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Simvastatin as Inhibitor of Cell Adhesion Mediated Drug Resistance in Patients With Refractory Multiple Myeloma.

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00399867
First Posted: November 15, 2006
Last Update Posted: December 20, 2006
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by:
Ludwig-Maximilians - University of Munich
  Purpose
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

Condition Intervention Phase
Multiple Myeloma Drug: Simvastatin Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by Ludwig-Maximilians - University of Munich:

Primary Outcome Measures:
  • antimyeloma activity as measured by the paraprotein
  • toxicity of simvastatin in combination with chemotherapy

Secondary Outcome Measures:
  • duration of remission, event free survival, overall survival

Estimated Enrollment: 30
Study Start Date: April 2005
Estimated Study Completion Date: April 2007
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 cytokines,upregulation 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 11g/dl, 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: 1.3 mg/m2 d1,4,8,11) or bendamustin (one cycle: 100 mg/m2 d1+2) 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).

  Eligibility

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • proven multiple myeloma,
  • refractory to ongoing chemotherapy (bortezomib,
  • bendamustin dexamethasone),
  • measurable paraprotein,
  • serum protein below 11 g/dl,
  • age over 18 years,
  • life expectancy greater 6 months,
  • contraception in women,
  • expected compliance,
  • written consent

Exclusion Criteria:

  • severe heart failure,
  • not controlled hypertension or diabetes,
  • risk factors for rhabdomyolysis,
  • creatinin kinase below 30ml/min,
  • active liver disease,
  • myopathy,
  • allergy to simvastatin,
  • pregnancy,
  • acute infectious disease
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00399867


Sponsors and Collaborators
Ludwig-Maximilians - University of Munich
Investigators
Principal Investigator: Bertold Emmerich, MD, PhD Medizinische Klinik Innenstadt, University Munich
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00399867     History of Changes
Other Study ID Numbers: SIMVA-272/04
Simva2005
272/04
First Submitted: November 14, 2006
First Posted: November 15, 2006
Last Update Posted: December 20, 2006
Last Verified: November 2006

Keywords provided by Ludwig-Maximilians - University of Munich:
multiple myeloma
refractory
cell adhesion mediated drug resistance

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Tissue Adhesions
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cicatrix
Fibrosis
Pathologic Processes
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors