM1 Gene Mutation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00893399
• Other study ID #: AMLSG 09-09
• Status: Completed
• Phase: Phase 3
• Start date: May 12, 2010
• Est. completion date: September 1, 2021

Study information

• Verified date: February 2023
• Source: University of Ulm
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 600
• Est. completion date: September 1, 2021
• Est. primary completion date: September 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• 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
• standard chemotherapy
Idarubicin, Etoposide, Cytarabine, ATRA, Pegfilgrastim

Locations

Country	Name	City	State
Austria	Medizinische Universitäts Graz	Graz
Austria	Universitätsklinikum Innsbruck	Innsbruck
Austria	Krankenhaus der Barmherzigen Schwestern Linz	Linz
Austria	Krankenhaus der Barmherzigen Schwestern Linz Betriebsgesellschaft m.b.H.	Linz
Austria	Krankenhaus der Elisabethinen Linz	Linz
Austria	Salzburger Landeskliniken	Salzburg
Austria	Hanuschkrankenhaus Wien	Wien
Germany	Klinikum Aschaffenburg-Alzenau	Aschaffenburg
Germany	Ubbo-Emmius-Klinik Aurich	Aurich
Germany	Helios Klinikum Bad Saarow	Bad Saarow
Germany	Charité Berlin - Campus Virchow Klinikum	Berlin
Germany	Vivantes Klinikum am Urban	Berlin
Germany	Vivantes Klinikum Neukölln	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
Germany	St. Franziskus Hospital	Flensburg
Germany	Klinikum Frankfurt Höchst GmbH	Frankfurt-Höchst
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Medizinisches Versorgungszentrum Osthessen GmbH	Fulda
Germany	Universitätsklinikum Gießen	Gießen
Germany	Wilhelm-Anton-Hospital gGmbH Goch	Goch
Germany	Universitätsklinikum Göttingen	Göttingen
Germany	Asklepios Klinik Altona	Hamburg
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Evangelisches Krankenhaus Hamm gGmbH	Hamm
Germany	Klinikum Hanau	Hanau
Germany	KRH Klinikum Hannover-Siloah	Hannover
Germany	Medizinische Hochschule Hannover	Hannover
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 rechts der Isar München	München
Germany	Klinikum Schwabing	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	Schwabisch Gmund
Germany	Diakonie-Klinikum Stuttgart	Stuttgart
Germany	Klinikum Stuttgart - Katharinenhospital	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

Sponsors (1)

Lead Sponsor	Collaborator
University of Ulm

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS)		four years
Secondary	Rates of complete remission after induction therapy (CR)		not later than 56 days
Secondary	Cumulative incidences of relapse (CIR) and death in CR (CID)		four years
Secondary	Event-free survival (EFS)		four years
Secondary	Days in hospital during each cycle and during the whole intervention		6 months
Secondary	Type, frequency, severity, timing and relatedness of AEs and laboratory abnormalities observed during different treatment cycles		6 months
Secondary	Incidence of infection after induction and consolidation therapy		6 months
Secondary	Duration of neutropenia and thrombocytopenia after induction and consolidation therapy		6 months
Secondary	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 according to Messerer et al [49]		two years after completion of therapy