Phase III Trial in Acute Promyelocytic Leukemia Patients

Study Overview
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Brief Summary
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Open label, randomised, phase III multicenter trial.

Detailed Description
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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).

Official Title
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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

Conditions
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Leukemia

Intervention / Treatment
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* Drug: arsenic trioxide
* Drug: idarubicin
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: all-trans retinoic acid
* Drug: all-trans retinoic acid (ATRA)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM A - ATO/ATRA<br> | Drug: arsenic trioxide<br>* 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).<br>Drug: all-trans retinoic acid (ATRA)<br>* 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).<br>|
| Active Comparator: ARM B - ATRA<br> | Drug: idarubicin<br>* 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.<br>Drug: mercaptopurine<br>* 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<br>Drug: methotrexate<br>* Maintenance therapy Methotrexate (MTX), 15 mg/m2/weekly intramuscularly. The dose will be adjusted according to toxicity during the follow-up period.<br>Drug: all-trans retinoic acid<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | As of 14th september 2010, all patients needed to evaluate the primary endpoint have been recruited. | At maximum 3.5 years from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute promyelocytic leukemia (M3), adult acute myeloid leukemia with t(15;17)(q22;q12), untreated adult acute myeloid leukemia