Phase III Trial in Acute Promyelocytic Leukemia Patients (APL0406)

• ClinicalTrials.gov Identifier: NCT00482833
• Recruitment Status: Completed
• First Posted: June 5, 2007
• Last Update Posted: October 12, 2022
• Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Collaborator: Study Alliance Leukemia (SAL) Group
• Information provided by (Responsible Party): Gruppo Italiano Malattie EMatologiche dell'Adulto

Tracking Information

• First Submitted Date: June 4, 2007
• First Posted Date: June 5, 2007
• Last Update Posted Date: October 12, 2022
• Study Start Date: August 2007
• Actual Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 28, 2012)

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.

• Original Primary Outcome Measures (submitted: June 4, 2007): Event-free survival at 2 years

Current Secondary Outcome Measures (submitted: August 20, 2012)

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

Original Secondary Outcome Measures (submitted: June 4, 2007)

• Rate of hematological complete remission
• Overall survival rate at 2 years
• Rate of incomplete remission at 2 years
• Incidence of hematological and non-hematological toxicity episodes during treatment as assessed by CTC-NCI
• Rate of molecular remission after 3rd consolidation course
• Assessment of acute promyelocytic leukemia/RARa transcript level reduction after induction and during consolidation
• Total hospitalization days during therapy
• Quality-of-life at the end of induction phase and at the end of the 3rd consolidation course

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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)."

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Leukemia

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).

• 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.

• 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).

Study Arms

• Experimental: ARM A - ATO/ATRA
  Interventions:

  • Drug: arsenic trioxide
  • Drug: all-trans retinoic acid (ATRA)
• Active Comparator: ARM B - ATRA
  Interventions:

  • Drug: idarubicin
  • Drug: mercaptopurine
  • Drug: methotrexate
  • Drug: all-trans retinoic acid

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 29, 2011): 276
• Original Enrollment (submitted: June 4, 2007): 162
• Actual Study Completion Date: October 17, 2019
• Actual Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Germany, Italy

Administrative Information

• NCT Number: NCT00482833
• Other Study ID Numbers: APL0406; GIMEMA-SAL-APL0406; EUDRACT-2006-006188-22
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Original Responsible Party: Not Provided
• Current Study Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Original Study Sponsor: Same as current
• Collaborators: Study Alliance Leukemia (SAL) Group

Investigators

• Study Chair: Francesco Lo Coco, MD; Azienda Ospedaliera Universitaria Policlinico Tor Vergata

• PRS Account: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Verification Date: October 2022