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

Multiple Myeloma Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00399867
• Other study ID #: SIMVA-272/04
• Secondary ID: Simva2005272/04
• Status: Completed
• Phase: Phase 2
• First received: November 14, 2006
• Last updated: December 19, 2006
• Start date: April 2005
• Est. completion date: April 2007

Study information

• Verified date: November 2006
• Source: Ludwig-Maximilians - University of Munich
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: April 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Simvastatin

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Ludwig-Maximilians - University of Munich

References & Publications (1)

Schmidmaier R, Baumann P, Simsek M, Dayyani F, Emmerich B, Meinhardt G. The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase. Blood. 2004 Sep 15;104(6):1825-32. Epub 2004 May 25. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	antimyeloma activity as measured by the paraprotein
Primary	toxicity of simvastatin in combination with chemotherapy
Secondary	duration of remission, event free survival, overall survival