Phase III Study of Chemotherapy in Combination With ATRA With or Without Gemtuzumab Ozogamicin in Patients With Acute Myeloid Leukemia and NPM1 Gene Mutation
18 Years
N/A
Both
Acute Myeloid Leukemia
Trial Information
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.
Inclusion Criteria:
- Patients with confirmed diagnosis of acute myeloid leukemia according to the World
Health Organization (WHO) classification.
- Presence of NPM1 mutation as assessed in one of the central AMLSG reference
laboratories.
- Age ≥ 18 years. There is no upper age limit.
- No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if
needed for up to 5 days during the diagnostic screening phase.
- Non-pregnant and non-nursing. Women of childbearing potential (WOCBP) must have a
negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL
within 72 hours prior to registration.
- Female patients in the reproductive age and male patients must agree to avoid getting
pregnant or to father a child while on therapy and within one year after the last
dose of chemotherapy.
- Women of child-bearing potential must either commit to continued abstinence from
heterosexual intercourse or begin two acceptable methods of birth control: one
highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's
vasectomy), and one additional effective method (e.g., latex condom, diaphragm,
or cervical cap).
- "Women of childbearing potential" is defined as a sexually active mature woman
who has not undergone a hysterectomy or who has had menses at any time in the
preceding 24 consecutive months.
- Men must use a latex condom during any sexual contact with women of childbearing
potential, even if they have undergone a successful vasectomy.
- Signed written informed consent.
Exclusion Criteria:
- AML with other recurrent genetic changes (according to WHO 2008):
- AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
- AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
- AML with t(15;17)(q22;q12); PML-RARA (or other translocations involving RARA)
- AML with t(9;11)(p22;q23); MLLT3-MLL (or other translocations involving MLL)
- AML with t(6;9)(p23;q34); DEK-NUP214
- AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1.
- Performance status WHO > 2.
- Patients with ejection fraction < 50% by MUGA or ECHO scan within 14 days of day 1.
- Organ insufficiency:
- creatinine > 1.5x upper normal serum level
- bilirubin, AST or ALP > 2.5x upper normal serum level, not attributable to AML
- heart failure NYHA III/IV
- severe obstructive or restrictive ventilation disorder.
- Uncontrolled infection.
- Severe neurological or psychiatric disorder interfering with ability of giving an
informed consent.
- Patients with a "currently active" second malignancy other than non-melanoma skin
cancers. Patients are not considered to have a "currently active" malignancy if they
have completed therapy and are considered by their physician to be at less than 30%
risk of relapse within one year.
- Known positive for HIV.
- Bleeding disorder independent of leukemia.
- No consent for registration, storage and processing of the individual
disease-characteristics and course as well as information of the family physician
about study participation.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Event-free Survival (EFS)
Outcome Time Frame:
two years
Safety Issue:
No
Principal Investigator
Richard F Schlenk, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
University of Ulm
Authority:
Germany: Federal Institute for Drugs and Medical Devices
Study ID:
AMLSG 09-09
NCT ID:
NCT00893399
Start Date:
February 2010
Completion Date:
February 2016
Related Keywords:
- Acute Myeloid Leukemia
- adult patients
- NPM1 mutation
- Leukemia
- Leukemia, Myeloid, Acute
- Leukemia, Myeloid
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