Clinical trial NCT02688140: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Promyelocytic Leukemia
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
Lead sponsor: Technische Universität Dresden
Sponsor class: OTHER
Collaborators: name: Gruppo Italiano Malattie EMatologiche dell'Adulto
name: Groupe Francophone des Myelodysplasies
name: HOVON - Dutch Haemato-Oncology Association
name: Programa para el Tratamiento de Hemopatías Malignas
name: German Federal Ministry of Education and Research
name: Teva Pharmaceuticals Europe
First posted: 2016-02-23
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Event-free survival
timeFrame: From date of randomization until the date of first documented event, assessed up to 66 months
Secondary outcomes:
measure: Rate of hematological complete remission
timeFrame: up to 60 days, from date of randomization until end of induction therapy
measure: Rate of early death within 30 days after randomization
timeFrame: up to 30 days after randomization
measure: Rate of overall survival (OS)
timeFrame: at 2 years
measure: Rate of cumulative incidence of secondary MDS or AML
timeFrame: assessed up to 66 months, from date of randomization until occurance of secondary AML or MDS
measure: Rate of cumulative incidence of relapse (CIR)
timeFrame: at 2 years
measure: Incidence of hematological and non-hematological toxicity
timeFrame: assessed up to 30 months after randomization
measure: Rate of molecular remission after the last consolidation cycle
timeFrame: up to 256 days after randomization
measure: Assessment of acute promyelocytic leukemia/RARa transcript level reduction after induction therapy until end of study
timeFrame: assessed up to 30 months after randomization
measure: Quality of Life at the end of induction therapy until the end of study
timeFrame: assessed up to 30 months after randomization
measure: To investigate differences in the immune reconstitution between the two arms
timeFrame: assessed up to 30 months after randomization
measure: Total hospitalization days during therapy
timeFrame: assessed up to 30 months after randomization
Other outcomes:
Locations:
city: Multiple Locations
country: France
facility: French-Belgian-Swiss APL study group
city: Multiple Locations
country: Germany
facility: AML-CG study group
city: Multiple Locations
country: Germany
facility: AML-SG study group
city: Multiple Locations
country: Germany
facility: OSHO study group
city: Multiple Locations
country: Germany
facility: SAL study group
city: Multiple Locations
country: Italy
facility: GIMEMA study group
city: Multiple Locations
country: Netherlands
facility: HOVON study group
city: Multiple Locations
country: Spain
facility: PETHEMA study group
Study officials:
affiliation: Technische Universität Dresden (TUD)
name: Uwe Platzbecker, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: