NCT00482833 · CITED IN SOURCE DOCUMENTS

Phase III Trial in Acute Promyelocytic Leukemia Patients

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2022-10-12

Open label, randomised, phase III multicenter trial.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

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
healthy Volunteers: false
maximum Age: 70 Years
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

intervention Names
Drug: arsenic trioxide
Drug: all-trans retinoic acid (ATRA)
label
ARM A - ATO/ATRA
type
EXPERIMENTAL
intervention Names
Drug: idarubicin
Drug: mercaptopurine
Drug: methotrexate
Drug: all-trans retinoic acid
label
ARM B - ATRA
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
ARM A - ATO/ATRA
description
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).
name
arsenic trioxide
type
DRUG
arm Group Labels
ARM B - ATRA
description
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.
name
idarubicin
type
DRUG
arm Group Labels
ARM B - ATRA
description
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
name
mercaptopurine
type
DRUG
arm Group Labels
ARM B - ATRA
description
Maintenance therapy Methotrexate (MTX), 15 mg/m2/weekly intramuscularly. The dose will be adjusted according to toxicity during the follow-up period.
name
methotrexate
type
DRUG
arm Group Labels
ARM B - ATRA
description
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.
name
all-trans retinoic acid
type
DRUG
arm Group Labels
ARM A - ATO/ATRA
description
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).
name
all-trans retinoic acid (ATRA)
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 276
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

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

secondary Outcomes

measure
Rate of hematological complete remission
time Frame
At maximum 60 days from induction therapy start
measure
Overall survival rate
time Frame
At 2 years from study entry
measure
Rate of cumulative incidence of relapse
time Frame
At 2 years from study entry
measure
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
measure
Rate of molecular remission after 3rd consolidation course
time Frame
At maximum 225 days grom consolidation therapy start
measure
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
measure
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
measure
Event free survival
time Frame
At 2 years from study entry
measure
Total hospitalization days during study therapy
time Frame
At maximum 3.5 years from study entry
measure
Event-free survival rate in the two arms
time Frame
At 2 years from study entry

Full study description

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)."

Source references

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.
pmid
25245446
type
DERIVED
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.
pmid
23841729
type
DERIVED