Phase III Study of Chemotherapy in Combination With ATRA With or Without Gemtuzumab Ozogamicin in Patients With Acute Myeloid Leukemia and NPM1 Gene Mutation
5.2.1. Choice of Standard Regimen
The protocol is based on the previous front line AMLSG protocols: AMLHD93 [50], AMLHD98A
[51], AMLHD98B [22], AMLSG 06-04 [52], AMLSG 07-04 [30]. In all these trials induction
therapy consisted on a combination of standard-dose cytarabine in combination with the
anthracycline idarubicin and the epipodophyllotoxin etoposide. The regimen is abbreviated
with ICE. Based on overall good results with ICE in terms of achievement of CR and, in
particular, the fact, that NPM1mut was established as a favourable predictive factor for
achievement of a complete remission after an induction therapy with ICE [13,16] the
chemotherapeutic components in the induction therapy of the AMLSG 09-09 protocol have
remained unchanged. As outlined in section 3.3, ATRA showed favourable results in NPM1mut
AML in one retrospective analysis of a randomized study [13] and in one interim analysis of
an active prospective randomized trial [30]. Since it is not possible to await the final
results of the AMLSG 07-04 protocol before start of the current AMLSG 09-09 protocol ATRA is
incorporated in both arms of the study based on the favourable clinical results in the
absence of additional ATRA-related toxicity.
Postremission therapy is based on repetitive cycles of HDAC as a standard therapy in
patients with normal karyotype AML [48,53]. Results of the German-Austrian AMLSG suggest
that two cycles of HDAC - in combination with an anthracycline or mitoxantrone - may be
equally effective [16]. In the current study, three courses of postremission with HDAC will
be given according to the preceding AMLSG 07-04 protocol for comparability [30].
5.2.2. Choice of Study Design
A standard two-arm randomized phase-III study design was chosen because all components and
additionally the combinations of treatment regimens had been evaluated in dosage and
efficacy in several phase II/III trials [13,16,22,30,34,52]. Based on these studies efficacy
and toxicity of the standard arm of the study is well established. The addition of GO to
induction and consolidation therapy in NPM1mut AML seems to be reasonable based on the
consistent association of NPM1mut AML with a characteristic immunophenotype, i.e., low or
absent CD34 expression and strong CD33 expression [7-11]. Due to the constitutional high
CD33 expression and potential efficacy in that high expression was correlated to high
response rates [33], GO represents a potentially highly effective agent in the treatment of
patients with NPM1mut AML. The combination of GO in a dosage of 3mg/m² to intensive
induction and consolidation treatment [32] as well as in combination with intensive salvage
therapy including ATRA [34] has been demonstrated to be save and well tolerated.
Interventional
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Event-free Survival (EFS)
two years
No
Richard F Schlenk, MD
Principal Investigator
University of Ulm
Germany: Federal Institute for Drugs and Medical Devices
AMLSG 09-09
NCT00893399
February 2010
February 2016
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