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Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia

NCT02688140

Description:

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML) characterized by consistent clinical, morphologic, and genetic features. According to the FAB classification APL is designated as"M3 leukemia" and assigned to the WHO defined type of AML with recurrent cytogenetic abnormalities, "acute promyelocytic leukemia with t(15;17)(q22;q12), (PML/RARα) and variants". Despite the dramatic progress achieved in frontline therapy of APL with ATRA plus anthracycline-based regimens, relapses still occur in approximately 20% of patients. Moreover, these regimens are associated with significant toxicities due to severe myelosuppression frequently associated with life-threatening infections and potentially serious late effects including development of secondary MDS/AML. In a recent randomized clinical trial in low/intermediate-risk APL (WBC ≤ 10 GPt/l APL0406 trial) a combination of arsenic trioxide (ATO) and ATRA has been shown to result into better survival with significantly lower toxicity rates compared to the standard ATRA + idarubicin (AIDA) therapy. Inspired by the results of this trial the investigators intend to perform a randomized study in high-risk APL (WBC at diagnosis > 10 GPt/l) comparing standard AIDA-based treatment with ATO/ATRA combination including low-doses idarubicin during induction. The investigators propose a modified ATO/ATRA protocol with the addition of two doses of IDA (50% compared to standard AIDA induction) for induction because of the anticipated need of adding anthracyclines to control hyperleukocytosis and to achieve long-term disease control in this high-risk APL population. This is followed by 4 cycles of ATO/ATRA consolidation therapy. As in the APL0406 study for low/intermediate-risk patients the investigators expect less severe hematologic toxicity and treatment-related mortality resulting in an improved outcome for patients in the experimental arm. Furthermore, from the start of consolidation, these patients (in contrast to the standard arm) can be treated on an outpatient basis, which is also considered to be associated with an improved quality of life. The study will be conducted as a European intergroup study.

Related Conditions:
  • Acute Promyelocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia
  • Official Title: A Randomized Phase III Study to Compare Arsenic Trioxide (ATO) Combined to ATRA and Idarubicin Versus Standard ATRA and Anthracyclines-based Chemotherapy (AIDA Regimen) for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: TUD-APOLLO-064
  • NCT ID: NCT02688140

Conditions

  • Acute Promyelocytic Leukemia

Interventions

DrugSynonymsArms
Arsenic trioxideATO, Trisenox (R), As2O3Arm A
IdarubicinIDAArm A
CytarabineAra-CArm B (standard chemotherapy)
Tretinoinall-trans retinoic acid, ATRAArm A
MitoxantroneMTZArm B (standard chemotherapy)
Mercaptopurine6-Mercaptopurine, 6-MPArm B (standard chemotherapy)
MethotrexateMTXArm B (standard chemotherapy)

Purpose

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML) characterized by consistent clinical, morphologic, and genetic features. According to the FAB classification APL is designated as"M3 leukemia" and assigned to the WHO defined type of AML with recurrent cytogenetic abnormalities, "acute promyelocytic leukemia with t(15;17)(q22;q12), (PML/RARα) and variants". Despite the dramatic progress achieved in frontline therapy of APL with ATRA plus anthracycline-based regimens, relapses still occur in approximately 20% of patients. Moreover, these regimens are associated with significant toxicities due to severe myelosuppression frequently associated with life-threatening infections and potentially serious late effects including development of secondary MDS/AML. In a recent randomized clinical trial in low/intermediate-risk APL (WBC ≤ 10 GPt/l APL0406 trial) a combination of arsenic trioxide (ATO) and ATRA has been shown to result into better survival with significantly lower toxicity rates compared to the standard ATRA + idarubicin (AIDA) therapy. Inspired by the results of this trial the investigators intend to perform a randomized study in high-risk APL (WBC at diagnosis > 10 GPt/l) comparing standard AIDA-based treatment with ATO/ATRA combination including low-doses idarubicin during induction. The investigators propose a modified ATO/ATRA protocol with the addition of two doses of IDA (50% compared to standard AIDA induction) for induction because of the anticipated need of adding anthracyclines to control hyperleukocytosis and to achieve long-term disease control in this high-risk APL population. This is followed by 4 cycles of ATO/ATRA consolidation therapy. As in the APL0406 study for low/intermediate-risk patients the investigators expect less severe hematologic toxicity and treatment-related mortality resulting in an improved outcome for patients in the experimental arm. Furthermore, from the start of consolidation, these patients (in contrast to the standard arm) can be treated on an outpatient basis, which is also considered to be associated with an improved quality of life. The study will be conducted as a European intergroup study.

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalInduction therapy: Patients receive idarubicin i.v. over 20 minutes on day 1 and 3, oral tretinoin twice daily on day 1-28 (max. up to day 60) and arsenic trioxide i.v. over 2 hours on day 5-28 (max. up to day 60). In case of morphological CR and regenerated blood counts, consolidation therapy should be started within 2-4 weeks after documented CR. Consolidation therapy: Patients receive oral tretinoin twice daily on day 1-14. Treatment with tretinoin repeats every 4 weeks for up to 7 courses. Patients also receive arsenic trioxide i.v. over 2 hours on days 1-5 in week 1-4. Treatment with arsenic trioxide repeats every 8 weeks for up to 4 courses.
  • Arsenic trioxide
  • Idarubicin
  • Tretinoin
Arm B (standard chemotherapy)Active ComparatorInduction therapy: Patients receive idarubicin i.v. over 20 minutes on day 1,3,5 and 7 and oral tretinoin twice daily on day 1-28 (max. up to day 60). In case of morphological CR and regenerated blood counts, consolidation therapy should be started within 2-4 weeks after documented CR Consolidation therapy: Patients receive oral tretinoin twice daily on day 1-45, idarubicin i.v. over 20 minutes on day 1-4 and day 31, cytarabine i.v. over 3 hours on day 1-4, over 8 hours on day 31-35, mitoxantrone i.v. over 30 minutes on day 16-20. Maintenance therapy (only for PML-RARa negative patients): Patients receive oral mercaptopurine once daily and methotrexate i.m./p.o. 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
  • Idarubicin
  • Cytarabine
  • Tretinoin
  • Mitoxantrone
  • Mercaptopurine
  • Methotrexate

