Clinical trial NCT00893399: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Keywords: adult patients
NPM1 mutation
Lead sponsor: University of Ulm
Sponsor class: OTHER
First posted: 2009-05-06
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)


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.

Primary outcomes:
measure: Overall survival (OS)
timeFrame: four years
Secondary outcomes:
measure: Rates of complete remission after induction therapy (CR)
timeFrame: not later than 56 days
measure: Cumulative incidences of relapse (CIR) and death in CR (CID)
timeFrame: four years
measure: Event-free survival (EFS)
timeFrame: four years
measure: Days in hospital during each cycle and during the whole intervention
timeFrame: 6 months
measure: Type, frequency, severity, timing and relatedness of AEs and laboratory abnormalities observed during different treatment cycles
timeFrame: 6 months
measure: Incidence of infection after induction and consolidation therapy
timeFrame: 6 months
measure: Duration of neutropenia and thrombocytopenia after induction and consolidation therapy
timeFrame: 6 months
measure: 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]
timeFrame: two years after completion of therapy
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medizinische Universitäts Graz
city: Innsbruck
country: Austria
facility: Universitätsklinikum Innsbruck
city: Linz
country: Austria
facility: Krankenhaus der Barmherzigen Schwestern Linz Betriebsgesellschaft m.b.H.
city: Linz
country: Austria
facility: Krankenhaus der Barmherzigen Schwestern Linz
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen Linz
city: Salzburg
country: Austria
facility: Salzburger Landeskliniken
city: Wien
country: Austria
facility: Hanuschkrankenhaus Wien
city: Aschaffenburg
country: Germany
facility: Klinikum Aschaffenburg-Alzenau
city: Aurich
country: Germany
facility: Ubbo-Emmius-Klinik Aurich
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Berlin
country: Germany
facility: Vivantes Klinikum am Urban
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Berlin
country: Germany
facility: Charité Berlin - Campus Virchow Klinikum
city: Bochum
country: Germany
facility: Knappschaftskrankenhaus Bochum-Langendreer
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig gGmbH
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Essen
country: Germany
facility: Kliniken Essen Süd, Ev. Krankenhaus Essen-Werden gGmbH
city: Esslingen
country: Germany
facility: Klinikum Esslingen
city: Flensburg
country: Germany
facility: St. Franziskus Hospital
city: Frankfurt-Höchst
country: Germany
facility: Klinikum Frankfurt Höchst GmbH
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Fulda
country: Germany
facility: Medizinisches Versorgungszentrum Osthessen GmbH
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen
city: Goch
country: Germany
facility: Wilhelm-Anton-Hospital gGmbH Goch
city: Göttingen
country: Germany
facility: Universitätsklinikum Göttingen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona
city: Hamm
country: Germany
facility: Evangelisches Krankenhaus Hamm gGmbH
city: Hanau
country: Germany
facility: Klinikum Hanau
city: Hannover
country: Germany
facility: KRH Klinikum Hannover-Siloah
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heilbronn
country: Germany
facility: SLK-Kliniken GmbH Heilbronn
city: Homburg
country: Germany
facility: Universitätskliniken des Saarlandes
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe gGmbH
city: Kiel
country: Germany
facility: Universitätsklinikum Kiel
city: Lebach
country: Germany
facility: Caritas-Krankenhaus Lebach
city: Lemgo
country: Germany
facility: Klinikum Lippe-Lemgo
city: Lüdenscheid
country: Germany
facility: Klinikum Lüdenscheid
city: Magdeburg
country: Germany
facility: Universitätsklinikum der Otto-von Guericke Universität Magdeburg
city: Mainz
country: Germany
facility: Klinikum der Johannes Gutenberg Universität Mainz
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: München
country: Germany
facility: Klinikum Schwabing
city: München
country: Germany
facility: Klinikum rechts der Isar München
city: Neuss
country: Germany
facility: Lukaskrankenhaus GmbH Neuss
city: Offenburg
country: Germany
facility: Ortenau Klinikum Offenburg Gengenbach
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg gGmbH
city: Passau
country: Germany
facility: Klinikum Passau
city: Saarbrücken
country: Germany
facility: Caritas-Klinik St. Theresia Saarbrücken
city: Schwabisch Gmund
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart - Katharinenhospital
city: Stuttgart
country: Germany
facility: Diakonie-Klinikum Stuttgart
city: Traunstein
country: Germany
facility: Klinikum Traunstein
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal
Study officials:
affiliation: University of Ulm
name: Hartmut Doehner, MD
role: PRINCIPAL_INVESTIGATOR
References: