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

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)

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Gemtuzumab Ozogamicin (Mylotarg); Drug: standard chemotherapy

• Study Type: Interventional
• Enrollment (Actual): 600
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Medizinische Universitäts Graz
  • Innsbruck, Austria, A-6020
    • Universitätsklinikum Innsbruck
  • Linz, Austria, A-4020
    • Krankenhaus der Elisabethinen Linz
  • Linz, Austria, A-4010
    • Krankenhaus der Barmherzigen Schwestern Linz Betriebsgesellschaft m.b.H.
  • Linz, Austria, A-4010
    • Krankenhaus Der Barmherzigen Schwestern Linz
  • Salzburg, Austria, A-5020
    • Salzburger Landeskliniken
  • Wien, Austria, A-1140
    • Hanuschkrankenhaus Wien
• Germany
  • Aschaffenburg, Germany, 63739
    • Klinikum Aschaffenburg-Alzenau
  • Aurich, Germany, 26603
    • Ubbo-Emmius-Klinik Aurich
  • Bad Saarow, Germany, 15526
    • Helios Klinikum Bad Saarow
  • Berlin, Germany, 12351
    • Vivantes Klinikum Neukölln
  • Berlin, Germany, 10967
    • Vivantes Klinikum Am Urban
  • Berlin, Germany, 13353
    • Charité Berlin - Campus Virchow Klinikum
  • Bochum, Germany, 44892
    • Knappschaftskrankenhaus Bochum-Langendreer
  • Bonn, Germany, 53111
    • Universitatsklinikum Bonn
  • Braunschweig, Germany, 38114
    • Städtisches Klinikum Braunschweig gGmbH
  • Bremen, Germany, 28177
    • Klinikum Bremen-Mitte
  • Darmstadt, Germany, 64283
    • Klinikum Darmstadt
  • Düsseldorf, Germany, 40225
    • Universitätsklinikum Düsseldorf
  • Essen, Germany, 45239
    • Kliniken Essen Süd, Ev. Krankenhaus Essen-Werden gGmbH
  • Esslingen, Germany, 73730
    • Klinikum Esslingen
  • Flensburg, Germany, 24939
    • St. Franziskus Hospital
  • Frankfurt-Höchst, Germany, 65929
    • Klinikum Frankfurt Höchst GmbH
  • Freiburg, Germany, 79106
    • Universitatsklinikum Freiburg
  • Fulda, Germany, 36043
    • Medizinisches Versorgungszentrum Osthessen GmbH
  • Gießen, Germany, 35392
    • Universitätsklinikum Gießen
  • Goch, Germany, 47574
    • Wilhelm-Anton-Hospital gGmbH Goch
  • Göttingen, Germany, 37075
    • Universitätsklinikum Göttingen
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Hamburg, Germany, 22763
    • Asklepios Klinik Altona
  • Hamm, Germany, 59063
    • Evangelisches Krankenhaus Hamm gGmbH
  • Hanau, Germany, 63450
    • Klinikum Hanau
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Hannover, Germany, 30449
    • KRH Klinikum Hannover-Siloah
  • Heilbronn, Germany, 74078
    • SLK-Kliniken GmbH Heilbronn
  • Homburg, Germany, 66421
    • Universitätskliniken des Saarlandes
  • Karlsruhe, Germany, 76133
    • Städtisches Klinikum Karlsruhe gGmbH
  • Kiel, Germany, 24116
    • Universitätsklinikum Kiel
  • Lebach, Germany, 66822
    • Caritas-Krankenhaus Lebach
  • Lemgo, Germany, 32657
    • Klinikum Lippe-Lemgo
  • Lüdenscheid, Germany, 58515
    • Klinikum Lüdenscheid
  • Magdeburg, Germany, 39120
    • Universitätsklinikum der Otto-von Guericke Universität Magdeburg
  • Mainz, Germany, 55131
    • Klinikum der Johannes Gutenberg Universität Mainz
  • Minden, Germany, 32429
    • Johannes Wesling Klinikum Minden
  • München, Germany, 80804
    • Klinikum Schwabing
  • München, Germany, 81675
    • Klinikum rechts der Isar München
  • Neuss, Germany, 41464
    • Lukaskrankenhaus GmbH Neuss
  • Offenburg, Germany, 77654
    • Ortenau Klinikum Offenburg Gengenbach
  • Oldenburg, Germany, 26133
    • Klinikum Oldenburg gGmbH
  • Passau, Germany, 94032
    • Klinikum Passau
  • Saarbrücken, Germany, 66113
    • Caritas-Klinik St. Theresia Saarbrücken
  • Schwabisch Gmund, Germany, 73557
    • Stauferklinikum Schwäbisch Gmünd
  • Stuttgart, Germany, 70174
    • Klinikum Stuttgart - Katharinenhospital
  • Stuttgart, Germany, 70176
    • Diakonie-Klinikum Stuttgart
  • Traunstein, Germany, 83278
    • Klinikum Traunstein
  • Trier, Germany, 54292
    • Krankenhaus der Barmherzigen Brüder
  • Tübingen, Germany, 72076
    • Universitatsklinikum Tubingen
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
  • Villingen-Schwenningen, Germany, 78050
    • Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH
  • Wuppertal, Germany, 42283
    • Helios Klinikum Wuppertal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; chemotherapy in combination with ATRA with gemtuzumab ozogamicin	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; Drug: standard chemotherapy; Idarubicin, Etoposide, Cytarabine, ATRA, Pegfilgrastim
Active Comparator: 2; chemotherapy in combination with ATRA without gemtuzumab ozogamicin	Drug: standard chemotherapy; Idarubicin, Etoposide, Cytarabine, ATRA, Pegfilgrastim

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival (OS)	four years

Secondary Outcome Measures

Outcome Measure	Time Frame
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
Days in hospital during each cycle and during the whole intervention	6 months
Type, frequency, severity, timing and relatedness of AEs and laboratory abnormalities observed during different treatment cycles	6 months
Incidence of infection after induction and consolidation therapy	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

Collaborators and Investigators

• Sponsor: University of Ulm
• Investigators: Principal Investigator: Hartmut Doehner, MD, University of Ulm

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2010
• Primary Completion (Actual): September 1, 2021
• Study Completion (Actual): September 1, 2021

Study Registration Dates

• First Submitted: May 5, 2009
• First Submitted That Met QC Criteria: May 5, 2009
• First Posted (Estimate): May 6, 2009

Study Record Updates

• Last Update Posted (Estimate): February 27, 2023
• Last Update Submitted That Met QC Criteria: February 24, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: adult patients; NPM1 mutation
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Antineoplastic Agents, Immunological; Gemtuzumab
• Other Study ID Numbers: AMLSG 09-09