Sparsentan for the Treatment of VEGF Signaling Pathway Inhibitor-Associated Proteinuria

Mass General Brigham

Status and phase: Not yet enrolling; Phase 1

Conditions: Proteinuric Kidney Disease; Proteinuria; Proteinuria in Nephrotic Range; Proteinuric Renal Disease

Treatments: Drug: No sparsentan; Drug: sparsentan

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT07224776

25-683

Details and patient eligibility

About

Single-center, open-label, two-stage pilot study examining the efficacy and safety of sparsentan for reducing high-grade proteinuria among patients with cancer who receive vascular endothelial growth factor inhibitors

Enrollment: 20 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Adults (≥ 18 years old) with active malignancy who are currently treated with VSPIs
2. New high-grade proteinuria, defined as ≥ 2+ proteinuria on dipstick or a calculated urinary protein-to-creatinine ratio ≥ 1.0 g/g
3. Able to provide written inform consent

Exclusion criteria

1. Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73m2

2. Baseline high grade proteinuria ≥ 2+ proteinuria on dipstick or a calculated urinary protein-to creatinine ratio or microalbumin-to-creatinine ≥ 1.0 g/g prior to VSPI initiation

3. Acute kidney injury defined as serum creatinine at least 1.5 times above the most proximal serum creatinine prior to VSPIs initiation

4. History of allergic reactions or angioedema to any angiotensin receptor blocker (ARB) or ERA, including sparsentan or irbesartan, or has a hypersensitivity to any of the excipients in the study medications.

5. Any potassium value >5 mEq/L in the 14 days preceding high-grade proteinuria

6. History of organ transplantation, with the exception of corneal transplants.

7. History of congestive heart failure (New York Heart Association Class II-IV)

8. History of clinically significant cerebrovascular disease (transient ischemic attack or stroke) and/or coronary artery disease (hospitalization for myocardial infarction or unstable angina, new onset of angina with positive functional tests, coronary angiogram revealing stenosis, or a coronary revascularization procedure) within 6 months prior to screening.

9. Jaundice, hepatitis, or known hepatobiliary disease (excluding asymptomatic cholelithiasis), or alanine aminotransferase and/or aspartate aminotransferase >2 times the upper limit of the normal at screening.

10. Body weight <50 kg at screening

11. Unable to hold renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), spironolactone, eplerenone, aliskiren, aldosterone blockers during run-in period

12. Concomitant use of the following medications:

    1. Inhibitors of endothelin system such as ambrisentan, bosentan, macitentan
    2. Potassium-sparing diuretics such as amiloride, triamterene
    3. Antiarrhythmic medications such as amiodarone, digoxin
    4. Weight loss medications such as orlistat or amphetamine derivative agents
    5. St. John's wort or other hypericum-derived products
    6. Strong CYP3A inhibitors such as ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, ritonavir- or cobicistat-boosted regimens, boceprevir, telaprevir, conivaptan, mibefradil

13. Pregnant or breastfeeding

14. Concurrent participation in a study with an alternative experimental therapy that may interact with sparsentan

15. Any condition that, in the view of the principal investigator, might place the patient at increased risk or compromise the integrity of the study

16. Conflict with other study

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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20 participants in 2 patient groups, including a placebo group

Treatment with sparsentan, an endothelin-1 antagonist

Active Comparator group

Description:

Participants will receive sparsentan 200 mg daily for 2 weeks, and will then titrate up to a target of 400 mg daily. After the Week 8 visit, patients will return to standard-of-care. We will compare the mean percent change in urine protein to creatinine ratio in patients treated with sparsentan versus historical controls who did not receive sparsentan.

Treatment:

Drug: sparsentan

Historical controls with high-grade proteinuria not treated with sparsentan

Placebo Comparator group

Description:

Participants must meet all eligibility criteria, but did not receive sparsentan. Historical controls will be matched based on age, sex, race, stage and cancer type

Treatment:

Drug: No sparsentan