Clinical trial NCT07018622: Protecting the Kidney's Proximal Tubules From Platinum-Based Chemotherapy Toxicity
Official title: Effect of Sodium-Glucose Cotransporter 2 Inhibition on Urinary Biomarkers of Kidney Injury After Platinum-Based Chemotherapy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Solid Tumors
Cisplatin Nephrotoxicity
Keywords: Solid Tumors
Platinum-Based Chemotherapy
Cisplatin
Carboplatin
Nephrotoxicity
Kidney Tubules, Proximal
SGLT2 Inhibitors
Kidney Injury Molecule-1
Renal Protection
Chemotherapy-Induced Kidney Injury
Randomized Controlled Trial
Urinary Biomarkers
Dapagliflozin
Lead sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Sponsor class: OTHER
First posted: 2025-06-12
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Patients with cancer who receive platinum-based chemotherapy are at increased risk of kidney injury caused by these drugs. This form of toxicity can lead to treatment delays, dose reductions, or permanent discontinuation of chemotherapy, all of which can negatively impact cancer outcomes and increase patient morbidity. Despite the clinical significance, there are currently no effective strategies to prevent platinum-induced kidney damage. Existing preventive measures-such as hydration, mannitol use, and magnesium supplementation-are limited and not always effective.

This clinical trial investigates whether a type of medication known as a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor, specifically dapagliflozin, can protect the kidneys from damage during platinum-based chemotherapy in patients with solid tumors. Researchers believe that blocking SGLT2 in the kidney may reduce toxicity in the proximal tubules-the area most affected by platinum drugs.

The primary goal of this study is to compare the levels of a specific urinary biomarker of kidney injury (called KIM-1) 72 hours after chemotherapy, between patients who receive dapagliflozin and those who receive a placebo. Lower levels of this biomarker may indicate that dapagliflozin is helping protect the kidneys.

Secondary goals include comparing additional urinary biomarkers of kidney damage and function-such as EGF (epidermal growth factor), N-acetyl-β-D-glucosaminidase (uNAG), albumin (AlbU), and β2-microglobulin (uβ2-m)-at 72 hours and 7 days after chemotherapy. The study will also assess:

The percentage of patients who develop acute kidney injury, Changes in estimated glomerular filtration rate (a measure of kidney function), Electrolyte abnormalities (sodium, magnesium, phosphorus), And any adverse events associated with dapagliflozin use. As exploratory objectives, the trial will also evaluate cancer treatment response between groups (using RECIST 1.1 criteria) and the overall safety and tolerability of dapagliflozin compared to placebo.

This is a randomized, double-blind, placebo-controlled clinical trial, meaning that participants will be randomly assigned to receive either dapagliflozin or a placebo, and neither the patients nor the study team will know who receives which treatment until the study ends.

The central hypothesis is that dapagliflozin will reduce urinary biomarkers of kidney injury by at least 50% compared to placebo, offering a potential protective strategy against platinum-induced nephrotoxicity without interfering with cancer treatment.

Detailed description: Platinum-based chemotherapy agents such as cisplatin and carboplatin are widely used in the treatment of various solid tumors due to their efficacy. However, their clinical utility is frequently limited by nephrotoxicity, predominantly targeting the proximal tubular epithelium. This can lead to acute kidney injury (AKI), electrolyte imbalances (notably hypomagnesemia, hyponatremia, and hypophosphatemia), and progression to chronic kidney disease (CKD). Current preventive strategies are largely supportive and include aggressive hydration, mannitol-induced diuresis, and magnesium supplementation, none of which offer specific cellular protection.

Recent evidence suggests that inhibitors of the sodium-glucose cotransporter type 2 (SGLT2 inhibitors or iSGLT2s), such as dapagliflozin, may confer renal protective effects beyond their original indication for type 2 diabetes mellitus. Mechanistically, SGLT2 inhibition reduces proximal tubular reabsorption of sodium and glucose, leading to improved tubular oxygenation and reduced inflammatory and oxidative stress signaling. This has been associated with reduced progression of CKD and favorable modulation of tubular injury markers in both diabetic and non-diabetic populations.

The present study, DAPA-ARMOR, is a randomized, double-blind, placebo-controlled clinical trial designed to assess the nephroprotective effects of dapagliflozin in adult patients with solid tumors undergoing platinum-based chemotherapy. The hypothesis is that short-term prophylactic administration of dapagliflozin can reduce proximal tubular injury, as evidenced by changes in urinary biomarkers.

