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Trial record 7 of 18 for:    "Acute Promyelocytic Leukemia" | "Methotrexate"

Phase III Trial in Acute Promyelocytic Leukemia Patients (APL0406)

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ClinicalTrials.gov Identifier: NCT00482833
Recruitment Status : Active, not recruiting
First Posted : June 5, 2007
Last Update Posted : October 22, 2018
Sponsor:
Collaborator:
Study Alliance Leukemia (SAL) Group
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto

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

Condition or disease Intervention/treatment Phase
Leukemia Drug: arsenic trioxide Drug: idarubicin Drug: mercaptopurine Drug: methotrexate Drug: all-trans retinoic acid Drug: all-trans retinoic acid (ATRA) Phase 3

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)."


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 276 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : August 2007
Actual Primary Completion Date : September 2012
Estimated Study Completion Date : December 2018


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

  1. 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.
  2. 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.
  3. 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.





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


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


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT00482833


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Austria
Universitätsklinik Innsbruck Hämatologie Onkologie
Innsbruck, Austria
Krankenhaus der Barmherzigen Schwestern Linz
Linz, Austria
Universitätsklinik für Innere Medizin III Salzburg
Salzburg, Austria
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, Germany
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, Italy
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Study Alliance Leukemia (SAL) Group
Investigators
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Study Chair: Francesco Lo Coco, MD Azienda Ospedaliera Universitaria Policlinico Tor Vergata

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT00482833     History of Changes
Other Study ID Numbers: APL0406
GIMEMA-SAL-APL0406
EUDRACT-2006-006188-22
First Posted: June 5, 2007    Key Record Dates
Last Update Posted: October 22, 2018
Last Verified: October 2018
Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
adult acute promyelocytic leukemia (M3)
adult acute myeloid leukemia with t(15;17)(q22;q12)
untreated adult acute myeloid leukemia
Additional relevant MeSH terms:
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Methotrexate
Leukemia
Leukemia, Promyelocytic, Acute
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Mercaptopurine
Idarubicin
Arsenic Trioxide
Tretinoin
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Keratolytic Agents