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Invloed van aminobifosfonaten en statinen op circulerende Vgamma9Vdelta2-T cellen.


- candidate number8306
- NTR NumberNTR2454
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR4-aug-2010
- Secondary IDs2010/70 METC VUmc
- Public TitleInvloed van aminobifosfonaten en statinen op circulerende Vgamma9Vdelta2-T cellen.
- Scientific TitleEffect of aminobiphosphonates and statins on circulating Vgamma9Vdelta2-T cells.
- ACRONYMABP statinen studie
- hypothesisVy9Vd2-T cells are lymphocytes that play an important role in antitumor immunity. They can be activated by phosphoantigens, which has recently been shown to result in their acquisition of antigen presenting call properties. Aminobisphosphonates are administered 3-4 weekly to patients with bone metastases from various malignancies in order to reduce the number of skeletal events. By inhibiting mevalonate metabolism (resulting in the accumulation of endogenous phosphoantigens) aminobisphosphonates can also result in the activation of Vy9Vd2-T cells. Since preclinical data indicate that statins inhibit endogenous phosphoantigen accumulation and Vy9Vd2-T cell activation, one can envision that statins can similarly inhibit the aminobisphosphonate-induced activation of Vy9Vd2-T cells in vivo. In this study the effects of aminobisphosphonate treatment and the inhibitory effects of the simultaneous use of statins on Vy9Vd2-T cells will be evaluated. This is relevant as data from e.g. breast cancer and prostate cancer patients indicate that aminobisphosphonates, via the activation of Vy9Vd2-T cells, can induce clinically relevant antitumor responses. Inhibition of this activation by the simultaneous use of statins could be detrimental in such circumstances.
- Healt Condition(s) or Problem(s) studiedBone metastases, Malignancy
- Inclusion criteria1. Patients with an indication for intravenous treatment with an aminobisphosphonate because of bone metastases of a malignant tumor;
2. WHO 0, 1, 2 performance score.
- Exclusion criteria1. WHO 3, 4 performance score;
2. Prior or current use of aminobisphosphonates;
3. Immunosuppressive medication (NSAID allowed);
4. Chemotherapy and/or radiotherapy in 4 weeks prior to start of aminobisphosphonate administration;
5. Renal insufficiency (creatinin clearance < 30 ml/min);
6. Liver enzyme abnormalities:
A. Bilirubin > 1.5 times ULN (upper limit of normal);
B. ASAT or ALAT > 2.5 times ULN (in absence of livermetastases);
C. ASAT or ALAT > 5 times ULN (in presence of livermetastases);
D. Concomitant use of strong inhibitors of CYP3A4, such as itraconazol, ketoconazol, erytromycin, claritromycin, hiv;
E. Protease inhibitors or grapefruit juice is contra-indicated.
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-sep-2010
- planned closingdate1-jul-2012
- Target number of participants40
- InterventionsConsenting 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 weken (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.
- Primary outcome1. Phenotypic (APC markers: CD1d, CD40, CD80, CD83, CD86, HLA-DR; activation/memory markers: CD25, CD27, CD45RA, CD45RO, CCR7) and functional (IFN-, TNF-, granzyme B) changes in the circulating pool of Vy9Vd2-T cells;
2. Occurrence of a febrile response.
- Secondary outcomeN/A
- TimepointsIn each patient 10 ml peripheral blood will be drawn (t=0, t=24 hr, t=1 week, t=3-4 weken (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.
- Trial web siteN/A
- statusstopped: trial finished
- CONTACT FOR PUBLIC QUERIESMD. PhD. J.J. Vliet, van der
- CONTACT for SCIENTIFIC QUERIESMD. PhD. J.J. Vliet, van der
- Sponsor/Initiator VU University Medical Center
- Funding
(Source(s) of Monetary or Material Support)
VU University Medical Center
- PublicationsN/A
- Brief summaryA 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 weken (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-, TNF-, 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.
- Main changes (audit trail)
- RECORD4-aug-2010 - 3-jun-2013


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