Phase III Trial in Acute Promyelocytic Leukemia Patients (APL0406)

A Randomised Phase III Study to Compare Arsenic Trioxide (ATO) Combined to ATRA Versus Standard ATRA and Anthracycline-Based Chemotherapy (AIDA Regimen) for Newly Diagnosed, Non High-Risk Acute Promyelocytic Leukemia

Open label, randomised, phase III multicenter trial.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: arsenic trioxide; Drug: all-trans retinoic acid (ATRA); Drug: idarubicin; Drug: mercaptopurine; Drug: methotrexate; Drug: all-trans retinoic acid

Detailed Description

• Arm I:

  • Induction therapy: Patients receive oral tretinoin twice daily and arsenic trioxide IV over 2 hours on days 1-60. Patients achieving hematological complete remission go on to receive consolidation therapy.
  • Consolidation therapy: Patients receive oral tretinoin twice daily on days 1-14. Treatment with tretinoin repeats every 4 weeks for up to 7 courses. Patients also receive arsenic trioxide IV over 2 hours on days 1-5 in weeks 1-4. Treatment with arsenic trioxide repeats every 8 weeks for up to 4 courses.

• Arm II:

  • Induction therapy: Patients receive tretinoin as in arm I induction therapy and idarubicin IV over 20 minutes on days 2, 4, 6, and 8. Patients achieving hematological complete remission go on to receive consolidation therapy.
  • Consolidation therapy: Patients receive oral tretinoin twice daily on days 1-45, idarubicin IV over 20 minutes on days 1-4 and day 31, and mitoxantrone hydrochloride IV over 30 minutes on days 16-20.

Marrow samples are collected after completion of consolidation therapy and analyzed by reverse transcriptase-PCR for molecular remission. Patients achieving molecular remission (PML-RARa negative) go on to receive maintenance therapy.

• Maintenance therapy: Patients receive oral mercaptopurine once daily and methotrexate intramuscularly once weekly for 3 months. Treatment with mercaptopurine and methotrexate repeats every 3 months for 7 courses. After completion of course 1 of mercaptopurine and methotrexate, patients receive oral tretinoin once daily on days 1-15*. Treatment with tretinoin repeats every 3 months for 6 courses.

NOTE: *Patients do not receive mercaptopurine and methotrexate during tretinoin administration.

After completion of study therapy, patients are followed periodically for 5 years.

As of 14th September 2010, all patients needed to evaluate the primary endpoint (162 patients) have been recruited but the trial accrual continued in order to assess one secondary outcome (QoL)."

