Myelodysplastic syndrome, Tipifarnib (ZARNESTRA), Bortezomib (VELCADE).
Conditions
Interventions
A phase I clinical trial in which the study subjects with MDS will receive 4 courses consisting of:
1. Starting cohort: Cohort 1: Cohort of 3 patients with a four-weekly cycle of ZARNESTRA 200 mg bid
2. Cohort 2: Cohort of 3 patients with a four-weekly cycle of ZARNESTRA 200 mg bid (days 1-21) combined with VELCADE 1.3 mg/m2/day intravenously on days 8, 15, and 22 every 4 weeks
3. Cohort 3: 2 parallel cohorts of 6 patients each with a 4-weekly cycle of ZARNESTRA 200 mg bid (days 1-21) combined with VELCADE 1.6 mg/m2/day intravenously on days 8, 15, and 22 every 4 weeks versu
4. Cohort –1, consisting of 3 patients with a four-weekly cycle of ZARNESTRA 200 mg bid (days 1-14) combined with VELCADE 1.0 mg/ m2/day on days 8, 15, and 22 every 4 weeks. This cohort will start if
5. Cohort –2, consisting of 3 patients with a four-weekly cycle of ZARNESTRA 200 mg bid (days 1-14) combined with VELCADE 0.7 mg/ m2/day on day 8,15 and 22 every 4 weeks. This cohort will start if in
Sponsors
Radboud University Nijmegen Medical Centre
Eligibility
Inclusion criteria
Inclusion criteria: 1. MDS (including the non-proliferative form of CMML, i.e. CMML with a WBC count 18 years; 4. WHO performance status 0-2; 5. Receiving no treatment for MDS other than supportive care.
Exclusion criteria
Exclusion criteria: 1. IPSS: Low risk and Intermediate-1 category; 2. Candidates for allogeneic stem cell transplantation; 3. Having received a stem cell transplantation (allogeneic or autologous); 4. Vitamine B-12 and folic acid deficiency; 5. HIV-1 positivity; 6. Has known or suspected hypersensitivity or intolerance to VELCADE or ZARNESTRA, or heparin or to Boron or Mannitol; 7. Clinically relevant liver (AST/ALT > 1.5 ULN and bilirubin > 2 mg/dl) or renal insufficiency (ECC <50%); 8. Significant, vascular, pulmonary, gastrointestinal, endocrine, rheumatologic, or metabolic disturbances; 9. Uncontrolled diabetes (if receiving anti-diabetic agents, subjects must be on a stable dose for at least 3 months before first dose of study drug); 10. Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure (Attachment 5, NYHA Classification of Cardiac Disease), uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis; 11. Pregnant or breastfeeding; 12. Peripheral neuropathy or neuropathic pain Grade 2 or higher as defined by NCI CTCAE version 3; 13. Receipt of extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy within 8 weeks before enrollment; 14. Serious medical or psychiatric illness likely to interfere with participation in this clinical study; 15. Use of enzyme-inducing anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine). Use of valproate because it acts as a histone deacetylase inhibitor. However, subjects may use other non-enzyme inducing anticonvulsants such as gabapentin or topiramate; 16. Necessity of immunosuppressive drugs, anti-apoptotic agents other than Velcade or Zarnestra, systemic corticosteroids or systemic retinoids, or any cancer therapy other than Velcade or Zarnestra during the treatment portion of this study; 17. Prior exposure to farnesyltransferase inhibitors or proteasome inhibitors; 18. Have received an experimental drug or used an experimental medical device within 8 weeks before the planned start of treatment. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study; 19. Hematopoietic growth factor therapy or other disease modulating therapy, including the chronic use of systemic corticosteroids or any use of systemic retinoids within 8 weeks before randomization; 20. Known allergy to imidazol derivatives such as clotrimazole, ketoconazole, miconazole, econazole, fenticonazole, isoconazole, sulconazole, ticonazole or terconazole; 21. Pregnant or lactating females 22. Having a desire to have children.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 1. Erythroid response according to revised IWG criteria (Cheson, 2006); 2. Platelet response according to revised IWG criteria; 3. Neutrophil response according to revised IWG criteria; 4. Marrow response in terms of complete remission, partial remission, stable disease, failure, relapse or disease progression according to revised IWG criteria; 5. Cytogenetic response according to revised IWG criteria; 6. Duration of hematological (erythroid, platelet and neutrophil), marrow and cytogenetic response and improvement; 7. Progression or transformation to leukemia according to FAB classification; 8. Time to relapse after complete remission, partial remission, stable disease, failure, relapse, disease progression or AML transformation (according to revised IWG criteria), censored at death; 9. Survival. | — |
Contacts
Public ContactTrial Data Center
Radboud University Nijmegen Medical Centre Department of Haematology 489 Theodoor Craanenlaan 1
Outcome results
None listed