Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by PETHEMA Foundation
Sponsor:
Information provided by (Responsible Party):
PETHEMA Foundation
ClinicalTrials.gov Identifier:
NCT00504764
First received: July 19, 2007
Last updated: November 19, 2013
Last verified: November 2013

July 19, 2007
November 19, 2013
July 2007
December 2014   (final data collection date for primary outcome measure)
  • Evaluate the hematological and molecular remission rate after induction and consolidation with ATO [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Evaluate the induction mortality with ATO in monotherapy [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Evaluate the hematological and molecular relapse rate in patients treated with autologous transplantation, allogenic transplantation or ATO + ATRA +/- Mylotarg [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Evaluate the hematological and molecular remission rate after induction and consolidation with ATO
  • Evaluate the induction mortality with ATO in monotherapy
  • Evaluate the hematological and molecular relapse rate in patients treated with autologous transplantation, allogenic transplantation or ATO + ATRA +/- Mylotarg
Complete list of historical versions of study NCT00504764 on ClinicalTrials.gov Archive Site
  • Evaluate kinetics of the MDR of PML/RARa during and after ATO [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Evaluate the mortality related with postremission treatment [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Side effects of ATO and the different treatments post-consolidation [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Evaluate kinetics of the MDR of PML/RARa during and after ATO
  • Evaluate the mortality related with postremission treatment
  • Side effects of ATO and the different treatments post-consolidation
  • Overall survival
Not Provided
Not Provided
 
Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
APL-R2007: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

Summary Acute promyelocytic leukemia is defined by a characteristic morphology (AML FAB M3/M3v), by the specific translocation t(15;17) and its molecular correlates (PML/RARa and RARa/PML). Thereby it can be separated from all other forms of acute leukemia.

By all-trans retinoic acid in combination with chemotherapy cure rates of 70 to 80% can be reached. On average, about 10% of patients still die in the early phase of the treatment and about 20 to 30% relapse. Molecular monitoring of the minimal residual disease (MRD) by qualitative nested RT-PCR and quantitative REAL-time PCR of PML/RARa allows to follow the individual kinetics of MRD and to identify patients with an imminent hematological relapse.

A standardized treatment for patients with relapsed APL has not yet been established. With arsenic trioxide (ATO) monotherapy remission rates over 80% were achieved and long-lasting molecular remissions are described. The drug was mostly well tolerated. ATO exerts a dose dependent dual effect on APL blasts, apoptosis in higher and partial differentiation in lower concentrations. ATO was also successfully administered before allogeneic and autologous transplantation. ATO is approved for the treatment of relapsed and refractory APL in Europe and in the USA.

After remission induction, there are several options for postremission therapy Previous studies shows that risk of relapse is higher in patients treated with ATO postremission in monotherapy , than in other that receive ATO plus chemotherapy or transplantation (TPH). Also, compared with chemotherapy, ATO induction and consolidation has a favorable impact in posterior response to transplantation. It is due to a low toxicity or a best quality of remission to TPH. It seems better, for these reasons, the intensification with TPH (autologous or allogenic) in patients with relapsed APL treated with ATO. For another hand, patients no candidates to TPH can be treated with ATO combined with other active agents in APL, as ATRA, anthracyclines o Mylotarg

Induction ATO 0.15 mg/kg/día IV in continuous perfusion 1-2 hours/day until complete response (CR) or maximum of 60 days.

Oral hydroxyurea treatment (initial dose 2 g/day)is recommended in patients with leucocyte counts at relapse >10x109/L or in the two first weeks of induction.

Isolated molecular relapsed patients will be treated with ATO (same dose) 5 days at week, during 6 weeks.

Consolidation ATO 0.15 mg/kg/día IV 5 days at week, during 5 weeks, combined with oral ATRA 45 mg/m²/day during the same 5 weeks.

Post-consolidation therapy TPH (autologous or allogenic) in candidate patients. In case of molecular remission, is recommended autologous-TPH.

Patients no candidates to auto-TPH or alo-TPH, should will follow treatment with ATO cycles + ATRA +/- Mylotarg.

  1. Option Alo-TPH If PCR post-consolidation is negative is recommended auto-TPH. However, if alo-TPH is decided, it will be done immediately without preceding chemotherapy.

