APL0406: Phase III Trial in Acute Promyelocytic Leukemia Patients

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00482833

Collaborator

Study Alliance Leukemia (SAL) Group (Other)

276

Enrollment

110

Locations

Arms

173

Duration (Months)

2.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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)."

Study Design

Study Type:

Interventional

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 :

Aug 1, 2007

Actual Primary Completion Date :

Sep 1, 2012

Anticipated Study Completion Date :

Jan 1, 2022

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Event-free survival [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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	Universitätsklinik Innsbruck Hämatologie Onkologie	Innsbruck	Austria
2	Krankenhaus der Barmherzigen Schwestern Linz	Linz	Austria
3	Universitätsklinik für Innere Medizin III Salzburg	Salzburg	Austria
4	Klinikum Bayreuth GmbH	Bayreuth	Germany
5	Charité Campus Benjamin Franklin Berlin	Berlin	Germany
6	Städt. Kliniken Bielefeld gem. GmbH	Bielefeld	Germany
7	Universitätsklinikum Bonn	Bonn	Germany
8	Ev. Diakonie-Krankenhaus gGmbH Bremen	Bremen	Germany
9	Klinikum Bremen-Mitte gGmbH	Bremen	Germany
10	Klinikum Chemnitz gGmbH	Chemnitz	Germany
11	Universitätsklinikum C. G. Carus Dresden	Dresden	Germany
12	Katholisches Klinikum Duisburg St. Johannes Hospital	Duisburg	Germany
13	Universitätsklinikum Düsseldorf	Düsseldorf	Germany
14	Uniklinikum Erlangen	Erlangen	Germany
15	Kliniken Essen Süd, Ev. Krankenhaus Essen-Werden gGmbH	Essen	Germany
16	Universitätsklinikum Essen	Essen	Germany
17	Städtische Kliniken Frankfurt a. M.-Höchst	Frankfurt/a. M. -Höchst	Germany
18	Uniklinik Frankfurt/Main	Frankfurt/Main	Germany
19	Universitätsklinikum Freiburg	Freiburg	Germany
20	Klinikum Fulda	Fulda	Germany
21	Universitätsklinikum Gießen und Marburg Gießen	Gießen	Germany
22	Universitätsklinikum Göttingen	Göttingen	Germany
23	Asklepios Klinik Hamburg Altona	Hamburg	Germany
24	Asklepios Klinik St. Georg Hamburg	Hamburg	Germany
25	Universitätsklinikum Hamburg Eppendorf	Hamburg	Germany
26	St. Marien-Hospital gem. GmbH Hamm	Hamm	Germany
27	Medizinische Hochschule Hannover	Hannover	Germany
28	Universitätsklinikum Heidelberg	Heidelberg	Germany
29	St. Bernward Krankenhaus Hildesheim	Hildesheim	Germany
30	Universitätsklinikum des Saarlandes Homburg/Saar	Homburg	Germany
31	Klinik für Knochenmarktransplantation und Hämatologie Idar-Oberstein	Idar-Oberstein	Germany
32	Westpfalz-Klinikum GmbH Kaiserslautern	Kaiserslautern	Germany
33	Caritas-Krankenhaus Lebach	Lebach	Germany
34	Klinikum Lippe Lemgo	Lippe	Germany
35	Uniklinikum Lübeck	Lübeck	Germany
36	Klinikum der Johannes Gutenberg Universität Mainz	Mainz	Germany
37	Universitätsklinikum Gießen und Marburg GmbH Marburg	Marburg	Germany
38	Carl-von-Basedow-Klinikum Merseburg	Merseburg	Germany
39	Johannes Wesling Klinikum Minden	Minden	Germany
40	Klinikum rechts der Isar (München)	München	Germany
41	Klinikum Nord Nürnberg	Nürnberg	Germany
42	Klinikum Passau	Passau	Germany
43	Universitätsklinikum Regensburg	Regensburg	Germany
44	Caritas-Klinik St. Theresia Saarbrücken	Saarbrücken	Germany
45	Diakonie-Krankenhaus Schwäbisch Hall	Schwäbisch-Hall	Germany
46	Diakonie-Klinikum Stuttgart	Stuttgart	Germany
47	Klinikum Stuttgart Bürgerhospital	Stuttgart	Germany
48	Robert Bosch Krankenhaus Stuttgart	Stuttgart	Germany
49	Krankenanstalt Mutterhaus der Borromäerinnen Trier	Trier	Germany
50	Krankenhaus der Barmherzigen Brüder Trier	Trier	Germany
51	Universitätsklinikum Tübingen	Tübingen	Germany
52	Universitätsklinikum Ulm	Ulm	Germany
53	Klinikum Villingen-Schwenningen	Villingen-Schwenningen	Germany
54	HELIOS Klinikum Wuppertal	Wuppertal	Germany
