To determine the antileukemic activity of combination chemotherapy including bortezomib as reinduction therapy in childhood relapsed/refractory ALL.
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Antileukemic activity of bortezomib when added to dexamethasone and vincristine
and intrathecal methotrexate, as determined by the absolute peripheral blood
(PB) blast count on day 8 of treatment. Morphology will be centrally reviewed.
Secondary outcome
- Antileukemic activity of bortezomib when added to dexamethasone and
vincristine and intrathecal methotrexate, as determined by the absolute bone
marrow (BM) blast percentage on day 8, and BM and PB analysis on day 22 of
treatment
- Feasibility of combining bortezomib with dexamethasone and vincristine and
intrathecal methotrexate, as determined by the percentage of patients in whom
bortezomib had to be dose-reduced or withdrawn because of toxicity.
- Toxicity of bortezomib when combined with dexamethasone and vincristine and
intrathecal methotrexate, as determined by the percentage of patients suffering
from grade III/IV toxicity in any field
- Determine the feasibility of combining a second cycle of bortezomib with
combination chemotherapy, its toxicity and antileukemic activity, as measured
after 6 weeks of therapy by bone marrow, peripheral blood and cerebrospinal
fluid
Additional exploratory endpoints
- Establish pharmacokinetics of bortezomib in children. For this purpose,
levels of bortezomib will be measured in bone marrow, peripheral blood and CSF
samples obtained at several time-points as clarified in the protocol, limited
to cycle one and the first and fourth administration of bortezomib.
- Explore pharmacodynamics of bortezomib, in particular by proteasome
inhibition as measured in BM and PB. This inhibition will be correlated with
pharmacokinetic data and clinical response to bortezomib. Time-points of
sampling will be detailed in the protocol.
Background summary
Childhood relapsed or refractory acute lymphoblastic leukemia (ALL) is one of
the most frequent causes of death in pediatric oncology. The main explanation
is that in this frequent type of childhood cancer, ALL cells are significantly
more resistant to conventional chemotherapy at relapse or refractory disease.
Thereofore, innovative new drugs are needed to imrpove prognosis. Proteasome
inhibitors (such as bortezomib or Velcade®) are a novel type of drugs, and
bortezomib has received FDA and EMEA approval for treatment of multiple
myelomas. Preclinical in-vitro as well as animal studies and more recent
preliminary studies performed in the USA in childhood relapsed ALL suggest that
bortezomib can be an active drug in ALL, however, as singel agent its activityw
as limited. As it may sensitize leukemic cells for conventional chemotehrapy,
this study investigates standard combination chemotherapy for ALL combined with
bortezomib. It was shown in two phase I studies in children performed in the
USA that bortezomib can be given safely to children at doses similar to that
in adults.
Study objective
To determine the antileukemic activity of combination chemotherapy including
bortezomib as reinduction therapy in childhood relapsed/refractory ALL.
Study design
This is a multicenter, multinational, open label, comparative and randomised
phase II study on the antileukemic activity of bortezomib with conventional
combination chemotherapy in relapsed/refractory ALL in children and
adolescents. The study will include one cohort of patients with
relapsed/refractory ALL, with treatment guidelines for all patients for 3
weeks. Thereafter, bortezomib may be repeated in combination with the same
conventional chemotherapy for patients with a good initial response to
reinduction therapy. Standard reinduction chemotherapy will consist of 2 weeks
of dexamethasone plus vincristine given twice, plus intrathecal administration
of methotrexate. In addition, all patients will be treated with one cycle of
bortezomib, consisting of 4 doses in 2 weeks. They will be randomised 1:1 in 2
arms, group A getting *early* bortezomib, starting at day 1 of therapy, and
group B getting *late* bortezomib, starting at day 8. Randomisation will be
stratified for the number of circulating leukemic blasts at diagnosis.
Intervention
Bortezomib is the investigational medicinal product (IMP) in this study, and
will be supplied free-of-charge. All other drugs will be derived from
commercially available stock as part of regular treatment.
Bortezomib will be given 4 times in 2 weeks, in blocks lasting 3 weeks.
Boretzomib can eitehr be given 'early' (from day 1 onwards), or 'late' (from
day 8 onwards).
Study burden and risks
Bortezomib could safely be given to children with cancer, according to two
published pediatric phase I studies. The maximum-tolerated dose is similar to
that in adults. Thousands of adults with multiple myeloma have already been
treated with this drug, so extensive experience exists. If toxicity occurs, it
usually is reversible. The risk of this therapy therefore is acceptable,
although in combination with vincristine there may be a higher risk for
peripheral neuropathy.
The burden will mainly consist of additional testing of bone marrow (BM),
cerebrospinal fluid (CSF) and peripheral blood (PB). All the procedures
required for these studies are routine in the care of children with leukemia.
BM together with CSF sampling is being done under general anaesthesia. PB
sampling will only be done in case of the presence of a central line.
Potential benefits are that bortezomib may add to the antileukemic activity of
standard drugs, i.e. dexamethasone and vincristine. Several lines of evidence
indicate this may be the case. Patients who respond can continue treatment
including bortezomib. Finally, the efficacy of bortezomib in childhood ALL can
only be studied in that population, since the biology of childhood ALL differs
significantly from that in adults.
Dr. Molewaterplein 60
3015GJ Rotterdam
NL
Dr. Molewaterplein 60
3015GJ Rotterdam
NL
Listed location countries
Age
Inclusion criteria
- Age between 6 months and 19 years
- patients with a second or subsequent relapsed ALL
- patients with first relapsed ALL after prior allogeneic stem cell transplantation in first complete remission
- patients with refractory first relapse of ALL, as defined by the ALL relapse protocol these patienst were enrolled in
- circulating leukemic blasts of at least 100/ul peripheral blood (i.e. at least 0.1x109/l)
- patients must take adequate contraceptives when of childbearing potential
- written informed consent
Exclusion criteria
- relapse not involving bone marrow
- symptomatic CNS leukemia
- Active uncontrolled infection
- Performance status (Lansky or Karnofsky score) of 60% or less
- Life expectancy of less than 6 weeks
- Existing peripheral neuropathy NCI grade 2 or higher
- Presence of acute diffuse infiltrative and/or pericardial disease
- Existing clinical signs of cardiotoxicity
- Previous allogeneic stem cell transplantation within 100 days
- Pregnant or breastfeeding
- Other contra-indications for chemotherapy, including no recovery from previous treatment
- Previous exposure to bortezomib
- other experimental or conventional antileukemic treatment within 7 days from start of bortezomib
- allergy to boron and its metabolites
- no concomitant anti-leukemic therapy other than according to this 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 | EUCTR2009-014037-25-NL |
| CCMO | NL29173.078.09 |