Phase III Trial in Acute Promyelocytic Leukemia Patients

Leukemia Clinical Trial

— APL0406  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00482833
• Other study ID #: APL0406
• Secondary ID: GIMEMA-SAL-APL04
• Status: Completed
• Phase: Phase 3
• Start date: August 2007
• Est. completion date: October 17, 2019

Study information

• Verified date: October 2022
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Open label, randomised, phase III multicenter trial.

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)."

Recruitment information / eligibility

• Status: Completed
• Enrollment: 276
• Est. completion date: October 17, 2019
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Promyelocytic, Acute

Intervention

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).
• 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.
• 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
• methotrexate
Maintenance therapy Methotrexate (MTX), 15 mg/m2/weekly intramuscularly. The dose will be adjusted according to toxicity during the follow-up period.
• 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.
• 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).

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto	Study Alliance Leukemia (SAL) Group

Countries where clinical trial is conducted

Austria,  Germany,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Rate of hematological complete remission		At maximum 60 days from induction therapy start
Secondary	Overall survival rate		At 2 years from study entry
Secondary	Rate of cumulative incidence of relapse		At 2 years from study entry
Secondary	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
Secondary	Rate of molecular remission after 3rd consolidation course		At maximum 225 days grom consolidation therapy start
Secondary	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
Secondary	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
Secondary	Event free survival		At 2 years from study entry
Secondary	Total hospitalization days during study therapy		At maximum 3.5 years from study entry
Secondary	Event-free survival rate in the two arms		At 2 years from study entry

External Links

•   GIMEMA Foundation Website