Primary objectivesFor part A of the study: -To determine the feasibility of Clofarabine when given at three possible dose levels together with standard induction cycles I and II in patients with AML/ RAEB with IPSS>=1.5 in a prospective…
ID
Source
Brief title
Condition
- Leukaemias
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A of the study:
Occurrence of DLT and duration of myelosuppression of the combination of
Clofarabine at three selected dose levels.
DLT is defined as
- Death
- Any non hematological toxicity CTCAE grade >= 4,
occurring within 30 days after start of cycles I or II and before the start of
the next cycle or a new treatment respectively.
The duration of myelosuppression is defined as the median time to recovery of
ANC > 0.5x109/L.
DLT and myelosuppression will be used in the decision process for dose
escalation, dose reduction and/or dose dose selection (see 17.1).
Part B of the study:
Event-free survival (EFS) (i.e., time from registration to induction failure,
death or relapse whichever occurs first).
Secondary outcome
Part A of the study:
Response and especially CR to chemotherapy cycles I and II
Part B of the study:
- Response and especially CR (including Cri) to chemotherapy cycles I and II
- Overall survival (OS) measured from the time of registration
- Disease-free interval (duration of the first CR) measured from the time of
achievement of CR to day of relapse or death from any cause (whichever occurs
first).
- Occurence of toxicities and treatment related mortality
- Time to hematopoietic recovery (ANC 0.5 and 1.0x109/L; platelets 50 and
100x109/L) after each treatment cycle.
- Number of platelet transfusions and last day of platelet transfusion after
each cycle.
Background summary
In this phase III study the new drug Clofarabine is added to the standard
chemotherapy
for remission induction therapy of adults age below 65 years, with acute
myeloid leukemia (AML) or
refractary anemia with excess of blasts (RAEB) with International Prognostic
Score System (IPSS) >=1.5.
The aim of this study is to examine whether the treatment outcome improves by
adding clofarabine.
Clofarabine is an drug that, if given as single medication to AML patients with
no further
treatment options, induces remissions (600 mg/m2).
In this study clofarabine is given in combination with the standard
chemotherapy consisting of cytarabine en idarubicine (cycle 1) and cytarabine
and amsacrine (cycle 2). Clofarabine is given on days 1-5 of the cycle in a 1
hour infusion. In the first part A of the study the feasebility of three dose
levels of clofarabine (10, 20, 15 mg/m2 for 5 days) will be
examined compared to the treatment without clofarabine in a randomized design.
In the study a risk analyses will be performed based on hematological,
clinical, cytogenetic and molecular data on which the choice for postremission
treatment is based (additional chemotherapy, autologous stem cell
transplantation or allogeneic stem cell
transplantation). Further, genexpression profiling analyses on leukemic cells
will be done and minimial
residual disease measurements at previously defined timepoints to be able to
correlate the effect of
therapy on these parameters afterwards.
Study objective
Primary objectives
For part A of the study:
-To determine the feasibility of Clofarabine when given at three possible dose
levels together with standard induction cycles I and II in patients with AML/
RAEB with IPSS>=1.5 in a prospective comparison to standard induction cycles I
and II without Clofarabine.
For part B of the study:
-To evaluate the effect of Clofarabine at the selected feasible dose level when
combined with remission induction chemotherapy cycles I and II as regards
clinical outcome (*event-free survival*) in comparison to remission induction
cycles I and II with no addition of Clofarabine in a phase III study.
Secondary objectives
For part A of the study:
- To investigate the clinical efficacy of Clofarabine in combination with
remission induction chemotherapy cycles I and II with regard to complete
remission rate at different dose levels of Clofarabine.
For part B of the study:
- To investigate the clinical efficacy of Clofarabine with regard to the
complete remission rate, disease free survival (DFS), risk of relapse and
overall survival (OS) when combined with remission induction chemotherapy
cycles I and II in all patients.
- To investigate the clinical efficacy of Clofarabine when combined with
remission induction chemotherapy cycles I and II in molecularly and
cytogenetically distinguishable subsets with regard to the complete remission
rate, disease free survival (DFS), risk of relapse and overall survival (OS).
- To investigate the tolerance and toxicity of Clofarabine in combination with
remission induction chemotherapy cycles I and II.
