Phase III Trial in Acute Promyelocytic Leukemia Patients (APL0406)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Study Alliance Leukemia (SAL) Group
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier:
NCT00482833
First received: June 4, 2007
Last updated: January 30, 2014
Last verified: January 2014
  Purpose

Open label, randomised, phase III multicenter trial.


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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:

Primary Outcome Measures:
  • Event-free survival [ Time Frame: At maximum 3.5 years from study entry ] [ Designated as safety issue: No ]
    As of 14th september 2010, all patients needed to evaluate the primary endpoint have been recruited.


Secondary Outcome Measures:
  • Rate of hematological complete remission [ Time Frame: At maximum 60 days from induction therapy start ] [ Designated as safety issue: No ]
  • Overall survival rate [ Time Frame: At 2 years from study entry ] [ Designated as safety issue: No ]
  • Rate of cumulative incidence of relapse [ Time Frame: At 2 years from study entry ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Rate of molecular remission after 3rd consolidation course [ Time Frame: At maximum 225 days grom consolidation therapy start ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Event free survival [ Time Frame: At 2 years from study entry ] [ Designated as safety issue: No ]
  • Total hospitalization days during study therapy [ Time Frame: At maximum 3.5 years from study entry ] [ Designated as safety issue: No ]
  • Event-free survival rate in the two arms [ Time Frame: At 2 years from study entry ] [ Designated as safety issue: No ]

Enrollment: 276
Study Start Date: August 2007
Estimated Study Completion Date: October 2016
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.


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)."

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00482833

  Show 110 Study Locations
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Study Alliance Leukemia (SAL) Group
Investigators
Study Chair: Francesco Lo Coco, MD Azienda Ospedaliera Universitaria Policlinico Tor Vergata
  More Information

Additional Information:
No publications provided by Gruppo Italiano Malattie EMatologiche dell'Adulto

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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
Study First Received: June 4, 2007
Last Updated: January 30, 2014
Health Authority: Italy: Ethics Committee

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:
Leukemia
Leukemia, Promyelocytic, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type
6-Mercaptopurine
Arsenic trioxide
Idarubicin
Methotrexate
Tretinoin
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Keratolytic Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014