Primary objectivesPart A of the study (if applicable):1. To assess the safety and tolerability of tosedostat added to standard induction chemotherapy for AMLand select the feasible dose level for part B of the study2. To assess in a randomized…
ID
Source
Brief title
Condition
- Leukaemias
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A:
DLT of tosedostat at three dose levels (120mg, 180mg and 240mg) added to
standard chemotherapy
DLT is defined as: Death within 31 days of start cycle I
Part B:
To assess in a randomized comparison the effect of the in Part A selected dose
of tosedostat on the CR
rate.
Secondary outcome
Part B
- Overall survival (time from registration till the death of the patient.)
- Event free survival (i.e., time from registration to induction failure (i.e.
no CR on induction), death or
relapse whichever occurs first)
- Disease free survival (time from CR on protocol treatment until relapse or
death, whichever comes first)
- Prognostic value of molecular markers and gene expression profiles of the
leukemia assessed at
diagnosis
- Prognostic value of minimal residual disease (MRD) measurements following
therapy by standardized
sampling of marrow/blood
Background summary
HOVON/SAKK Cooperative groups concentrate their developmental therapeutic
efforts for the 66+ yrs age
segment of AML patients and very poor risk AML of any age, on developing
effective treatments for these
patients, for whom current treatment in spite of active clinical research has
remained highly
unsatisfactory. Therefore new treatment modalities are introduced and evaluated
in combination with
standard chemotherapy. For this an approach is chosen with multiple parallel
randomized phase II studies
that will be conducted within the frame of a master protocol.
This will allow for introducing and evaluating new treatment modalities in
combination with standard
chemotherapy.
In this randomized Phase II study tosedostat is added to the standard
chemotherapy for remission
induction therapy of adults of age 66 years or older with acute myeloid
leukaemia(AML), refractory anemia
with excess of blasts(RAEB) with International Prognostic Score System (IPSS)>+
1.5 or patients< 66
year with very poor risk AML. The aim of this study is to examine whether the
addition of tosedostat to
standard chemotherapy is feasible and whether the percentage of patients
achieving a Complete
Remission is promising enough as compared to the control arm to start a Phase
III study. Tosedostat is
given orally in addition to daunorubicin and cytosin-arabinoside in cycle I and
to cytosin-arabinoside in
Cycle II during day 1-21. In the first part A of the study the feasibility of
three dose levels (10,15,20mg)
will be compared to the treatment without tosedostat in a randomized design. In
the second part of the
study the assigned dose will be tested compared to the control arm with CR as
primary endpoint.
Study objective
Primary objectives
Part A of the study (if applicable):
1. To assess the safety and tolerability of tosedostat added to standard
induction chemotherapy for AML
and select the feasible dose level for part B of the study
2. To assess in a randomized comparison the effect of tosedostat on the CR rate.
Part B of the study:
1. To assess the safety and tolerability of tosedostat added to standard
induction chemotherapy for AML
as regards the selected dose level of tosedostat
2. To assess in a randomized comparison the effect of the in Part A selected
dose of tosedostat on the
CR rate.
Secondary objectives
For part B:
1. To determine the efficacy profile (event free survival and disease free
survival and overall survival)
associated with the two therapy regimens.
2. To measure MRD by immunophenotyping in relation to clinical response
parameters.
3. To identify potential biomarkers predictive of response, event free survival
and disease free survival.by
exploratory genomic analysis (microarray, gene mutations)
Study design
This is a prospective, open label, multicenter study that is conducted in the
frame of a masterprotocol with
multiple parallel randomized phase II studies. The scheme of this design
consists of one arm with the
standard treatment for AML as compared to various arms with experimental
treatments. Patients in this
study are treated with standard induction chemotherapy with or without
lenalidomide. During the first part
A of the studies the feasibility of combining lenalidomide with DNR/Ara-C will
be evaluated and the dose of
lenalidomide will be selected. Decisions regarding dose escalation,
continuation with starting dose level or
stopping, are based on the incidence of DLT (dose limiting toxicity: death
within 31 days of start cycle I
and before start cycle II .) During part B of the study that will be conducted
with the selected dose of the
added new drug, the CR rate (primary endpoint) and secondary endpoints (EFS,
DFS, OS, as well as MRD
and genomic profiling) will be assessed.
