Sunitinib Treatment on Tissue Sodium Accumulation (TSS2)

NCT ID: NCT04368546

Last Updated: 2021-01-27

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 6 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2015-11-01
• Study Completion Date: 2020-03-01

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.

Conditions

Renal Cell Cancer Metastatic; Hypertension; Sodium Imbalance

Study Design

• Observational Model Type: CASE_CROSSOVER
• Study Time Perspective: PROSPECTIVE

Study Groups

Patients

Metastatic cell carcinoma patients before sunitinib treatment, after 4 week on, after 2 week off and finally again 4 week on medication.

Sunitinib

Intervention Type: DRUG

Healthy controls

Age-matched subjects without known disease.

No interventions assigned to this group

Interventions

Sunitinib

Intervention Type: DRUG

Other Intervention Names

Diagnostic test: 23Na-MRI

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

German Heart Institute

OTHER

Sponsor Role: collaborator

Charite University, Berlin, Germany

OTHER

Sponsor Role: lead

Responsible Party

Dr. Lajos Marko

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dominik Müller, PhD

Role: STUDY_DIRECTOR

Group leader at the Max Delbruck Center for Molecular Medicine

Locations

Experimental and Clinical Research Center, Clinical Research Unit

Berlin, , Germany

Countries

Germany

References

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.

Reference Type: BACKGROUND

PMID: 21900879 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20733093 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19412173 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23339169 (View on PubMed)

Other Identifiers

EA1/044/15

Identifier Type: OTHER

Identifier Source: secondary_id

ChariteU-ECRC-TSS2

Identifier Type: -

Identifier Source: org_study_id