Ignite Creation Date:
2024-05-05 @ 5:08 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00399867
Status:
COMPLETED
Last Update Posted:
2006-12-20
First Post:
2006-11-14
Brief Title:
Simvastatin as Inhibitor of Cell Adhesion Mediated Drug Resistance in Patients With Refractory Multiple Myeloma
Sponsor:
Ludwig-Maximilians - University of Munich
Organization:
Ludwig-Maximilians - University of Munich
Study Overview
Official Title:
Determination of the Efficacy and Feasibility of Simvastatin as Inhibitor of Cell Adhesion Mediated Drug Resistance in Patients With Refractory Multiple Myeloma - a Phase II Clinical Trial
Status:
COMPLETED
Status Verified Date:
2006-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
In vitro statins inhibitors of the HMG-CoA-reductase have been shown to overcome cell adhesion mediated drug resistance at very low concentrations The purpose of the study is to investigate the in vivo efficacy of simvastatin as inhibitor of cell adhesion mediated drug resistance Patients refractory to ongoing chemotherapy will receive concomitantly simvastatin and response will be monitored by paraprotein levels
Detailed Description:
Multiple Myeloma MM is an incurable haematological neoplasm that is characterized by homing survival and proliferation of malignant antibody producing plasma cells in the bone marrow All clinically relevant symptoms cytopenia hyperproteinemia and proteinuria with renal insufficiency hypercalcemia osteolysis are due to the aggressive infiltration of the whole bone marrow by MM cells while all other solid and lymphoid organs including the peripheral blood are normally spared From these clinical observations and from many preclinical studies it is evident that adhesion of MM cells to the bone marrow cells characterizes the biology of this disease Adhesion of MM cells leads to the secretion of stimulatory cytokinesupregulation of adhesion molecules proliferation of MM cells and drug resistance
Statins like simvastatin inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A HMG-CoA reductase which catalyzes the conversion of HMG-CoA to mevalonate Interestingly in MM models statins induce apoptosis inhibit proliferation overcome primary and secondary drug resistance and synergize with cytotoxic drugs Oligonucleotide microarray analyses demonstrated that de novo and acquired drug resistance are associated with an increase of HMG-CoA reductase gene expression We have shown before that adhesion of MM cells to bone marrow stromal cells mediates strong multidrug resistance and that this can be overcome by co-treatment with simvastatin in non-toxic concentrations Interestingly statin induced apoptosis in MM cells is not hampered by adhesion to bone marrow stromal cells
Based upon these comprehensive preclinical findings clinical trials to investigate the in-vivo antimyeloma activity of statins are urgently needed Our in vitro studies demonstrated that inhibition of cell adhesion mediated drug resistance by simvastatin is possible at low concentrations of about 1µM We therefore suggested that cell adhesion mediated drug resistance can be treated with approved doses of simvastatin 80mg daily Consequently we initiate a pilot phase II trial to investigate feasibility and clinical effects of simvastatin concomitantly with chemotherapy as preparation for a randomized trial
As the primary goal is to prove the hypothesis that simvastatin can overcome drug resistance in vivo only patients not responding to chemotherapy will be included Chemotherapy is defined as bortezomib and bendamustin as both are effective and approved drugs in the therapy of relapsed myeloma Further inclusion criteria are age over 18 years proven MM serum protein below 11gdl life expectancy 3 months and treatment indication with measurable paraprotein In the case of no change paraprotein increase less than 25 and paraprotein decline less than 50 after two cycles of bortezomib one cycle 13 mgm2 d14811 or bendamustin one cycle 100 mgm2 d12 the patients will receive two further cycles with concomitant simvastatin treatment 80 mg daily starting two days before chemotherapy and stopping two days after chemotherapy Exclusion criteria are severe organ failure and risk factors for rhabdomyolysis untreated hypothyroidism active liver disease terminal renal insufficiency acute infectious disease myopathy heriditary myopathy in the family history alcohol abuse comedication with itraconazole ketoconazole erythromycin clarithromycin HIV protease inhibitors nefazodone cyclosporine fibrates niacin amiodarone verapamil
Statins like simvastatin inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A HMG-CoA reductase which catalyzes the conversion of HMG-CoA to mevalonate Interestingly in MM models statins induce apoptosis inhibit proliferation overcome primary and secondary drug resistance and synergize with cytotoxic drugs Oligonucleotide microarray analyses demonstrated that de novo and acquired drug resistance are associated with an increase of HMG-CoA reductase gene expression We have shown before that adhesion of MM cells to bone marrow stromal cells mediates strong multidrug resistance and that this can be overcome by co-treatment with simvastatin in non-toxic concentrations Interestingly statin induced apoptosis in MM cells is not hampered by adhesion to bone marrow stromal cells
Based upon these comprehensive preclinical findings clinical trials to investigate the in-vivo antimyeloma activity of statins are urgently needed Our in vitro studies demonstrated that inhibition of cell adhesion mediated drug resistance by simvastatin is possible at low concentrations of about 1µM We therefore suggested that cell adhesion mediated drug resistance can be treated with approved doses of simvastatin 80mg daily Consequently we initiate a pilot phase II trial to investigate feasibility and clinical effects of simvastatin concomitantly with chemotherapy as preparation for a randomized trial
As the primary goal is to prove the hypothesis that simvastatin can overcome drug resistance in vivo only patients not responding to chemotherapy will be included Chemotherapy is defined as bortezomib and bendamustin as both are effective and approved drugs in the therapy of relapsed myeloma Further inclusion criteria are age over 18 years proven MM serum protein below 11gdl life expectancy 3 months and treatment indication with measurable paraprotein In the case of no change paraprotein increase less than 25 and paraprotein decline less than 50 after two cycles of bortezomib one cycle 13 mgm2 d14811 or bendamustin one cycle 100 mgm2 d12 the patients will receive two further cycles with concomitant simvastatin treatment 80 mg daily starting two days before chemotherapy and stopping two days after chemotherapy Exclusion criteria are severe organ failure and risk factors for rhabdomyolysis untreated hypothyroidism active liver disease terminal renal insufficiency acute infectious disease myopathy heriditary myopathy in the family history alcohol abuse comedication with itraconazole ketoconazole erythromycin clarithromycin HIV protease inhibitors nefazodone cyclosporine fibrates niacin amiodarone verapamil
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 27204 | None | None | None |
| Simva2005 | None | None | None |