To determine if the addition of midostaurin to daunorubicin/ cytarabine induction, high dose cytarabine consolidation, and continuation therapy improves overall survival (OS) in both the mutant FLT3-ITD and FLT-3 TKD AML patients.
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall survival (OS) in the mutant AML FLT3-ITD and the FLT3-TKD patients is
the primary endpoint. The OS time is the period from the date of registration
in the study until death by any cause.
Secondary outcome
Four secondary endpoints will be analyzed in this study:
1) Complete response (CR) rate in the remission induction stage of the study
2) event- free survival (EFS)
3) disease- free survival (DFS)
4) the DFS rate one year after completing the planned continuation phase
Background summary
Previously untreated patients with AML under 60 years of age overall are
treated with inductionchemotherapy with an anthracycline and cytarabine,
followed by consolidation therapy with high-dose cytarabine (HiDAC). In this
age group, an overall complete response (CR) rate of 65% to 80% can be
expected. However, presence of the FLT3 mutation in AML patients (of any age)
is poor prognostic factor. In these patients an equivalent CR rate is achieved,
however the relapse rate, disease free survival (DFS), event free survival
(EFS) en overall survival (OS) at 5 years are significantly worse.
Midostaurin (PKC412) blocks an enzyme, produced by a gene known as FLT3, that
may have a role in the survival and growth of AML cells. The addition of a
targeted agent against FLT3 offers the possibility for significant therapeutic
advantage in AML patients expressing FLT3.
Study objective
To determine if the addition of midostaurin to daunorubicin/ cytarabine
induction, high dose cytarabine consolidation, and continuation therapy
improves overall survival (OS) in both the mutant FLT3-ITD and FLT-3 TKD AML
patients.
Study design
A phase III randomized, double blind study
Intervention
Patients will be randomly assigned to one of the two treatment groups:
Treatment 1)
A standard combination of chemotherapy drugs during remission induction
chemotherapy that includes cytarabine (or ara-C, for short), daunorubicin, and
the experimental drug midostaurin. After successfully completing remission
induction, patients will receive four courses of high-dose ara-C consolidation
chemotherapy together with the experimental drug midostaurin. Finally, after
completing remission consolidation therapy, the patients will receive
continuation therapy with midostaurin for twelve (12) months.
Treatment 2)
As of treatment 1, however instead of midostaurin the patients will receive a
placebo.
Study burden and risks
Total duration of the treatment is 18 months. Patients are followed for a
maximum of 10 years after completion of the treatment. During induction and
consolidation therapy the patient will be folowed intensively by the physician.
During continuation therapy the patient will be seen monthly. During the post
treatment follow-up the frequency of hospital visits varies between once every
2 months (year 1 and 2) to once every quarter (year 3 and 4) and yearly (other
years).
Women of childbearing potential must either commit to continued abstinence from
heterosexual intercourse or commit to two acceptable methods of birth control
(one highly effective and one additional effective method) at the same time.
This should be commenced before receiving midostaurin/placebo therapy and
continue for 12 weeks after completion of all midostaurin therapy.
Men must agree not to father a child and must use a latex condom during any
sexual contact with women of childbearing potential while taking
midostaurin/placebo and for 12 weeks after therapy is stopped, even if they
have undergone a successful vasectomy.
The following most common side effects with the use of Midostaurin have been
reported up to now:
Lowered white blood cell count/ platelet count / red blood cells
Nausea, vomiting, headache, changes in liver function tests, loss of appetite,
fever, rash, hair loss, fatigue
Risks and side effects related to bone marrow aspirations (biopsies): pain or
discomfort at the site where the needle is inserted as well as possible
bleeding, bruising or swelling. There is also a very small chance that you
could develop an infection at the site of the procedure.
A number of chemotherapy agents have a risk of causing another cancer (second
malignancy). Cytarabine, daunorubicin, and midostaurin are not known to
increase the risk of second malignancies, but may be shown at a later time to
result in the development of these second malignancies.
Raapopseweg 1
6824 DP Arnhem
NL
Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
Inclusion criteria
*Unequivocal diagnosis of AML (>20% blasts in the bone marrow based on the WHO classification), excluding M3 (acute promyelocytic leukemia).
*Documented FLT3 mutation (ITD or point mutation), determined by analysis in a protocol-designed FLT3 screening laboratory.
*Age greater than or equal to 18 years and less than 60 years.
*AML patients with a history of antecedent myelodyspasia (MDS) remain eligible for treatment on this trial, but must not have had prior cytotoxic therapy (e.g. azacitidine or decitabine).
*Bilirubin < 2.5 times upper limit of normal.
Exclusion criteria
*No prior chemotherapy for leukemia or myelodysplasia with the following exceptions:
i. emergency leukapheresis
ii. emergency treatment for hyperleukocytosis with hydroxyurea for less than or equal to 5 days
iii. cranial RT for CNS leukostasis (one dose only)
iv. growth factor/cytokine support
*Patients who have developed therapy related AML after prior RT or chemotherapy for another cancer or disorder are not eligible.
*Patients with symptomatic congestive heart failure are not eligible.
*Pregnant or nursing patients may not be enrolled
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-006852-37-NL |
| CCMO | NL24604.091.08 |