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

Phase 3

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Gemtuzumab Ozogamicin (Mylotarg); Drug: standard chemotherapy

• Registration Number: NCT00893399
• Lead Sponsor: University of Ulm

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)

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2009-05-05
• Study First Submitted QC: 2009-05-05
• Study First Posted: 2009-05-06
• Study Start: 2010-05-12
• Primary Completion: 2021-09-01
• Study Completion: 2021-09-01
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-24
• Last Update Posted: 2023-02-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 600

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	Gemtuzumab Ozogamicin (Mylotarg)	chemotherapy in combination with ATRA with gemtuzumab ozogamicin
1	standard chemotherapy	chemotherapy in combination with ATRA with gemtuzumab ozogamicin
2	standard chemotherapy	chemotherapy in combination with ATRA without gemtuzumab ozogamicin

Primary Outcome Measures

Name	Time	Method
Overall survival (OS)	four years

Secondary Outcome Measures

Name	Time	Method
Days in hospital during each cycle and during the whole intervention	6 months
Incidence of infection after induction and consolidation therapy	6 months
Rates of complete remission after induction therapy (CR)	not later than 56 days
Cumulative incidences of relapse (CIR) and death in CR (CID)	four years
Event-free survival (EFS)	four years
Type, frequency, severity, timing and relatedness of AEs and laboratory abnormalities observed during different treatment cycles	6 months
Duration of neutropenia and thrombocytopenia after induction and consolidation therapy	6 months
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

Trial Locations

Locations (60)

Universitätsklinikum Innsbruck; 🇦🇹 Innsbruck, Austria

Universitätsklinikum Düsseldorf; 🇩🇪 Düsseldorf, Germany

Ubbo-Emmius-Klinik Aurich; 🇩🇪 Aurich, Germany

Krankenhaus der Barmherzigen Schwestern Linz Betriebsgesellschaft m.b.H.; 🇦🇹 Linz, Austria

Vivantes Klinikum am Urban; 🇩🇪 Berlin, Germany

Medizinische Universitäts Graz; 🇦🇹 Graz, Austria

Asklepios Klinik Altona; 🇩🇪 Hamburg, Germany

Salzburger Landeskliniken; 🇦🇹 Salzburg, Austria

Hanuschkrankenhaus Wien; 🇦🇹 Wien, Austria

Krankenhaus der Barmherzigen Schwestern Linz; 🇦🇹 Linz, Austria

Caritas-Krankenhaus Lebach; 🇩🇪 Lebach, Germany

Klinikum Lippe-Lemgo; 🇩🇪 Lemgo, Germany

Krankenhaus der Elisabethinen Linz; 🇦🇹 Linz, Austria

Klinikum Aschaffenburg-Alzenau; 🇩🇪 Aschaffenburg, Germany

Helios Klinikum Bad Saarow; 🇩🇪 Bad Saarow, Germany

Charité Berlin - Campus Virchow Klinikum; 🇩🇪 Berlin, Germany

Vivantes Klinikum Neukölln; 🇩🇪 Berlin, Germany

Knappschaftskrankenhaus Bochum-Langendreer; 🇩🇪 Bochum, Germany

Klinikum Bremen-Mitte; 🇩🇪 Bremen, Germany

Klinikum Darmstadt; 🇩🇪 Darmstadt, Germany

Städtisches Klinikum Braunschweig gGmbH; 🇩🇪 Braunschweig, Germany

Universitätsklinikum Bonn; 🇩🇪 Bonn, Germany

Klinikum Esslingen; 🇩🇪 Esslingen, Germany

Kliniken Essen Süd, Ev. Krankenhaus Essen-Werden gGmbH; 🇩🇪 Essen, Germany

Universitätsklinikum Göttingen; 🇩🇪 Göttingen, Germany

St. Franziskus Hospital; 🇩🇪 Flensburg, Germany

Medizinisches Versorgungszentrum Osthessen GmbH; 🇩🇪 Fulda, Germany

Klinikum Frankfurt Höchst GmbH; 🇩🇪 Frankfurt-Höchst, Germany

Universitätsklinikum Gießen; 🇩🇪 Gießen, Germany

Universitätsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Evangelisches Krankenhaus Hamm gGmbH; 🇩🇪 Hamm, Germany

Klinikum Hanau; 🇩🇪 Hanau, Germany

KRH Klinikum Hannover-Siloah; 🇩🇪 Hannover, Germany

Universitätskliniken des Saarlandes; 🇩🇪 Homburg, Germany

Universitätsklinikum der Otto-von Guericke Universität Magdeburg; 🇩🇪 Magdeburg, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Germany

SLK-Kliniken GmbH Heilbronn; 🇩🇪 Heilbronn, Germany

Städtisches Klinikum Karlsruhe gGmbH; 🇩🇪 Karlsruhe, Germany

Klinikum Lüdenscheid; 🇩🇪 Lüdenscheid, Germany

Universitätsklinikum Kiel; 🇩🇪 Kiel, Germany

Lukaskrankenhaus GmbH Neuss; 🇩🇪 Neuss, Germany

Johannes Wesling Klinikum Minden; 🇩🇪 Minden, Germany

Klinikum der Johannes Gutenberg Universität Mainz; 🇩🇪 Mainz, Germany

Ortenau Klinikum Offenburg Gengenbach; 🇩🇪 Offenburg, Germany

Stauferklinikum Schwäbisch Gmünd; 🇩🇪 Schwabisch Gmund, Germany

Klinikum Stuttgart - Katharinenhospital; 🇩🇪 Stuttgart, Germany

Klinikum Traunstein; 🇩🇪 Traunstein, Germany

Diakonie-Klinikum Stuttgart; 🇩🇪 Stuttgart, Germany

Krankenhaus der Barmherzigen Brüder; 🇩🇪 Trier, Germany

Universitätsklinikum Tübingen; 🇩🇪 Tübingen, Germany

Helios Klinikum Wuppertal; 🇩🇪 Wuppertal, Germany

Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH; 🇩🇪 Villingen-Schwenningen, Germany

Universitätsklinikum Freiburg; 🇩🇪 Freiburg, Germany

Wilhelm-Anton-Hospital gGmbH Goch; 🇩🇪 Goch, Germany

Klinikum Oldenburg gGmbH; 🇩🇪 Oldenburg, Germany

Caritas-Klinik St. Theresia Saarbrücken; 🇩🇪 Saarbrücken, Germany

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

Klinikum Schwabing; 🇩🇪 München, Germany

Klinikum rechts der Isar München; 🇩🇪 München, Germany

Klinikum Passau; 🇩🇪 Passau, Germany