Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

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Brief Title

Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

Official Title

APL-R2007: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

Brief Summary

      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
    

Detailed Description

      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.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Evaluate the hematological and molecular remission rate after induction and consolidation with ATO

Secondary Outcome

 Evaluate kinetics of the MDR of PML/RARa during and after ATO

Condition

Acute Promyelocytic Leukemia

Intervention

Arsenic Trioxide


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

60

Start Date

July 2007

Completion Date

October 2014

Primary Completion Date

October 2014

Eligibility Criteria

        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 )
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Sanz Miguel Angel, Dr, , 

Location Countries

Spain

Location Countries

Spain

Administrative Informations


NCT ID

NCT00504764

Organization ID

LAP-R2007


Responsible Party

Sponsor

Study Sponsor

PETHEMA Foundation


Study Sponsor

Sanz Miguel Angel, Dr, Study Chair, Hospital La Fe


Verification Date

October 2014