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Study of Low-Dose Cytarabine and Etoposide With or Without All-Trans Retinoic Acid in Older Patients Not Eligible for Intensive Chemotherapy With Acute Myeloid Leukemia and NPM1 Mutation

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ClinicalTrials.gov Identifier: NCT01237808
Recruitment Status : Completed
First Posted : November 10, 2010
Last Update Posted : August 1, 2018
Sponsor:
Collaborator:
German Federal Ministry of Education and Research
Information provided by (Responsible Party):
Prof. Dr. Hartmut Doehner, University of Ulm

Brief Summary:

This is a randomized, Phase-III, two-arm, open-label, multi-center study in adult patients with AML and NPM1 mutation ineligible for intensive chemotherapy.

Sample size: 144 patients

Investigator's sites: 50-55 sites in Germany and Austria (2-10 patients per trial site are expected to be included into the trial)

Estimated treatment duration of an individual patient: 8 months (Follow-Up period per patient will last additional 2 years)


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Drug: Cytarabine Drug: Etoposide Drug: All-trans retinoic acid (ATRA) Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 144 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of Low-Dose Cytarabine and Etoposide With or Without All-Trans Retinoic Acid in Older Patients Not Eligible for Intensive Chemotherapy With Acute Myeloid Leukemia and NPM1 Mutation
Study Start Date : March 2011
Actual Primary Completion Date : July 13, 2018
Actual Study Completion Date : July 13, 2018


Arm Intervention/treatment
Active Comparator: Standard arm
6 cycles of chemotherapy (low-dose cytarabine and etoposide) without ATRA
Drug: Cytarabine
in all treatment cycles: Cytarabine 20 mg/day, s.c., bid, days 1-7; (total dose 280 mg).

Drug: Etoposide
first treatment cycle Etoposide 50 mg/m²/day, continuously i.v., days 1-3; (total dose 150 mg/m2) treatment cycles 2 to 6 Etoposide 100 mg/day, p.o. or i.v. (over 1 hour), days 1-3; (total dose 300 mg).

Experimental: Investigational arm
6 cycles of chemotherapy (low-dose cytarabine and etoposide) with ATRA (All-trans-Retinoic acid)
Drug: Cytarabine
in all treatment cycles: Cytarabine 20 mg/day, s.c., bid, days 1-7; (total dose 280 mg).

Drug: Etoposide
first treatment cycle Etoposide 50 mg/m²/day, continuously i.v., days 1-3; (total dose 150 mg/m2) treatment cycles 2 to 6 Etoposide 100 mg/day, p.o. or i.v. (over 1 hour), days 1-3; (total dose 300 mg).

Drug: All-trans retinoic acid (ATRA)
in all treatment cycles: ATRA 45 mg/m²/day p.o., days 8-10, ATRA 15 mg/m²/day p.o., days 11-28, with or shortly after meals distributed on 3 doses per day.




Primary Outcome Measures :
  1. overall survival [ Time Frame: 2 years and 8 months ]

Secondary Outcome Measures :
  1. Rate of Complete remission [ Time Frame: 8 months ]
  2. cumulative incidence of relapse [ Time Frame: 2 years and 8 months ]
  3. cumulative incidence of death in complete remission [ Time Frame: 2 years and 8 months ]
  4. event-free survival [ Time Frame: 2 years and 8 months ]
  5. Rate of early deaths (ED)/hypoplastic deaths (HD) [ Time Frame: 8 months ]
  6. Type, frequency, severity, timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during different treatment cycles [ Time Frame: 8 months ]
    adverse events graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.0

  7. Incidence of infection after each treatment cycle [ Time Frame: 8 months ]
  8. Duration of neutropenia after each treatment cycle [ Time Frame: 8 months ]
  9. Duration of thrombocytopenia after each treatment cycle [ Time Frame: 8 months ]
  10. Duration of hospitalization after each treatment cycle [ Time Frame: 8 months ]
  11. Quality of life [ Time Frame: 2 years and 8 months ]
    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.33



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Ages Eligible for Study:   61 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with confirmed diagnosis of acute myeloid leukemia according to the World Health Organization (WHO) classification (including de novo AML, t-AML and s-AML)
  • Presence of NPM1 mutation as assessed in one of the central AMLSG reference laboratories.
  • Age > 60 years. There is no upper age limit.
  • No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if needed for up to 10 days during the diagnostic screening phase.
  • Signed written informed consent
  • Men must give their informed consent that they do not father a baby and must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy. (while on therapy and for 3 month after the last dose of chemotherapy)
  • WHO performance status ≤ 3
  • Patients not eligible for intensive chemotherapy according to at least one of the following criteria