Intervention
In the experimental arm tosedostat will be added to the standard daunorubicin
?cytarabin-arabinoside
in cycle I and to cytarabine-arabinoside in cycle II
The study starts at dose level 120mg orally days 1-21 in cycle I and on days
1-56 in cycle II. If possible the dose will be escalated to 240mg. At
each dose level the decision to stop or escalate will be made on the basis of
the incidence of DLT defined
as Death within 31 days of start cycle I and before start cycle II.
Study burden and risks
The addition of tosedostat can increase the possibilities of toxicities.
Tosedostat has been given as
monotherapy and not with this peticular antileukemic standard chemotherapy
regimen. So unexpected toxicities are possible.
Tosedostat is associated with myelosuppression and other toxicities like
fatigue, diarhea en peripheral edema. Besides these toxicities, skin rash,
nausea, infections en other complaints are described that are probably more
related to the underlying disease than the medication, like cardiac
arrhythmias, fever and dizziness.
At time of the normal bone marrow punctions a limited amount of extra bone
marrow will be collected via the same needle. This is abouth 30 ml at start and
10 ml at follow up .
With regards to the patients that participate in the pharmacokinetic studies:
For measuring the concentration of tosedostat daunorubicine and cytarabine in
blood, extra blood will be collected on
days 1, 2, 3, 22 and 23 of cycle 1 via a special infusion needle at several
timepoints. The total amount of blood to be
collected is about 280 ml.
De Boelelaan 1117
Amsterdam 1007 MB
NL
De Boelelaan 1117
Amsterdam 1007 MB
NL
Listed location countries
Age
Inclusion criteria
· Patients eligible for standard chemotherapy.
· Patients >= 66 years with a cytopathologically confirmed diagnosis according WHO
classification of
o AML (not APL) or
o refractory anemia with excess of blasts (RAEB) with
an IPSS score >= 1.5
OR
Patients of any age >= 18 years with a cytopathologically confirmed diagnosis
according WHO classification of
o AML with very poor risk AML
· Subjects with secondary AML progressing from antecedent (at least 4 months
duration) myelodysplasia are also eligible.
· SGOT (AST) and SGPT (ALT) <= 1.5 x the upper limit of the normal range (ULN) at
the laboratory where the analyses were performed.
· Total serum bilirubin level <= 1.5 x the ULN at the laboratory where the analysis
was performed.
· Serum creatinine concentration <= 1.5 x the ULN at the laboratory where the
analysis was performed.
· WHO performance status <= 2
· Written informed consent.
· Female patients of childbearing potential must have a negative serum pregnancy
test within 2 weeks prior to enrollment.
· Male and female patients must use an effective contraceptive method during the
study and for a minimum of 6 months after study treatment
Exclusion criteria
· Acute promyelocytic leukemia
· Patients previously treated for AML (any antileukemic therapy including
investigational agents), a short treatment period (< 2 weeks) with Hydroxyurea is
allowed
· Past or current history (within the last 2 years prior to randomization) of
malignancies except for the indication under this study and curatively treated:
* Basal and squamous cell carcinoma of the skin
* in situ carcinoma of the cervix
· Blast crisis of chronic myeloid leukemia
· Clinically significant (i.e. active) cardiovascular disease, for example
cerebrovascular accidents (<= 6 months prior to randomization), myocardial
infarction (<= 6 months prior to randomization), unstable angina, New York Heart
Association (NYHA) grade II or greater congestive heart failure
· Patients with a history of non-compliance to medical regimens or who are
considered unreliable with respect to compliance
· Patients with any serious concomitant medical condition which could, in the
opinion of the investigator, compromise participation in the study.
· Patients who have senile dementia, mental impairment or any other psychiatric
disorder that prohibits the patient from understanding and giving informed
consent.
· Pregnant or lactating patients.
· Current concomitant chemotherapy, radiation therapy, or immunotherapy other
than as specified in the protocol.
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 | EUCTR2009-014455-68-NL |
| CCMO | NL30483.078.09 |