To assess the safety of treatment with escalating dosages of VELCADE in combination with ZARNESTRA in subjects with Intermediate-2 or high risk MDS according to the IPSS classification.
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety (type, frequency, and severity [National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) version 3.0] of adverse events,
and relationship of adverse events to VELCADE in combination with ZARNESTRA)
Secondary outcome
1) Effectivity in terms of hematologic improvement, number of patients with a
complete or partial response of stable disease, number of patients with a
cytogenetic response (all defined according to revised International Working
Group Criteria)
2) Effects of bortezomib and tipifarnib on ubiquitine and proteasome pathways
and apoptotic gene expression profiles (translational research)
Background summary
The myelodysplastic syndromes (MDS) form a heterogeneous group of clonal stem
cell disorders characterized by peripheral cytopenias and dysplastic features
in blood and bone marrow. Prognosis can be expressed in the International
Prognostic Scoring System (IPSS) score. Patients with a intermediary-2 or high
risk MDS have worse survival and a relatively high risk of developing acute
myeloid leukemia (AML). Current treatment in selected, mostly younger patients,
consists of intensive chemotherapy, sometimes followed by stem cell
transplantation. Patients for whom this treatment is too toxic will receive
supportive care. Tipifarnib is a farnesyl transferase inhibitor, which inhibits
farnesylation of the RAS protein, so that RAS is impaired in its function. In
MDS, RAS is sometimes mutated, which leads to cell proliferation and inhibition
of apoptosis. Tipifarnib treatment patients with MDS has resulted in a complete
response in some patients with MDS. Bortezomib is a proteasome inhibitor, wich
results in apoptosis induction, among others. Because of the functional
characteristics of tipifarnib and bortezomib, we may see a synergistic action
of this combination in MDS patients. We expect this combination to be less
toxic than intensive chemotherapy and/or stem cell transplantation.
Study objective
To assess the safety of treatment with escalating dosages of VELCADE in
combination with ZARNESTRA in subjects with Intermediate-2 or high risk MDS
according to the IPSS classification.
Study design
A phase 1 single center study. 3 patients will be included in 3 sequential
cohorts in which escalating dosages of the combination of bortezomib and
tipifarnib will be studied. In the 3rd cohort, 12 patients will be randomized.
A higher dose of tipifarnib and a lower dose of bortezomib will be compared
with a lower dose of tipifarnib and a higher dose of bortezomib.
Patients will receive 4 cycles of 4 weeks with in each cycle tipifarnib orally
on day 1-21 and 3 weekly injections of bortezomib. At the start of each cycle,
response will be evaluated by laboratory results and a bone marrow aspirate. In
case of disease progression, therapy will be discontinued. In case of a partial
respons after 4 cycles, or a complete response after 3 or 4 cycles, 2
additional cycles may be given.
If a patient experiences a grade 3-4 (according to CTCAE) study related
toxicity, his cohort will be expanded with 3 additional patients. If no
additional patients experience a grade 3-4 study related toxicity,
dose-escalation may continue in the next cohort, which may start only after two
cycles have been evaluated in the previous cohort. If a grade 3-4 toxicity
occurs, dose reductions will take place within individual patients as defined
in the protocol.
Intervention
Treatment with escalating dosages of VELCADE in combination with ZARNESTRA in 4
to 6 cycles of 4 weeks.
Study burden and risks
Patients will come to the hospital once weekly during treatment. Adverse events
and laboratory samples will be collected to monitor toxicity and response and
patients will receive bortezomib intravenously. At screening, at the end of
treatment and every 4 weeks during treatment, a physical examination and a bone
marrow aspiration will be performed. At screening, a bone marrow biopsy will be
taken. The most common risks of Velcade are fatigue, neuropathy,
myelosuppression and gastro-intestinal discomforts such as constipation and
nausea. Tipifarnib has the same risks, except for neuropathy, which does occur
but less frequently and less serious. The combination of Tipifarnib and
Bortezomib may have a synergistic effect in effectivity but possibly also in
toxicity.
Geert Grooteplein zuid 10
6525 GA
Nederland
Geert Grooteplein zuid 10
6525 GA
Nederland
Listed location countries
Age
Inclusion criteria
MDS (including the non-proliferative form of CMML, i.e. CMML with a WBC count < 12,0 x 109) /L with < 30% blast cells in the bone marrow and with < 5% circulating blasts).
IPSS score: Intermediate Risk-2 or High Risk
Age at the time of obtaining informed consent 18 years or older
WHO performance status 0-2
Exclusion criteria
IPSS score: low risk and intermediate-1 category.
Candidates for allogeneic stem cell transplantation.
Clinical relevant liver (AST/ALT equal to or higer than 1,5 ULN and bilirubin equal to or higher than 2 mg/dl) or renal insufficiency (ECC < 50 %).
Significant vascular, pulmonary, gastrointestinal, endocrine, rheumatologic, or metabolic disturbances.
Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment.
Receipt of extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy within 8 weeks before enrollment.
Having received a stem cell transplantation.
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 | EUCTR2006-004588-68-NL |
| CCMO | NL13820.091.06 |