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A Randomized Trial Assessing the Role of Arsenic Trioxide and/or ATRA During Consolidation Course in Newly Diagnosed Acute Promyelocytic Leukemia (APL)


Phase 3
18 Years
N/A
Open (Enrolling)
Both
Leukemia, Promyelocytic, Acute

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Trial Information

A Randomized Trial Assessing the Role of Arsenic Trioxide and/or ATRA During Consolidation Course in Newly Diagnosed Acute Promyelocytic Leukemia (APL)


Definition: Extended description of the protocol, including information not already
contained in other fields, such as comparison(s) studied.

APL is a specific type of acute myeloid leukemia (AML) characterized by its morphology (M3
or M3v in the FAB classification), t(15;17) translocation leading to PML-RARa fusion gene,
and by a specific coagulopathy combining D.I.C., fibrinolysis and non specific proteolysis.
ATRA can differentiate APL blasts in VITRO and in vivo. The combination of ATRA and
anthracycline based chemotherapy yields CR rates greater than 90% in newly diagnosed APL.
With early introduction of anthracycline AraC chemotherapy during induction treatment, and
maintenance combining continuous 6MP and MTX to intermittent ATRA, the relapse risk in APL
therefore now appears to be in the range of 10 to 15%.

Nevertheless, 5 to 10% of the patients do not achieve CR and 10% to 15% still relapse.
Another subset of patients (5 to 7% in APL 93 trial including 17% of patients aged greater
than 65 years) die in CR, from complications of the consolidation treatment phase, mainly
from infection during chemotherapy induced aplasia. Failure to achieve CR with current
treatment approaches is almost exclusively due to early death during induction treatment.
Causes of death are predominantly bleeding, ATRA syndrome and less often infection. Early
deaths predominate in elderly patients and patients with high WBC counts. Reducing the
amount of chemotherapy administered to newly diagnosed APL patients diminishes this
toxicity. The Spanish PETHEMA group reported results of two successive phase II trials in
newly diagnosed APL with ATRA and chemotherapy with intercalating agents (idarubicin and
mitoxantrone) without AraC followed by maintenance combining ATRA and low dose chemotherapy
(LPA96 and LPA99 trials). Results appeared similar to those of the best arm of APL 93 trial,
but with less toxicity and only 2 to 3 % death in CR were seen, including in elderly
patients.

Arsenic trioxide (As2O3 or ATO) is an effective agent in relapsing or refractory APL, which
induced 85% hematological and 79% molecular CR rates in a pivotal US study. The interest of
ATO in the front-line therapy of newly-diagnosed APL has been strongly suggested in three
studies which showed high complete remission rate, low incidence of relapse and limited
toxicity.

In this study, patients will be stratified based on age (≤ 70 years and > 70 years) and WBC
count at diagnosis (WBC<10.000/mm3 and >10.000 /mm3).

-Patients aged 70 years or less with WBC<10.000/mm3.

In this population (about 70 % of APL) the best treatment group of APL2000 trial (ATRA with
early introduction of anthracycline-AraC chemotherapy but where Idarubicin will be
substituted for Daunorubicin, followed by 2 anthracycline-AraC consolidation courses and
maintenance combining continuous chemotherapy and intermittent ATRA) will be compared to the
same regimen, but without AraC during consolidation courses which will be replaced by:

- either ATO

- or ATRA It is hoped that the investigational arms will further increase the event-free
survival at 2 years, with reduced toxicity and without increasing the relapse rate by
comparison with a classical anthracycline-AraC consolidation regimen.

- Patients aged 70 years or less with WBC>10.000/mm3 Patients ages 70 years or less
with initial WBC counts > 10000/mm3 (ie very high counts for APL), which represent
about 20% of APL, remain at relatively high risk of relapse even with the current
reference treatment. The main objective of the study will be to test the addition
of ATO during consolidation courses to our current standard ATRA and chemotherapy
regimen. Patients will receive the best treatment group of APL 2000 trial (but
where Idarubicin will be substituted for Daunorubicin) with or without ATO during
the 2 consolidation cycles.

- Patients older than 70 years with WBC<10.000 /mm3. Elderly patients with initial
WBC ≤ 10000/m3 (about 8% of APL) and no contra indication to this treatment will
receive a regimen with reduced cumulative dose of chemotherapy but addition of ATO
during consolidation courses and during the first year of maintenance treatment.
The main purpose of this non randomized part of the trial is to reduce the early
death mortality and death in CR observed in elderly patients, without increasing
the relapse rate.

- Patients older than 70 years with WBC>10.000 /mm3. Elderly patients with initial
WBC > 10000/m3 (about 2 to 3% of APL) and no contra indication to intensive
regimen will receive the same regimen as those with low WBC but with moderate
doses of Aracytine during the induction and during the first consolidation course.
The main purpose of this non randomized part of the trial is to reduce the early
death mortality and death in CR observed in elderly patients, without increasing
the relapse rate.


Inclusion Criteria:



- Diagnosis of APL based on morphological grounds, which will have to be confirmed by
the presence of t(15;17) and/or PML-RARA rearrangement with characterization of the
bcr subtype (PML-RAR characterization).

- Untreated patients.

- No contraindication to intensive chemotherapy (especially well documented cardiac
contraindication to idarubicin).

- In female patients: absence of pregnancy and adequate contraceptive methods (due to
teratogenetic effects of ATRA in early pregnancy).

- Absence of Hypersensitivity to Arsenic derivatives.

- No QT interval prolongation or complete atria-ventricular block.

- Written informed consent.

Exclusion Criteria:

- Patients already treated.

- Patients with contraindication to intensive chemotherapy, especially well documented
cardiac contraindication to Idarubicin.

- In female patients: pregnancy or absence of adequate contraceptive Methods

- QT interval prolongation or complete atria-ventricular block.

- Hypersensitivity to Arsenic derivatives.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

For Patients aged 70 years or less with WBC<10.000/mm3, The primary end point will be event free survival at 2 years from CR achievement

Outcome Description:

For Patients aged 70 years or less with WBC<10.000/mm3, The primary end point

Outcome Time Frame:

during de study

Safety Issue:

Yes

Principal Investigator

Lionel ADES, MD,PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris

Authority:

France: Ministry of Health

Study ID:

P050604

NCT ID:

NCT00378365

Start Date:

October 2006

Completion Date:

September 2016

Related Keywords:

  • Leukemia, Promyelocytic, Acute
  • Acute promyelocytic leukaemia
  • ATRA
  • Idarubicin
  • Arsenic trioxide
  • Patient with a newly acute promyelocytic leukaemia (APL)
  • Unmapped MeSH term
  • Leukemia
  • Leukemia, Promyelocytic, Acute

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