    If PCR post-consolidation is positive, should done alo-TPH.

  2. Option Auto-TPH If PCR post-consolidation is negative it will be administered one cycle of MTZ + Ara-C follow by auto-TPH.

    In cas of failure: a) if patient has autologous stem cells preserved (PCR negative) are suitable for auto-TPH; b) patients with HLA-compatible donor who are suitable for allogenic stem cell transplantation should be transplanted; c) Patients who are not eligible for allogenic or autologous transplantation, receive various cycles with ATO + ATRA combined or not with Mylotarg.

    If PCR post-consolidation is positive and patient is eligible for allogenic TPH, should be done a allogenic TPH.

    If patient is no eligible for allogenic TPH or dont has compatible donor, will be administrate one cycle of MTZ + Ara-C and collect stem cells. Autologous transplantation will be done if after this cycle, a molecular remission is obtained. No molecular remission or no enough stem cells collection, patient follows treatment with subsequent cycles of ATO + ATRA combined or no with Mylotarg.

  3. ATO + ATRA combined or no with Mylotarg Patients no eligible to autologous TPH or allogenic TPH follows treatment with subsequent cycles of ATO + ATRA combined or no with Mylotarg.

If Mylotarg is no possible, treatment will be with subsequent cycles of ATO + ATRA.

ATO + ATRA + Mylotarg: Mylotarg 6 mg/m2 day 1, ATO 0.15 mg/kg days 1 to 5 and 8 to 12, and ATRA 45 mg/m2/d days 1 to 15. Doses of mylotarg should be reduced to 3 mg/m2 in patients aged over 60 years. Administration of 3 cycles with a month interval, follow of 3 to 6 cycles of ATO + ATRA without Mylotarg. After, ATRA 45 mg/m2/d 15 days every 3 months until complete two years of maintenance.

ATO + ATRA: ATO 0.15 mg/kg days 1 to 5 and 8 to 12, and ATRA 45 mg/m2/d days 1 to 15, every 29 days. Administration of 9 cycles, and followed by ATRA 45 mg/m2/d during 15 days every 3 months until complete two years of maintenance.

Interventional
Phase 4
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Acute Promyelocytic Leukemia
  • Drug: Arsenic Trioxide

    Induction ATO 0.15 mg/kg/day IV until CR or a maximum of 60 days In isolated molecular relapse ATO will be administered at same dose, 5 days a week, during 6 weeks.

    Consolidation ATO 0.15 mg/kg/day IV 5 days week, during 5 weeks

  • Procedure: Autologous Transplantation
    Autologous Transplantation
  • Procedure: Allogenic Transplantation
    Allogenic Transplantation
  • Drug: ATRA
    Consolidation: ATRA 45 mg/m²/day oral during 5 weeks
Not Provided
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
60
July 2015
December 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • ECOG ≤ 3.
  • Patients in first or subsequent hematological or molecular relapse of APL
  • Persistence of a positive PCR (positive PCR after 3 consolidation cycles of first line therapy).
  • Diagnostic measures Confirmation of relapse by RT-PCR of PML/RARa, cytogenetics, FISH or positive PGM3.
  • Age over 18 years (No upper age limit)
  • Informed consent of the patient

Exclusion Criteria:

  • ECOG 4.
  • Heart failure NYHA grade III and IV.
  • Renal or hepatic failure WHO grade ³III
  • Positive HIV.
  • Psychological dysfunction
  • Associated active neoplasia
  • Pregnancy.
  • Arsenic Hypersensibility.
  • QTc-interval prolonged over 460 msec before therapy (normal electrolytes, no other drugs prolonging the QT-interval )
Both
18 Years and older
No
Contact: Sanz Miguel Angel, Dr 34 (96) 197 3057 msanz@uv.es
Contact: Priego Miguel, Data manager 34 635 964 539 miguepriego@gmail.com
Spain
 
NCT00504764
LAP-R2007
Yes
PETHEMA Foundation
PETHEMA Foundation
Not Provided
Study Chair: Sanz Miguel Angel, Dr Hospital La Fe
Study Chair: Esteve Jordi, Dr Hospital Clinic of Barcelona
Study Chair: Montesinos Pau, Dr Hospital general de Valencia
PETHEMA Foundation
November 2013

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