Clinical trial NCT04368546: Sunitinib Treatment on Tissue Sodium Accumulation (TSS2)
Official title: Effect of Sunitinib Treatment on Tissue Sodium Accumulation in Patients With Renal Cancer: a Pilot Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Renal Cell Cancer Metastatic
Hypertension
Sodium Imbalance
Keywords: Sunitinib
Tyrosine kinases-inhibitor
Sodium
MRI
Skin
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: German Heart Institute
First posted: 2020-04-29
Enrollment: 6
Sex: MALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CROSSOVER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with metastatic renal cell carcinome in the primary care of the Charité - Universitätsmedizin Berlin as well as healthy subjects without known disease recruited in the Charité - Universitätsmedizin Berlin and healthy volunteers form the Max-Delbrück Center of Molecular Medicine

Brief summary: Here, it is investigated how sunitinib, a tyrosine kinase-inhibitor targeting vascular endothelial growth factor receptors, might influence sodium homeostasis in the skin and if this is related to a well-described treatment side-effect of sunitinib, hypertension.

Detailed description: Tyrosine kinases-inhibitors targeting vascular endothelial growth factor (VEGF)-receptors (RTKIs) are increasingly used in oncology in several metastatic tumor types. These agents are featured by toxicities including hypertension. According to a new insight, sodium in response to a high dietary sodium intake, is accumulated in a hyperosmolar way in the interstitial compartment. In response to this high sodium concentration cells of the mononuclear phagocytic system (MPS) are activated resulting in an increased production of VEGF-C, activation of VEGF type 3 receptors and formation of a lymphatic capillary network, involved in clearance of interstitial sodium. Blockade of stimulation of VEGF-C receptors or depletion of MPS cells in rodents has been associated with salt-sensitive hypertension.

Sunitinib is an orally-active, multitarget RTKI mainly used for the treatment of patients with metastatic renal cancer and imatinib-resistant gastrointestinal stromal tumors. Sunitinib blocks all three VEGF receptors subtypes, including VEGF-receptor type 3.

The investigators hypothesize that treatment of patients with sunitinib is associated with tissue sodium accumulation and this accumulation contributes to the rise in blood pressure. Tissue sodium is measured by using a newly developed 23Na magnetic resonance-imaging (MRI) technique which allows a non-invasive and contrast agent-free sodium content measurement in the muscle and skin of the lower leg.

Eligibility criteria: Inclusion Criteria:

* Age men \> 18 years
* Life-expectation \> 3 months
* Stable weight
* Blood pressure below 140/90 mmHg at baseline
* Estimated glomerular filtration rate \> 45 ml/min/1.73m2
* Willingness to give written informed consent

Exclusion Criteria:

* Heart failure
* Liver disease with ascites
* Nephrotic syndrome
* Gastrointestinal complaints, preventing normal daily food intake or diarrhea
* Any form of diabetes mellitus
* Known autoimmune diseases
* Acute or chronic infection
* Alcohol or substance abuse

Primary outcomes:
measure: Skin sodium
timeFrame: 3 months (before, 4 weeks on, 2 weeks off and 4 weeks on medication)
Secondary outcomes:
measure: Plasma VEGF-C
timeFrame: 3 months (before, 4 weeks on, 2 weeks off and 4 weeks on medication)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Experimental and Clinical Research Center, Clinical Research Unit
Study officials:
affiliation: Group leader at the Max Delbruck Center for Molecular Medicine
name: Dominik Müller, PhD
role: STUDY_DIRECTOR
References:
citation: Kandula P, Agarwal R. Proteinuria and hypertension with tyrosine kinase inhibitors. Kidney Int. 2011 Dec;80(12):1271-7. doi: 10.1038/ki.2011.288. Epub 2011 Sep 7.
citation: Kappers MH, van Esch JH, Sluiter W, Sleijfer S, Danser AH, van den Meiracker AH. Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels. Hypertension. 2010 Oct;56(4):675-81. doi: 10.1161/HYPERTENSIONAHA.109.149690. Epub 2010 Aug 23.
citation: Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Muller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009 May;15(5):545-52. doi: 10.1038/nm.1960. Epub 2009 May 3.
citation: Kopp C, Linz P, Dahlmann A, Hammon M, Jantsch J, Muller DN, Schmieder RE, Cavallaro A, Eckardt KU, Uder M, Luft FC, Titze J. 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension. 2013 Mar;61(3):635-40. doi: 10.1161/HYPERTENSIONAHA.111.00566. Epub 2013 Jan 21.