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

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)

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: Cytarabine; Drug: Etoposide; Drug: All-trans retinoic acid (ATRA)

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 61 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 (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.

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
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
overall survival	2 years and 8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Complete remission		8 months
cumulative incidence of relapse		2 years and 8 months
cumulative incidence of death in complete remission		2 years and 8 months
event-free survival		2 years and 8 months
Rate of early deaths (ED)/hypoplastic deaths (HD)		8 months
Type, frequency, severity, timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during different treatment cycles	adverse events graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.0	8 months
Incidence of infection after each treatment cycle		8 months
Duration of neutropenia after each treatment cycle		8 months
Duration of thrombocytopenia after each treatment cycle		8 months
Duration of hospitalization after each treatment cycle		8 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.33	2 years and 8 months

Collaborators and Investigators

• Sponsor: University of Ulm
• Collaborators: German Federal Ministry of Education and Research
• Investigators: Principal Investigator: Hartmut Döhner, MD, University Hospital of Ulm

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): July 13, 2018
• Study Completion (Actual): July 13, 2018

Study Registration Dates

• First Submitted: November 9, 2010
• First Submitted That Met QC Criteria: November 9, 2010
• First Posted (Estimate): November 10, 2010

Study Record Updates

• Last Update Posted (Actual): August 1, 2018
• Last Update Submitted That Met QC Criteria: July 31, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: AML; NPM1 Mutation; elderly patients (>60 years); unfit for intensive chemotherapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Keratolytic Agents; Etoposide; Cytarabine; Tretinoin
• Other Study ID Numbers: AMLSG 15-10