• Study Type: Interventional
• Enrollment (Actual): 276
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
    • Universitätsklinik Innsbruck Hämatologie Onkologie
  • Linz, Austria
    • Krankenhaus Der Barmherzigen Schwestern Linz
  • Salzburg, Austria
    • Universitätsklinik für Innere Medizin III Salzburg
• Germany
  • Bayreuth, Germany
    • Klinikum Bayreuth GmbH
  • Berlin, Germany
    • Charité Campus Benjamin Franklin Berlin
  • Bielefeld, Germany
    • Städt. Kliniken Bielefeld gem. GmbH
  • Bonn, Germany
    • Universitatsklinikum Bonn
  • Bremen, Germany
    • Ev. Diakonie-Krankenhaus gGmbH Bremen
  • Bremen, Germany
    • Klinikum Bremen-Mitte gGmbH
  • Chemnitz, Germany
    • Klinikum Chemnitz gGmbH
  • Dresden, Germany
    • Universitätsklinikum C. G. Carus Dresden
  • Duisburg, Germany
    • Katholisches Klinikum Duisburg St. Johannes Hospital
  • Düsseldorf, Germany
    • Universitätsklinikum Düsseldorf
  • Erlangen, Germany
    • Uniklinikum Erlangen
  • Essen, Germany
    • Universitätsklinikum Essen
  • Essen, Germany
    • Kliniken Essen Süd, Ev. Krankenhaus Essen-Werden gGmbH
  • Frankfurt/Main, Germany
    • Uniklinik Frankfurt/Main
  • Frankfurt/a. M. -Höchst, Germany
    • Städtische Kliniken Frankfurt a. M.-Höchst
  • Freiburg, Germany
    • Universitatsklinikum Freiburg
  • Fulda, Germany
    • Klinikum Fulda
  • Gießen, Germany
    • Universitätsklinikum Gießen und Marburg Gießen
  • Göttingen, Germany
    • Universitätsklinikum Göttingen
  • Hamburg, Germany
    • Universitatsklinikum Hamburg Eppendorf
  • Hamburg, Germany
    • Asklepios Klinik Hamburg Altona
  • Hamburg, Germany
    • Asklepios Klinik St. Georg Hamburg
  • Hamm, Germany
    • St. Marien-Hospital gem. GmbH Hamm
  • Hannover, Germany
    • Medizinische Hochschule Hannover
  • Heidelberg, Germany
    • Universitatsklinikum Heidelberg
  • Hildesheim, Germany
    • St. Bernward Krankenhaus Hildesheim
  • Homburg, Germany
    • Universitätsklinikum des Saarlandes Homburg/Saar
  • Idar-Oberstein, Germany
    • Klinik für Knochenmarktransplantation und Hämatologie Idar-Oberstein
  • Kaiserslautern, Germany
    • Westpfalz-Klinikum GmbH Kaiserslautern
  • Lebach, Germany
    • Caritas-Krankenhaus Lebach
  • Lippe, Germany
    • Klinikum Lippe Lemgo
  • Lübeck, Germany
    • Uniklinikum Lübeck
  • Mainz, Germany
    • Klinikum der Johannes Gutenberg Universität Mainz
  • Marburg, Germany
    • Universitätsklinikum Gießen und Marburg GmbH Marburg
  • Merseburg, Germany
    • Carl-von-Basedow-Klinikum Merseburg
  • Minden, Germany
    • Johannes Wesling Klinikum Minden
  • München, Germany
    • Klinikum rechts der Isar (München)
  • Nürnberg, Germany
    • Klinikum Nord Nürnberg
  • Passau, Germany
    • Klinikum Passau
  • Regensburg, Germany
    • Universitätsklinikum Regensburg
  • Saarbrücken, Germany
    • Caritas-Klinik St. Theresia Saarbrücken
  • Schwäbisch-Hall, Germany
    • Diakonie-Krankenhaus Schwäbisch Hall
  • Stuttgart, Germany
    • Diakonie-Klinikum Stuttgart
  • Stuttgart, Germany
    • Klinikum Stuttgart Bürgerhospital
  • Stuttgart, Germany
    • Robert Bosch Krankenhaus Stuttgart
  • Trier, Germany
    • Krankenanstalt Mutterhaus der Borromäerinnen Trier
  • Trier, Germany
    • Krankenhaus der Barmherzigen Brüder Trier
  • Tübingen, Germany
    • Universitatsklinikum Tubingen
  • Ulm, Germany
    • Universitätsklinikum Ulm
  • Villingen-Schwenningen, Germany
    • Klinikum Villingen-Schwenningen
  • Wuppertal, Germany
    • Helios Klinikum Wuppertal
• Italy
  • Alessandria, Italy
    • Ospedale Civile SS. Antonio E Biagio DI Alessandria
  • Ascoli Piceno, Italy
    • Ospedale Gen.le. Prov.le "C.G. Mazzoni"
  • Avellino, Italy
    • Az.Ospedaliera S.G.Moscati
  • Bari, Italy
    • Ematologia con trapianto- AOU Policlinico Consorziale di Bari
  • Bergamo, Italy
    • Divisione di Ematologia - Ospedali Riuniti
  • Bologna, Italy
    • Istituto di Ematologia e Oncologia Medica "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
  • Bolzano, Italy
    • Azienda Sanitaria di Bolzano - Ospedale Centrale - Ematologia e Centro TMO
  • Brescia, Italy
    • Spedali Civili di Brescia
  • Cagliari, Italy
    • ASL N.8 - Ospedale "A. Businco" - Unità Operativa di Ematologia e Trapianto di Midollo
  • Catania, Italy
    • Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
  • Catanzaro, Italy
    • Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
  • Ferrara, Italy
    • Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna
  • Genova, Italy
    • Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"
  • Latina, Italy
    • Divisione di Ematologia Ospedale "Santa Maria Goretti"
  • Lecce, Italy
    • ST. V. Fazzi
  • Messina, Italy
    • Azienda Ospedaliera Papardo
  • Messina, Italy
    • A.O. Universitaria Policlinico Martina di Messina
  • Milano, Italy
    • UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
  • Milano, Italy
    • Irccs Fondazione Centro S. Raffaele Del Monte Tabor
  • Milano, Italy
    • Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
  • Modena, Italy
    • Centro Oncologico Modenese - Dipartimento di Oncoematologia
  • Monza, Italy
    • Azienda Ospedaliera S. Gerardo di Monza
  • Napoli, Italy
    • Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
  • Napoli, Italy
    • Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"
  • Napoli, Italy
    • A.S.L. Napoli 1 Ospedale San Giovanni Bosco
  • Napoli, Italy
    • Servizio Sanitario Nazionale - Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" - Struttura Complessa di Ematologia - Div. TERE- 4° piano - Padiglione Palermo
  • Nocera Inferiore, Italy
    • ASL SA/1 di Nocera Inferiore
  • Orbassano, Italy
    • A.O. Universitaria S. Luigi Gonzaga Di Orbassano
  • Palermo, Italy
    • Ospedali Riuniti "Villa Sofia-Cervello"
  • Palermo, Italy
    • Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"
  • Parma, Italy
    • Cattedra di Ematologia CTMO Università degli Studi di Parma
  • Pavia, Italy
    • IRCCS Policlinico S. Matteo di Pavia
  • Perugia, Italy
    • Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia
  • Pesaro, Italy
    • Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
  • Pescara, Italy
    • U.O. Ematologia Clinica - Azienda USL di Pescara
  • Potenza, Italy
    • Ematologia - Ospedale San Carlo
  • Ravenna, Italy
    • Ospedale S. Maria delle Croci di Ravenna
  • Reggio Calabria, Italy
    • Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
  • Rionero in Vulture, Italy
    • IRCCS Centro di Riferimento Oncologico di Basilicata
  • Roma, Italy
    • Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
  • Roma, Italy
    • Ospedale S. Eugenio
  • Roma, Italy
    • Università degli Studi - Policlinico di Tor Vergata
  • Roma, Italy
    • Azienda Osp. S. Giovanni/Addolorata
  • Roma, Italy
    • Divisione di Ematologia - Ospedale S. Camillo
  • Roma, Italy
    • Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
  • Roma, Italy
    • Policlinico Campus Biomedico
  • Roma, Italy
    • Policlinico Universitario Gemelli di Roma
  • Rome, Italy
    • IRCCS Istituto Regina Elena
  • San Giovanni Rotondo, Italy
    • Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
  • Sassari, Italy
    • Serv. di Ematologia Ist. di Ematologia ed Endocrinologia
  • Siena, Italy
    • U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
  • Torino, Italy
    • SCDO Ematologia 2 AOU S.Giovanni Battista
  • Udine, Italy
    • Clinica Ematologica - Policlinico Universitario
  • Varese, Italy
    • Ospedale di Circolo e Fondazione Macchi
  • Verona, Italy
    • Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
  • Vicenza, Italy
    • ULSS N.6 Osp. S. Bortolo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

