Effect of Aminobiphosphonates and Statins on Circulating Vgamma9Vdelta2-T Cells

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.

Study Overview

• Status: Completed
• Conditions: Bone Metastases of a Malignant Tumor
• Intervention / Treatment: Drug: Aminobiphosphonate; Drug: Simvastatin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081HV
    • VU University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aminobiphosphonates	Drug: Aminobiphosphonate; Patients will receive standard intravenous biphosphonate treatment
Experimental: Aminobiphosphonates and Statin	Drug: Aminobiphosphonate; Patients will receive standard intravenous biphosphonate treatment; Drug: Simvastatin; 40 mg once daily

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: J J van der Vliet, MD, PhD, Amsterdam UMC, location VUmc

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: August 4, 2010
• First Submitted That Met QC Criteria: August 10, 2010
• First Posted (Estimate): August 11, 2010

Study Record Updates

• Last Update Posted (Estimate): June 14, 2013
• Last Update Submitted That Met QC Criteria: June 13, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: 2010/70