    • HCT-CI Score >2
    • Patient's decision
    • age ≥ 75 years

Exclusion Criteria:

The presence of any of the following will exclude a patient from study enrollment:

  • All other AML subtypes, in particular those 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
  • No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician and all other treating physicians about study participation
  • Bleeding disorder independent of leukemia
  • Uncontrolled infection
  • Known positive for HIV, HBV or HCV
  • 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)
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01237808


Locations
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Germany
Ubbo-Emmius Klinik Aurich
Aurich, Germany, 26603
Charité Universitätsmedizin Berlin
Berlin, Germany, 13353
University Hospital of Bonn
Bonn, Germany, 53111
Städtisches Klinikum Braunschweig
Braunschweig, Germany, 38114
Klinikum Bremen-Mitte gGmbH
Bremen, Germany, 28177
Kliniken Essen Süd, Evangelischs Krankenhaus
Essen, Germany, 45239
Klinikum Esslingen
Esslingen, Germany, 73730
Medizinische Universitätsklinik
Freiburg, Germany, 79106
Medizinisches Versorgungszentrum Osthessen GmbH
Fulda, Germany, 36043
Universitätsklinikum Gießen
Gießen, Germany, 35392
Wilhelm- Anton- Hospital gGmbH
Goch, Germany, 47574
Universitätsmedizin Göttingen
Göttingen, Germany, 37075
University Hospital of Hamburg Eppendorf
Hamburg, Germany, 20246
Asklepios Klinik Altona
Hamburg, Germany, 22763
Medical Department III, Hospital of Hannover-Siloah
Hannover, Germany, 30449
Medizinische Hochschule Hannover
Hannover, Germany, 30625
SLK-Kliniken Heilbronn GmbH
Heilbronn, Germany, 74078
Department of Internal Medicine I, University Hospital of Saarland
Homburg, Germany, 66421
Staedtisches Klinikum Karlsruhe
Karlsruhe, Germany, 76133
Department of Interial Medicine /Hematology and Oncology, Caritas Hospital Lebach
Lebach, Germany, 66822
Klinikum der Johannes Gutenberg Universität Mainz
Mainz, Germany, 55131
Klinikum rechts der Isar der TU Muenchen
Muenchen, Germany, 81675
Stauferklinikum Schwäbisch Gmünd
Mutlangen, Germany, 73557
Pius Hospital Oldenburg
Oldenburg, Germany, 26133
Krankenhaus der Barmherzigen Brueder
Regensburg, Germany, 93049
Caritas-Klinik St. Theresia
Saarbrücken, Germany, 66113
Clinikal Cetner of Stuttgart, Center of Oncology
Stuttgart, Germany, 70174
Diakonie-Klinikum Stuttgart
Stuttgart, Germany, 70176
Krankenhaus der Barmherzigen Brüder Trier
Trier, Germany, 54292
Universitätsklinikum Tübingen
Tübingen, Germany, 72076
University hospital of Ulm
Ulm, Germany, 89081
Medical Center II - Hematology/Oncology, Clinical Center Villingen-Schwenningen
Villingen - Schwenningen, Germany, 78050
Helios Klinikum Wuppertal
Wuppertal, Germany, 42283
Sponsors and Collaborators
University of Ulm
German Federal Ministry of Education and Research
Investigators
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Principal Investigator: Hartmut Döhner, MD University Hospital of Ulm

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Responsible Party: Prof. Dr. Hartmut Doehner, Prof. Dr., University of Ulm
ClinicalTrials.gov Identifier: NCT01237808     History of Changes
Other Study ID Numbers: AMLSG 15-10
First Posted: November 10, 2010    Key Record Dates
Last Update Posted: August 1, 2018
Last Verified: July 2018

Keywords provided by Prof. Dr. Hartmut Doehner, University of Ulm:
AML
NPM1 Mutation
elderly patients (>60 years)
unfit for intensive chemotherapy

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Etoposide
Etoposide phosphate
Tretinoin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Keratolytic Agents
Dermatologic Agents