• Signed written informed consent according to IGH/EU/GCP and national local laws
• Newly diagnosed APL by cytomorphology, confirmed also by molecular analysis*.
• Age ≤18 < 71 years
• WHO performance status 0 -2 included
• WBC at diagnosis ≤ 10 x 109/L
• Serum total bilirubin ≤ 3.0 mg/dL (≤ 51µmol/L)
• Serum creatinine ≤ 3.0 mg/dL (≤ 260 µmol/L)

The confirmation of diagnosis at genetic level (microspeckled PML nuclear distribution by PGM3 monoclonal antibody and/or PML/RARa fusion by RT-PCR and/or demonstration of t(15;17) by karyotyping) will be mandatory for patient eligibility. However, in order to avoid delay in treatment initiation, patients can be randomised on the basis of morphologic diagnosis only and before the results of genetic tests are available.

Exclusion criteria

• Age < 18 and ≥ 71
• WBC at diagnosis > 10 x 109/L
• Other active malignancy at time of study entry
• Lack of diagnostic confirmation at genetic level
• Significant arrhythmias, EKG abnormalities (*see below) or neuropathy
• Other cardiac contraindications for intensive chemotherapy (L-VEF <50%)
• Uncontrolled, life-threatening infections
• Severe non-controlled pulmonary or cardiac disease

• Women who are either pregnant or breast feeding, or of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they meet one of the following definitions:

  • Amenorrhea;
  • post surgical bilateral oophorectomy with or without hysterectomy;
  • using a highly effective method of birth control (defined as those which result in a failure rate less than 1% per year) when used consistently and correctly such as implants, injectables, oral contraceptives, IUDs, sexual abstinence or vasectomized partner.
• Concomitant severe psychiatric disorder

• HIV positivity

  *EKG abnormalities:

  • Congenital long QT syndrome;
  • History or presence of significant ventricular or atrial tachyarrhythmia
  • Clinically significant resting bradycardia (<50 beats per minute)
  • QTc > 450 msec on screening EKG (using the QTcF formula detailed on page 18)
  • Right bundle branch block plus left anterior hemiblock, bifascicular block
• Use of other investigational drugs at the time of enrolment or within 30 days before study entry