55	Ospedale Civile SS. Antonio e Biagio di Alessandria	Alessandria	Italy
56	Ospedale Gen.le. Prov.le "C.G. Mazzoni"	Ascoli Piceno	Italy
57	Az.Ospedaliera S.G.Moscati	Avellino	Italy
58	Ematologia con trapianto- AOU Policlinico Consorziale di Bari	Bari	Italy
59	Divisione di Ematologia - Ospedali Riuniti	Bergamo	Italy
60	Istituto di Ematologia e Oncologia Medica "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi	Bologna	Italy
61	Azienda Sanitaria di Bolzano - Ospedale Centrale - Ematologia e Centro TMO	Bolzano	Italy
62	Spedali Civili di Brescia	Brescia	Italy
63	ASL N.8 - Ospedale "A. Businco" - Unità Operativa di Ematologia e Trapianto di Midollo	Cagliari	Italy
64	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania	Italy
65	Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia	Catanzaro	Italy
66	Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna	Ferrara	Italy
67	Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"	Genova	Italy
68	Divisione di Ematologia Ospedale "Santa Maria Goretti"	Latina	Italy
69	ST. V. Fazzi	Lecce	Italy
70	A.O. Universitaria Policlinico Martina di Messina	Messina	Italy
71	Azienda ospedaliera Papardo	Messina	Italy
72	IRCCS Fondazione Centro S. Raffaele del Monte Tabor	Milano	Italy
73	Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Milano	Italy
74	UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico	Milano	Italy
75	Centro Oncologico Modenese - Dipartimento di Oncoematologia	Modena	Italy
76	Azienda ospedaliera S. Gerardo di Monza	Monza	Italy
77	A.S.L. Napoli 1 Ospedale San Giovanni Bosco	Napoli	Italy
78	Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"	Napoli	Italy
79	Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli	Italy
80	Servizio Sanitario Nazionale - Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" - Struttura Complessa di Ematologia - Div. TERE- 4° piano - Padiglione Palermo	Napoli	Italy
81	ASL SA/1 di Nocera Inferiore	Nocera Inferiore	Italy
82	A.O. Universitaria S. Luigi Gonzaga di Orbassano	Orbassano	Italy
83	Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"	Palermo	Italy
84	Ospedali Riuniti "Villa Sofia-Cervello"	Palermo	Italy
85	Cattedra di Ematologia CTMO Università degli Studi di Parma	Parma	Italy
86	IRCCS Policlinico S. Matteo di Pavia	Pavia	Italy
87	Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della MIsericordia	Perugia	Italy
88	Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore	Pesaro	Italy
89	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara	Italy
90	Ematologia - Ospedale San Carlo	Potenza	Italy
91	Ospedale S. Maria delle Croci di Ravenna	Ravenna	Italy
92	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria	Italy
93	IRCCS Centro di riferimento Oncologico di Basilicata	Rionero in Vulture	Italy
94	Azienda Osp. S. Giovanni/Addolorata	Roma	Italy
95	Divisione di Ematologia - Ospedale S. Camillo	Roma	Italy
96	Ospedale S. Eugenio	Roma	Italy
97	Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma	Italy
98	Policlinico Campus Biomedico	Roma	Italy
99	Policlinico Universitario Gemelli di Roma	Roma	Italy
100	Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia	Roma	Italy
101	Università degli Studi - Policlinico di Tor Vergata	Roma	Italy
102	IRCCS Istituto Regina Elena	Rome	Italy
103	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	Italy
104	Serv. di Ematologia Ist. di Ematologia ed Endocrinologia	Sassari	Italy
105	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena	Italy
106	SCDO Ematologia 2 AOU S.Giovanni Battista	Torino	Italy
107	Clinica Ematologica - Policlinico Universitario	Udine	Italy
108	Ospedale di circolo e Fondazione Macchi	Varese	Italy
109	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona	Italy
110	ULSS N.6 Osp. S. Bortolo	Vicenza	Italy