- To assess the effect of Clofarabine on peripheral CD34 cell numbers for
autologous peripheral blood transplantation.
- To determine the prognostic value of molecular markers and gene expression
profiles of the leukemia assessed at diagnosis.
- To evaluate the treatment effects according minimal residual disease (MRD)
measurements following therapy by standardized sampling of marrow/blood.
- To evaluate the outcome of allogeneic sibling or unrelated donor SCT and
autologous SCT in cytogenetically and molecularly defined prognostic subgroups
of patients.
Study design
Part A: A prospective feasibility study of remission induction chemotherapy
combined with Clofarabine at a maximum of 3 dose levels (10, 15, 20 mg/m2).
Part B: Subsequent to completion of the feasibility study (part A), the value
of Clofarabine at the selected dose level when combined with standard induction
chemotherapy will be investigated in a phase III randomized study.
Intervention
In the experimental arm clofarabine administered in a 1 hours infusion at day
1-5, will be added to idarubine-cytarabine in
cycle I and to amsacrine-cytarabine in cycle II.
The study starts at a dose level of 10 mg/m2, and if possible escalating to 20
mg/m2. If 20 mg/m2 is
not feasible we return to the intermediate dose level of 15 mg/m2, and we
return to 10 mg/m2 if 15
mg/m2 is not feasible as well. At each dose level the decision to stop or
escalate will be made on the basis
of (a) the incidence of Dose Limiting Toxicities (DLTs) in the arm treated with
clofarabine versus the
incidence of DLTs in the control arm and (b) the duration of myelosuppression
in the clofarabine arm
compared to the control arm.
Study burden and risks
The addition of clofarabine can increase the possibility of toxicities.
Although clofarabine is given before
and seems to be tolerated well, possibly not all toxicities are known.
Clofarabine causes nausea and alopecia. Further it reduces the production of
blood as other
chemotherapy does.
Further toxicities of clofarabine known from previous research are liver
dysfunction.
At time of the normal bone marrow punctions at start and follow up a limited
amount of extra bone
marrow will be collected via the same needle. This is abouth 30 ml.
's Gravendijkwal 230
Rotterdam 3015 CE
NL
's Gravendijkwal 230
Rotterdam 3015 CE
NL
Listed location countries
Age
Inclusion criteria
- Age 18-65 years, inclusive
-Subjects with
-a cytopathologically confirmed diagnosis of AML according WHO classification (excluding acute promyelocytic leukaemia) or
- a diagnosis of refractory anemia with excess of blasts (RAEB) and IPSS score >=1.5 or
- patients with therapy-related AML/RAEB or
- patients with biphenotypic leukemia
- Adequate renal and hepatic function tests as indicated by the following laboratory values:
- Serum creatinine <=1.0 mg/dl (<= 88.7 micromol/L); if serum creatinine >1.0 mg/dl (>88.7 micromol/L), then the glomerular filtration rate (GFR) must be >60 ml/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where the predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine in mg/dl)^-1.154 x (age in years)^-0.203 x (0.742 if patient is female) x (1.212 if patient is black)
NOTE: if serum creatinine is measured in micromol/L, recalculate it in mg/dl according to the equation: 1 mg/dl = 88.7 micromol/L) and used above mentioned formula.
- Serum bilirubin <=1.5 × upper limit of normal (ULN)
- Aspartate transaminase (AST)/alanine transaminase (ALT) <=2.5 × ULN
- Alkaline phosphatase <= 2.5 × ULN
* WHO performance status 0, 1 or 2 (see Appendix I)
* Written informed consent
Exclusion criteria
- Acute promyelocytic leukaemia
- Previous treatment for AML or RAEB, except hydroxyurea
- Concurrent history active malignancy in two past years prior to diagnosis except for:
* basal and squamous cell carcinoma of the skin
*in situ carcinoma of the cervix
- Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera),
-Cardiac dysfunction as defined by:
* Myocardial infarction within the last 6 months of study entry, or
*Reduced left ventricular function with an ejection fraction < 50% as measured by MUGA
scan or echocardiogram (another method for measuring cardiac function is acceptable), or
- Unstable angina, or
- Unstable cardiac arrhythmias
- Pregnant or lactating females
- Unwilling or not capable to use effective means of birth control
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 | EUCTR2009-011613-24-NL |
| CCMO | NL28591.078.09 |