Effect of Aminobiphosphonates and Statins on Circulating Vgamma9Vdelta2-T Cells

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effects of aminobiphosphonate treatment on the phenotype and function of circulating Vgamma9Vdelta2-T cells and to determine whether these effects are inhibited by simultaneous treatment with statins.

Detailed Description
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A total of 40 patients will be entered in this study. Half of the patients will receive standard intravenous treatment with aminobsiphosphonates, the other half will be additionally be treated with a statin. Patients already receiving statin treatment will continue this treatment, other patients will be asked whether they are willing to be treated with a statin for a maximum of 5 weeks. Consenting patients will be randomized to receive i.v. aminobisphosponates plus or minus simvastatin 40 mg once daily. Simvastatin will be started one week prior to the first administration of aminobisphosphonates and continued for a maximum of 5 weeks. In each patient 10 ml peripheral blood will be drawn (t=0, t=24 hr, t=1 week, t=3-4 weeks (prior to the 2nd aminobisphosphonate administration). In addition, patients will be requested to measure their temperature thrice daily during the 2 days following the first aminobisphosponate administration. This, because a relation between the occurrence of a febrile response upon aminobisphosponate administration and an activation and expansion of Vy9Vd2-T cells has been suggested. Peripheral blood mononuclear cells will be isolated from the drawn peripheral blood. Using intra- and extracellular flowcytometry Vy9Vd2-T cells will be characterized phenotypically (APC markers: CD1d, CD40, CD80, CD83, CD86, HLA-DR; activation/memory markers: CD25, CD27, CD45RA, CD45RO, CCR7) and functionally (IFN-γ, TNF-α, granzyme B). In addition, the frequency of CD3+, CD4+, CD8+ T cells, NK cells, B cells, iNKT cells, CD4+CD25+ regulatory T cells, and circulating dendritic cells will be assessed.

Official Title
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Effect of Aminobiphosphonates and Statins on Circulating Vgamma9Vdelta2-T Cells

Conditions
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Bone Metastases of a Malignant Tumor

Intervention / Treatment
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* Drug: Aminobiphosphonate
* Drug: Simvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with an indication for intravenous treatment with an aminobiphosphonate because of a malignant tumor WHO 0,1,2 performance score Exclusion Criteria: WHO 3, 4 performance score prior or current use of aminobisphosphonates -immunosuppressive medication (NSAID allowed) chemotherapy and/or radiotherapy in 4 weeks prior to start of aminobisphosphonate administration renal insufficiency (creatinine clearance < 30 ml/min) liver enzyme abnormalities: bilirubin > 1.5 times ULN (upper limit of normal) ASAT or ALAT > 2.5 times ULN (in absence of liver metastases) ASAT or ALAT > 5 times ULN (in presence of liver metastases) concomitant use of strong inhibitors of CYP3A4, such as itraconazole, ketoconazole, erytromycin, clarithromycin, hiv-protease inhibitors or grapefruit juice is contra-indicated.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aminobiphosphonates<br>Aminobiphosphonates | Drug: Aminobiphosphonate<br>* Patients will receive standard intravenous biphosphonate treatment<br>|
| Experimental: Aminobiphosphonates and Statin<br>Aminobiphosphonates and Statin | Drug: Aminobiphosphonate<br>* Patients will receive standard intravenous biphosphonate treatment<br>Drug: Simvastatin<br>* 40 mg once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phenotypic (APC markers: CD1d, CD40, CD80, CD83, CD86, HLA-DR; activation/memory markers: CD25, CD27, CD45RA, CD45RO, CCR7)changes in the circulating pool of Vy9Vd2-T cells. | Peripheral blood mononuclear cells will be isolated from the drawn peripheral blood. Using intra- and extracellular flowcytometry Vy9Vd2-T cells will be characterized phenotypically (APC markers: CD1d, CD40, CD80, CD83, CD86, HLA-DR; activation/memory markers: CD25, CD27, CD45RA, CD45RO, CCR7). | 5 weeks | 
| Occurrence of a febrile response | Patients will be requested to measure their temperature thrice daily during the 2 days following the first aminobisphosponate administration. This, because a relation between the occurrence of a febrile response upon aminobisphosponate administration and an activation and expansion of Vy9Vd2-T cells has been suggested. | 2 days | 
| Functional (IFN-γ, TNF-α, granzyme B) changes in the circulating pool of Vy9Vd2-T cells. | Peripheral blood mononuclear cells will be isolated from the drawn peripheral blood. Using intra- and extracellular flowcytometry Vy9Vd2-T cells will be characterized functionally (IFN-γ, TNF-α, granzyme B). | 5 weeks |