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Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia (TUD-APOLLO-064)

Primary Purpose

Acute Promyelocytic Leukemia

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Arsenic trioxide
Idarubicin
Cytarabine
Tretinoin
Mitoxantrone
Mercaptopurine
Methotrexate
Sponsored by
Technische Universität Dresden
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Promyelocytic Leukemia focused on measuring 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

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • French-Belgian-Swiss APL study group
  • AML-CG study group
  • AML-SG study group
  • OSHO study group
  • SAL study group
  • GIMEMA study group
  • HOVON study group
  • PETHEMA study group

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm A

Arm B (standard chemotherapy)

Arm 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.

Induction therapy: Patients receive idarubicin i.v. over 20 minutes on day 1,3,5 and 7, 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 I: IDA 5 mg/m2 i.v. day 1-4 Ara-C 1000 mg/m2/3h i.v. day 1-4 ATRA 45 mg/m2 p.o. day 1-15 Consolidation II: MTZ 10 mg/m2 i.v. day 1-5 ATRA 45 mg/m2 p.o. day 1-15 Consolidation III: IDA 12 mg/m2 i.v. day 1 Ara-C 150 mg/m2 every 8h i.v. day 1-5 ATRA 45 mg/m2 p.o. day 1-15 Maintenance (duration 7 cycles = 2 years; one cycle lasts 106 days): 6-MP 50 mg/m2 p.o. Cycle 1-7: day 1-91 (followed by 15 days of ATRA on days 92-106) MTX 15mg/m2 i.m./p.o. Cycle 1-7: once weekly for 91 days (followed by 15 days of ATRA on days 92-106) ATRA 45 mg/m2 p.o. Cycle 1-6: day 92-106 Cycle 7: without ATRA Administration (treatment break of 6-MP and MTX during ATRA administration)

Outcomes

Primary Outcome Measures

Event-free survival
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

Rate of hematological complete remission
Rate of early death within 30 days after randomization
Rate of overall survival (OS)
Rate of cumulative incidence of secondary MDS or AML
Rate of cumulative incidence of relapse (CIR)
Incidence of hematological and non-hematological toxicity
Rate of molecular remission after the last consolidation cycle
Assessment of acute promyelocytic leukemia/RARa transcript level reduction after induction therapy until end of study
Quality of Life at the end of induction therapy until the end of study
To investigate differences in the immune reconstitution between the two arms
Total hospitalization days during therapy

Full Information

First Posted
February 11, 2016
Last Updated
August 4, 2022
Sponsor
Technische Universität Dresden
Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto, Groupe Francophone des Myelodysplasies, HOVON - Dutch Haemato-Oncology Association, Programa para el Tratamiento de Hemopatías Malignas, German Federal Ministry of Education and Research, Teva Pharmaceuticals Europe
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1. Study Identification

Unique Protocol Identification Number
NCT02688140
Brief Title
Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia
Acronym
TUD-APOLLO-064
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

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 2016 (undefined)
Primary Completion Date
January 2025 (Anticipated)
Study Completion Date
January 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Technische Universität Dresden
Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto, Groupe Francophone des Myelodysplasies, HOVON - Dutch Haemato-Oncology Association, Programa para el Tratamiento de Hemopatías Malignas, German Federal Ministry of Education and Research, Teva Pharmaceuticals Europe

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
280 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm A
Arm Type
Experimental
Arm 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.
Arm Title
Arm B (standard chemotherapy)
Arm Type
Active Comparator
Arm Description
Induction therapy: Patients receive idarubicin i.v. over 20 minutes on day 1,3,5 and 7, 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 I: IDA 5 mg/m2 i.v. day 1-4 Ara-C 1000 mg/m2/3h i.v. day 1-4 ATRA 45 mg/m2 p.o. day 1-15 Consolidation II: MTZ 10 mg/m2 i.v. day 1-5 ATRA 45 mg/m2 p.o. day 1-15 Consolidation III: IDA 12 mg/m2 i.v. day 1 Ara-C 150 mg/m2 every 8h i.v. day 1-5 ATRA 45 mg/m2 p.o. day 1-15 Maintenance (duration 7 cycles = 2 years; one cycle lasts 106 days): 6-MP 50 mg/m2 p.o. Cycle 1-7: day 1-91 (followed by 15 days of ATRA on days 92-106) MTX 15mg/m2 i.m./p.o. Cycle 1-7: once weekly for 91 days (followed by 15 days of ATRA on days 92-106) ATRA 45 mg/m2 p.o. Cycle 1-6: day 92-106 Cycle 7: without ATRA Administration (treatment break of 6-MP and MTX during ATRA administration)
Intervention Type
Drug
Intervention Name(s)
Arsenic trioxide
Other Intervention Name(s)
ATO, Trisenox (R), As2O3
Intervention Type
Drug
Intervention Name(s)
Idarubicin
Other Intervention Name(s)
IDA
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
Ara-C
Intervention Type
Drug
Intervention Name(s)
Tretinoin
Other Intervention Name(s)
all-trans retinoic acid, ATRA
Intervention Type
Drug
Intervention Name(s)
Mitoxantrone
Other Intervention Name(s)
MTZ
Intervention Type
Drug
Intervention Name(s)
Mercaptopurine
Other Intervention Name(s)
6-Mercaptopurine, 6-MP
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
MTX
Primary Outcome Measure Information:
Title
Event-free survival
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
Time Frame
From date of randomization until the date of first documented event, assessed up to 66 months
Secondary Outcome Measure Information:
Title
Rate of hematological complete remission
Time Frame
up to 60 days, from date of randomization until end of induction therapy
Title
Rate of early death within 30 days after randomization
Time Frame
up to 30 days after randomization
Title
Rate of overall survival (OS)
Time Frame
at 2 years
Title
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
Title
Rate of cumulative incidence of relapse (CIR)
Time Frame
at 2 years
Title
Incidence of hematological and non-hematological toxicity
Time Frame
assessed up to 30 months after randomization
Title
Rate of molecular remission after the last consolidation cycle
Time Frame
up to 256 days after randomization
Title
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
Title
Quality of Life at the end of induction therapy until the end of study
Time Frame
assessed up to 30 months after randomization
Title
To investigate differences in the immune reconstitution between the two arms
Time Frame
assessed up to 30 months after randomization
Title
Total hospitalization days during therapy
Time Frame
assessed up to 30 months after randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Uwe Platzbecker, Prof. Dr.
Organizational Affiliation
Technische Universität Dresden (TUD)
Official's Role
Principal Investigator
Facility Information:
Facility Name
French-Belgian-Swiss APL study group
City
Multiple Locations
Country
France
Facility Name
AML-CG study group
City
Multiple Locations
Country
Germany
Facility Name
AML-SG study group
City
Multiple Locations
Country
Germany
Facility Name
OSHO study group
City
Multiple Locations
Country
Germany
Facility Name
SAL study group
City
Multiple Locations
Country
Germany
Facility Name
GIMEMA study group
City
Multiple Locations
Country
Italy
Facility Name
HOVON study group
City
Multiple Locations
Country
Netherlands
Facility Name
PETHEMA study group
City
Multiple Locations
Country
Spain

12. IPD Sharing Statement

Learn more about this trial

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

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