The primary endpoint is the difference in urinary levels of Kidney Injury Molecule-1 (KIM-1) 72 hours after platinum administration, between the intervention (dapagliflozin) and control (placebo) arms.

Secondary endpoints include changes in additional urinary biomarkers associated with tubular injury and repair:

uEGF (urinary Epidermal Growth Factor) uNAG (N-acetyl-β-D-glucosaminidase) uAlb (urinary albumin) uβ2-microglobulin These biomarkers will be measured at baseline, 72 hours (±3 days), and 168 hours (±7 days) after chemotherapy administration.

Additional secondary endpoints include:

Incidence of AKI at 72 hours and 7 days post-chemotherapy (defined per KDIGO criteria), Changes in estimated glomerular filtration rate (eGFR) using the CKD-EPI 2021 equation (Cystatin C and creatinine-based), Incidence of chemotherapy-related electrolyte disturbances (Na, Mg, P), Frequency and severity of adverse events graded according to the CTCAE (Common Terminology Criteria for Adverse Events).

Exploratory outcomes will assess:

Cancer response rate using RECIST 1.1 criteria at the first post-randomization imaging evaluation, Tolerability of dapagliflozin during chemotherapy. The study drug (dapagliflozin) or placebo will be administered starting 24 hours prior to platinum chemotherapy and continued for a total of 4 days, covering the period of expected peak tubular exposure and injury.

Participants will be stratified by type of platinum agent used. Urine and blood samples will be collected at pre-specified timepoints for biomarker analysis and laboratory monitoring.

The study design aims to ensure high internal validity while capturing clinically relevant endpoints that could inform future strategies to mitigate chemotherapy-induced nephrotoxicity without compromising oncologic efficacy.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent form
* Diagnosis of a solid tumor requiring a platinum-based chemotherapy regimen (cisplatin or carboplatin)
* Expected survival \> 4 months
* ECOG performance status 0-2

Exclusion Criteria:

* History of nephrectomy
* History of kidney transplant
* Concurrent use of known nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, cyclophosphamide, ifosfamide, methotrexate)
* Type 1 diabetes mellitus
* Poorly controlled type 2 diabetes (HbA1c \> 8% or fasting glucose \> 200 mg/dL in the past month)
* Active glomerulopathy
* Prior use of SGLT2 inhibitors or current indication for their use
* eGFR \< 20 ml/min/1.73 m²
* Active urinary tract infection
* Unresolved obstructive uropathy
* Participation in another clinical trial
* History of recurrent genitourinary infections

Primary outcomes:
measure: Urinary KIM-1/Creatinine (uKIM-1/Cr) expression at 72 hours
timeFrame: 72 hours (Day 3) after platinum administration
Secondary outcomes:
measure: Urinary Epidermal Growth Factor levels adjusted by creatinine (EGF/Cr)
timeFrame: Baseline to Day 3 and Day 7
measure: Urinary N-acetyl-β-D-glucosaminidase levels adjusted by creatinine (uNAG/Cr)
timeFrame: Baseline to Day 3 and Day 7
measure: Urinary Albumin levels adjusted by creatinine (AlbU/Cr)
timeFrame: Baseline to Day 3 and Day 7
measure: Urinary β2-microglobulin levels adjusted by creatinine (uβ2-m/Cr)
timeFrame: Baseline to Day 3 and Day 7
measure: Urinary Kidney Injury Molecule-1 levels adjusted by creatinine (KIM-1/Cr)
timeFrame: Baseline to day 7 after platinum administration
measure: Incidence of Acute Kidney Injury (AKI) at 72 hours and Day 7
timeFrame: Baseline to Day 3 and Day 7
measure: Estimated Glomerular Filtration Rate (eGFR) at 72 hours and Day 7
timeFrame: 72 hours (Day 3), 168 hours (Day 7) after platinum administration
measure: Safety and tolerability of dapagliflozin in patients with solid tumors receiving platinum-based chemotherapy
timeFrame: From first dose of study drug through 4 weeks of follow-up
Other outcomes:
measure: Electrolyte abnormalities (sodium, magnesium, phosphorus) at 72 hours and Day 7
timeFrame: 72 hours (Day 3), 168 hours (Day 7) after platinum administration
measure: Oncologic response by RECIST 1.1 criteria
timeFrame: Up to 24 weeks post-randomization
Locations:
city: Mexico
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán"
state: Tlalpan
Study officials:
affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
name: Juan M Mejía-Vilet, PhD
role: PRINCIPAL_INVESTIGATOR
References: