Clinical trial NCT00482833: Phase III Trial in Acute Promyelocytic Leukemia Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
Keywords: adult acute promyelocytic leukemia (M3)
adult acute myeloid leukemia with t(15;17)(q22;q12)
untreated adult acute myeloid leukemia
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
Collaborators: name: Study Alliance Leukemia (SAL) Group
First posted: 2007-06-05
Enrollment: 276
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Open label, randomised, phase III multicenter trial.

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)."

Eligibility criteria: 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

Primary outcomes:
measure: Event-free survival
timeFrame: At maximum 3.5 years from study entry
Secondary outcomes:
measure: Rate of hematological complete remission
timeFrame: At maximum 60 days from induction therapy start
measure: Overall survival rate
timeFrame: At 2 years from study entry
measure: Rate of cumulative incidence of relapse
timeFrame: At 2 years from study entry
measure: Incidence of hematological and non-hematological toxicity episodes during treatment as assessed by CTC-NCI
timeFrame: At maximum 60 days from induction therapy start and at maximum 225 days from consolidation therapy start
measure: Rate of molecular remission after 3rd consolidation course
timeFrame: At maximum 225 days grom consolidation therapy start
measure: Assessment of acute promyelocytic leukemia/RARa transcript level reduction after induction and during consolidation therapy
timeFrame: At maximum 60 days from induction therapy start and at maximum 225 days from consolidation therapy start
measure: Quality of life at the end of induction therapy and at the end of the 3rd consolidation course
timeFrame: At maximum 60 days from induction therapy start and at maximum 225 days from consolidation therapy start
measure: Event free survival
timeFrame: At 2 years from study entry
measure: Total hospitalization days during study therapy
timeFrame: At maximum 3.5 years from study entry
measure: Event-free survival rate in the two arms
timeFrame: At 2 years from study entry
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Universitätsklinik Innsbruck Hämatologie Onkologie
city: Linz
country: Austria
facility: Krankenhaus der Barmherzigen Schwestern Linz
city: Salzburg
country: Austria
facility: Universitätsklinik für Innere Medizin III Salzburg
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth GmbH
city: Berlin
country: Germany
facility: Charité Campus Benjamin Franklin Berlin
city: Bielefeld
country: Germany
facility: Städt. Kliniken Bielefeld gem. GmbH
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Bremen
country: Germany
facility: Ev. Diakonie-Krankenhaus gGmbH Bremen
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte gGmbH
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Dresden
country: Germany
facility: Universitätsklinikum C. G. Carus Dresden
city: Duisburg
country: Germany
facility: Katholisches Klinikum Duisburg St. Johannes Hospital
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Erlangen
country: Germany
facility: Uniklinikum Erlangen
city: Essen
country: Germany
facility: Kliniken Essen Süd, Ev. Krankenhaus Essen-Werden gGmbH
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt/a. M. -Höchst
country: Germany
facility: Städtische Kliniken Frankfurt a. M.-Höchst
city: Frankfurt/Main
country: Germany
facility: Uniklinik Frankfurt/Main
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Fulda
country: Germany
facility: Klinikum Fulda
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen und Marburg Gießen
city: Göttingen
country: Germany
facility: Universitätsklinikum Göttingen
city: Hamburg
country: Germany
facility: Asklepios Klinik Hamburg Altona
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg Hamburg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Hamm
country: Germany
facility: St. Marien-Hospital gem. GmbH Hamm
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Hildesheim
country: Germany
facility: St. Bernward Krankenhaus Hildesheim
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes Homburg/Saar
city: Idar-Oberstein
country: Germany
facility: Klinik für Knochenmarktransplantation und Hämatologie Idar-Oberstein
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH Kaiserslautern
city: Lebach
country: Germany
facility: Caritas-Krankenhaus Lebach
city: Lippe
country: Germany
facility: Klinikum Lippe Lemgo
city: Lübeck
country: Germany
facility: Uniklinikum Lübeck
city: Mainz
country: Germany
facility: Klinikum der Johannes Gutenberg Universität Mainz
city: Marburg
country: Germany
facility: Universitätsklinikum Gießen und Marburg GmbH Marburg
city: Merseburg
country: Germany
facility: Carl-von-Basedow-Klinikum Merseburg
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: München
country: Germany
facility: Klinikum rechts der Isar (München)
city: Nürnberg
country: Germany
facility: Klinikum Nord Nürnberg
city: Passau
country: Germany
facility: Klinikum Passau
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Saarbrücken
country: Germany
facility: Caritas-Klinik St. Theresia Saarbrücken
city: Schwäbisch-Hall
country: Germany
facility: Diakonie-Krankenhaus Schwäbisch Hall
city: Stuttgart
country: Germany
facility: Diakonie-Klinikum Stuttgart
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart Bürgerhospital
city: Stuttgart
country: Germany
facility: Robert Bosch Krankenhaus Stuttgart
city: Trier
country: Germany
facility: Krankenanstalt Mutterhaus der Borromäerinnen Trier
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder Trier
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Villingen-Schwenningen
country: Germany
facility: Klinikum Villingen-Schwenningen
city: Wuppertal
country: Germany
facility: HELIOS Klinikum Wuppertal
city: Alessandria
country: Italy
facility: Ospedale Civile SS. Antonio e Biagio di Alessandria
city: Ascoli Piceno
country: Italy
facility: Ospedale Gen.le. Prov.le "C.G. Mazzoni"
city: Avellino
country: Italy
facility: Az.Ospedaliera S.G.Moscati
city: Bari
country: Italy
facility: Ematologia con trapianto- AOU Policlinico Consorziale di Bari
city: Bergamo
country: Italy
facility: Divisione di Ematologia - Ospedali Riuniti
city: Bologna
country: Italy
facility: Istituto di Ematologia e Oncologia Medica "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
city: Bolzano
country: Italy
facility: Azienda Sanitaria di Bolzano - Ospedale Centrale - Ematologia e Centro TMO
city: Brescia
country: Italy
facility: Spedali Civili di Brescia
city: Cagliari
country: Italy
facility: ASL N.8 - Ospedale "A. Businco" - Unità Operativa di Ematologia e Trapianto di Midollo
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
city: Ferrara
country: Italy
facility: Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna
city: Genova
country: Italy
facility: Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"
city: Latina
country: Italy
facility: Divisione di Ematologia Ospedale "Santa Maria Goretti"
city: Lecce
country: Italy
facility: ST. V. Fazzi
city: Messina
country: Italy
facility: A.O. Universitaria Policlinico Martina di Messina
city: Messina
country: Italy
facility: Azienda ospedaliera Papardo
city: Milano
country: Italy
facility: IRCCS Fondazione Centro S. Raffaele del Monte Tabor
city: Milano
country: Italy
facility: Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
city: Milano
country: Italy
facility: UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
city: Modena
country: Italy
facility: Centro Oncologico Modenese - Dipartimento di Oncoematologia
city: Monza
country: Italy
facility: Azienda ospedaliera S. Gerardo di Monza
city: Napoli
country: Italy
facility: A.S.L. Napoli 1 Ospedale San Giovanni Bosco
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Napoli
country: Italy
facility: Servizio Sanitario Nazionale - Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" - Struttura Complessa di Ematologia - Div. TERE- 4° piano - Padiglione Palermo
city: Nocera Inferiore
country: Italy
facility: ASL SA/1 di Nocera Inferiore
city: Orbassano
country: Italy
facility: A.O. Universitaria S. Luigi Gonzaga di Orbassano
city: Palermo
country: Italy
facility: Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"
city: Palermo
country: Italy
facility: Ospedali Riuniti "Villa Sofia-Cervello"
city: Parma
country: Italy
facility: Cattedra di Ematologia CTMO Università degli Studi di Parma
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo di Pavia
city: Perugia
country: Italy
facility: Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della MIsericordia
city: Pesaro
country: Italy
facility: Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Potenza
country: Italy
facility: Ematologia - Ospedale San Carlo
city: Ravenna
country: Italy
facility: Ospedale S. Maria delle Croci di Ravenna
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Rionero in Vulture
country: Italy
facility: IRCCS Centro di riferimento Oncologico di Basilicata
city: Roma
country: Italy
facility: Azienda Osp. S. Giovanni/Addolorata
city: Roma
country: Italy
facility: Divisione di Ematologia - Ospedale S. Camillo
city: Roma
country: Italy
facility: Ospedale S. Eugenio
city: Roma
country: Italy
facility: Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
city: Roma
country: Italy
facility: Policlinico Campus Biomedico
city: Roma
country: Italy
facility: Policlinico Universitario Gemelli di Roma
city: Roma
country: Italy
facility: Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
city: Roma
country: Italy
facility: Università degli Studi - Policlinico di Tor Vergata
city: Rome
country: Italy
facility: IRCCS Istituto Regina Elena
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Sassari
country: Italy
facility: Serv. di Ematologia Ist. di Ematologia ed Endocrinologia
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Torino
country: Italy
facility: SCDO Ematologia 2 AOU S.Giovanni Battista
city: Udine
country: Italy
facility: Clinica Ematologica - Policlinico Universitario
city: Varese
country: Italy
facility: Ospedale di circolo e Fondazione Macchi
city: Verona
country: Italy
facility: Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
city: Vicenza
country: Italy
facility: ULSS N.6 Osp. S. Bortolo
Study officials:
affiliation: Azienda Ospedaliera Universitaria Policlinico Tor Vergata
name: Francesco Lo Coco, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.