Eligibility Criteria

        Inclusion Criteria:

          -  Informed consent

          -  Women or men with a newly diagnosed APL by cytomorphology, confirmed by molecular
             analysis*

          -  Age ≥ 18 and ≤ 65 years

          -  ECOG performance status 0-3

          -  WBC at diagnosis > 10 GPt/l

          -  Serum total bilirubin ≤ 3.0 mg/dl (≤ 51 µmol/l)

          -  Serum creatinine ≤ 3.0 mg/dl (≤ 260 µmol/l)

          -  Women must fulfill at least one of the following criteria in order to be eligible for
             trial inclusion:

          -  Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum
             FSH > 40 U/ml)

          -  Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy

          -  Continuous and correct application of a contraception method with a Pearl Index of <1%
             (e.g. implants, depots, oral contraceptives, -intrauterine device - IUD)

          -  Sexual abstinence

          -  Vasectomy of the sexual partner

               -  The confirmation of diagnosis at genetic level (microspeckled PML nuclear
                  distribution by PGM3 monoclonal antibody and/or PML/RARa fusion by RT-PCR or
                  fluorescence in situ hybridization (FISH) and/or demonstration of t(15;17) at
                  karyotyping) will be mandatory for patient eligibility. However, in order to
                  avoid delay in treatment initiation, patients can be randomized on the basis of
                  morphologic diagnosis only and before the results of genetic tests are available

        Exclusion Criteria:

          -  Patients who are not eligible for chemotherapy as per discretion of the treating
             physician

          -  APL secondary to previous radio- or chemotherapy for non-APL disease

          -  Other active malignancy at time of study entry (exception: basal-cell carcinoma)

          -  Lack of diagnostic confirmation at genetic level

          -  Significant arrhythmias, ECG abnormalities:

          -  Congenital long QT syndrome;

          -  History or presence of significant ventricular or atrial tachyarrhythmia;

          -  Clinically significant resting bradycardia (<50 beats per minute)

          -  QTc >500msec on screening ECG for both genders (using the QTcF formula detailed on
             protocol)

          -  Right bundle branch block plus left anterior hemiblock, bifascicular block

          -  Other cardiac contraindications for intensive chemotherapy (L-VEF <50%)

          -  Uncontrolled, life-threatening infections

          -  Severe non controlled pulmonary or cardiac disease

          -  Severe hepatic or renal dysfunction

          -  HIV and/or active hepatitis C infection

          -  Pregnant or breast-feeding patients

          -  Allergy to trial medication or excipients in study medication

          -  Substance abuse; medical, psychological or social conditions that may interfere with
             the patients participation in the study or evaluation of the study results

          -  Use of other investigational drugs at the time of enrolment or within 30 days before
             study entry
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival
Time Frame:From date of randomization until the date of first documented event, assessed up to 66 months
Safety Issue:
Description:events are: no achievement of haematological complete remission after induction therapy; no achievement of molecular remission after the last consolidation course; relapse; death including early death or development of secondary AML or MDS

Secondary Outcome Measures

Measure:Rate of hematological complete remission
Time Frame:up to 60 days, from date of randomization until end of induction therapy
Safety Issue:
Description:
Measure:Rate of early death within 30 days after randomization
Time Frame:up to 30 days after randomization
Safety Issue:
Description:
Measure:Rate of overall survival (OS)
Time Frame:at 2 years
Safety Issue:
Description:
Measure:Rate of cumulative incidence of secondary MDS or AML
Time Frame:assessed up to 66 months, from date of randomization until occurance of secondary AML or MDS
Safety Issue:
Description:
Measure:Rate of cumulative incidence of relapse (CIR)
Time Frame:at 2 years
Safety Issue:
Description:
Measure:Incidence of hematological and non-hematological toxicity
Time Frame:assessed up to 30 months after randomization
Safety Issue:
Description:
Measure:Rate of molecular remission after the last consolidation cycle
Time Frame:up to 256 days after randomization
Safety Issue:
Description:
Measure:Assessment of acute promyelocytic leukemia/RARa transcript level reduction after induction therapy until end of study
Time Frame:assessed up to 30 months after randomization
Safety Issue:
Description:
Measure:Quality of Life at the end of induction therapy until the end of study
Time Frame:assessed up to 30 months after randomization
Safety Issue:
Description:
Measure:To investigate differences in the immune reconstitution between the two arms
Time Frame:assessed up to 30 months after randomization
Safety Issue:
Description:
Measure:Total hospitalization days during therapy
Time Frame:assessed up to 30 months after randomization
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Technische Universität Dresden

Trial Keywords

  • APL
  • acute promyelocytic leukemia (M3)
  • high-risk acute promyelocytic leukemia (APL/AML M3)
  • acute myeloid leukemia with t(15;17)(q22;q12)
  • newly diagnosed
  • high-risk

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