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Trial record 3 of 18 for:    "Acute Promyelocytic Leukemia" | "Methotrexate"

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

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ClinicalTrials.gov Identifier: NCT02688140
Recruitment Status : Recruiting
First Posted : February 23, 2016
Last Update Posted : June 21, 2018
Sponsor:
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
Information provided by (Responsible Party):
Technische Universität Dresden

Tracking Information
First Submitted Date  ICMJE February 11, 2016
First Posted Date  ICMJE February 23, 2016
Last Update Posted Date June 21, 2018
Study Start Date  ICMJE June 2016
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 17, 2016)
Event-free survival [ Time Frame: From date of randomization until the date of first documented event, assessed up to 66 months ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02688140 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 17, 2016)
  • Rate of hematological complete remission [ Time Frame: up to 60 days, from date of randomization until end of induction therapy ]
  • Rate of early death within 30 days after randomization [ Time Frame: up to 30 days after randomization ]
  • Rate of overall survival (OS) [ Time Frame: at 2 years ]
  • 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 ]
  • Rate of cumulative incidence of relapse (CIR) [ Time Frame: at 2 years ]
  • Incidence of hematological and non-hematological toxicity [ Time Frame: assessed up to 30 months after randomization ]
  • Rate of molecular remission after the last consolidation cycle [ Time Frame: up to 256 days after randomization ]
  • 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 ]
  • Quality of Life at the end of induction therapy until the end of study [ Time Frame: assessed up to 30 months after randomization ]
  • To investigate differences in the immune reconstitution between the two arms [ Time Frame: assessed up to 30 months after randomization ]
  • Total hospitalization days during therapy [ Time Frame: assessed up to 30 months after randomization ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia
Official Title  ICMJE 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Promyelocytic Leukemia
Intervention  ICMJE
  • Drug: Arsenic trioxide
    Other Names:
    • ATO
    • Trisenox (R)
    • As2O3
  • Drug: Idarubicin
    Other Name: IDA
  • Drug: Cytarabine
    Other Name: Ara-C
  • Drug: Tretinoin
    Other Names:
    • all-trans retinoic acid
    • ATRA
  • Drug: Mitoxantrone
    Other Name: MTZ
  • Drug: Mercaptopurine
    Other Names:
    • 6-Mercaptopurine
    • 6-MP
  • Drug: Methotrexate
    Other Name: MTX
Study Arms  ICMJE
  • Experimental: Arm A

    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.

    Interventions:
    • Drug: Arsenic trioxide
    • Drug: Idarubicin
    • Drug: Tretinoin
  • Active Comparator: Arm B (standard chemotherapy)

    Induction 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

    Interventions:
    • Drug: Idarubicin
    • Drug: Cytarabine
    • Drug: Tretinoin
    • Drug: Mitoxantrone
    • Drug: Mercaptopurine
    • Drug: Methotrexate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 17, 2016)
280
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2022
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Uwe Platzbecker, Prof. Dr. +49 351 458 ext 3192 uwe.platzbecker@uniklinikum-dresden.de
Contact: Michaela Sauer +49 351 458 ext 3192 michaela.sauer@uniklinikum-dresden.de
Listed Location Countries  ICMJE France,   Germany,   Italy,   Netherlands,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02688140
Other Study ID Numbers  ICMJE TUD-APOLLO-064
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Technische Universität Dresden
Study Sponsor  ICMJE Technische Universität Dresden
Collaborators  ICMJE
  • 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
Investigators  ICMJE
Principal Investigator: Uwe Platzbecker, Prof. Dr. Technische Universität Dresden (TUD)
PRS Account Technische Universität Dresden
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP