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

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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

Brief Summary

      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.
    


Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Event-free survival

Secondary Outcome

 Rate of hematological complete remission

Condition

Acute Promyelocytic Leukemia

Intervention

Arsenic trioxide

Study Arms / Comparison Groups

 Arm A
Description:  Induction 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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

280

Start Date

June 2016

Completion Date

January 2022

Primary Completion Date

November 2021

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
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Uwe Platzbecker, Prof. Dr., +49 351 458, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT02688140

Organization ID

TUD-APOLLO-064


Responsible Party

Sponsor

Study Sponsor

Technische Universität Dresden

Collaborators

 Gruppo Italiano Malattie EMatologiche dell'Adulto

Study Sponsor

Uwe Platzbecker, Prof. Dr., Principal Investigator, Technische Universität Dresden (TUD)


Verification Date

February 2020