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: ARM A - ATO/ATRA	Drug: arsenic trioxide; Induction Arsenic Trioxide (As2O3=ATO), 0.15 mg/Kg IV over 2 hours daily starting on day 1. ATO will be continued until hematological CR or for a maximum of 60 days. Consolidation ATO, 0.15 mg/Kg IV over 2 hours daily for 5 days every week. Treatment will be continued for 4 weeks on and 4 weeks off, for a total of 4 cycles (last cycle administered on weeks 25 - 28).; Drug: all-trans retinoic acid (ATRA); Induction All-trans retinoic acid (ATRA), 45 mg/m²/day will be administered orally in two equally divided doses and rounded to the nearest 10 mg increment, starting on day 1. ATRA treatment will be continued until hematological complete remission (CR, see below for definition) or for a maximum of 60 days. Consolidation ATRA, 45 mg/m²/day will be administered orally in two equally divided doses and rounded to the nearest 10 mg increment. Treatment will be administered for 2 weeks on 2 weeks off and for a total of 7 cycles (last cycle administered on weeks 25 - 26).
Active Comparator: ARM B - ATRA	Drug: idarubicin; Induction Idarubicin, 12 mg/m² on days 2, 4, 6 and 8 by short (20') intravenous infusion . If no hematological CR is achieved by 60 days after start of induction, patient will go off-study. Consolidation 1st cycle Idarubicin, 5 mg/m2/day by short (20') intravenous infusion on days 1, 2, 3, 4. 3rd cycle Idarubicin, 12 mg/m2/day as short (20') intravenous infusion only on day 1.; Drug: mercaptopurine; Maintenance therapy 6-Mercaptopurine (6-MP), 50 mg/m2/day orally. The dose will be adjusted according to hematopoietic toxicity during the follow-up period; Drug: methotrexate; Maintenance therapy Methotrexate (MTX), 15 mg/m2/weekly intramuscularly. The dose will be adjusted according to toxicity during the follow-up period.; Drug: all-trans retinoic acid; Induction ATRA, 45 mg/m²/day will be administered orally in two equally divided doses and rounded to the nearest 10 mg increment, starting on day 1. ATRA treatment will be continued until hematological CR and for a maximum of 60 days. Consolidation; st cycle ATRA, 45 mg/m2/day, will be administered orally in two equally divided doses and rounded to the nearest 10 mg increment, starting from day 1 to day 15.; nd cycle ATRA, 45 mg/m2/day will be administered orally in two equally divided doses and rounded to the nearest 10 mg increment, starting from day 1 to day 15.; rd cycle ATRA, 45 mg/m2/day will be administered orally in two equally divided doses and rounded to the nearest 10 mg increment, starting from day 1 to day 15. Maintenance therapy ATRA, 45 mg/m2/day orally, for 15 days every three months until a two year period is completed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	As of 14th september 2010, all patients needed to evaluate the primary endpoint have been recruited.	At maximum 3.5 years from study entry

Secondary Outcome Measures

Outcome Measure	Time Frame
Rate of hematological complete remission	At maximum 60 days from induction therapy start
Overall survival rate	At 2 years from study entry
Rate of cumulative incidence of relapse	At 2 years from study entry
Incidence of hematological and non-hematological toxicity episodes during treatment as assessed by CTC-NCI	At maximum 60 days from induction therapy start and at maximum 225 days from consolidation therapy start
Rate of molecular remission after 3rd consolidation course	At maximum 225 days grom consolidation therapy start
Assessment of acute promyelocytic leukemia/RARa transcript level reduction after induction and during consolidation therapy	At maximum 60 days from induction therapy start and at maximum 225 days from consolidation therapy start
Quality of life at the end of induction therapy and at the end of the 3rd consolidation course	At maximum 60 days from induction therapy start and at maximum 225 days from consolidation therapy start
Event free survival	At 2 years from study entry
Total hospitalization days during study therapy	At maximum 3.5 years from study entry
Event-free survival rate in the two arms	At 2 years from study entry

Collaborators and Investigators

• Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Collaborators: Study Alliance Leukemia (SAL) Group
• Investigators: Study Chair: Francesco Lo Coco, MD, Azienda Ospedaliera Universitaria Policlinico Tor Vergata

Publications and helpful links

General Publications

• Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. doi: 10.1200/JCO.2014.55.3453. Epub 2014 Sep 22.
• Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lubbert M, Hanel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Dohner K, Sauer M, Ganser A, Amadori S, Mandelli F, Dohner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. doi: 10.1056/NEJMoa1300874.

Helpful Links

• GIMEMA Foundation website

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): October 17, 2019

Study Registration Dates

• First Submitted: June 4, 2007
• First Submitted That Met QC Criteria: June 4, 2007
• First Posted (Estimate): June 5, 2007

Study Record Updates

• Last Update Posted (Actual): October 12, 2022
• Last Update Submitted That Met QC Criteria: October 10, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: adult acute myeloid leukemia with t(15;17)(q22;q12); untreated adult acute myeloid leukemia; adult acute promyelocytic leukemia (M3)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Leukemia, Promyelocytic, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Keratolytic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Arsenic Trioxide; Methotrexate; Idarubicin; Mercaptopurine; Tretinoin
• Other Study ID Numbers: APL0406; GIMEMA-SAL-APL0406; EUDRACT-2006-006188-22