Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04902846 |
| Other study ID # |
ICITOX |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 19, 2021 |
| Est. completion date |
December 30, 2025 |
Study information
| Verified date |
October 2023 |
| Source |
Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León |
| Contact |
Ana Isabel Morales Martín, PhD |
| Phone |
+34923294400 |
| Email |
amorales[@]usal.es |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
In recent years, immunotherapy has been postulated as one of the most effective strategy in
the fight against cancer. The greatest success in this field has been achieved through the
inhibition of molecules involved in the brake of the adaptive immune response. The compounds
capable of blocking the action of these molecules constitute the "immune checkpoint
inhibitors" (ICI). Despite its efficacy, the treatment with ICI causes adverse effects, and
in the case of kidney damage, the prognosis has been shown to worsen in cancer patients who
develop renal dysfunction. Currently, the diagnosis based on laboratory tests is insufficient
to predict the underlying kidney injury and identify the type of damage. The hypothesis
proposed that the renal lesion could be subclinical, and therefore the possibility of using
new urinary biomarkers could be a useful diagnostic tool that would allow these patients to
be managed in a preventive (risk markers) and early way (early markers), and even to
elucidate if renal damage is due to this therapy or to other factors (differential diagnostic
markers). To develop this hypothesis it is proposed to validate biomarkers in patients
treated with ICI by developing a prospective study. The diagnostic products derived from this
study will improve the clinical practice of cancer treatment with ICI, and therefore the
expectancy and quality of life of patients.
Description:
During the last decade, advances in the knowledge of both the immune response to tumors, as
well as the understanding of their evasion mechanisms, has made it possible to design
treatments aimed at improving said response and increasing patient survival in figures up to
now unthinkable. The greatest success in this field has been achieved through the inhibition
of molecules involved in the braking of the adaptive immune response: the so-called CTLA-4
(cytotoxic T-lymphocyte antigen-4) and PD-1 (programmed cell death protein-1), with their
respective ligands. The compounds capable of blocking the action of these molecules
constitute the so-called "immune checkpoint inhibitors" (ICI).
As with conventional therapies, the adverse effects that these drugs develop in many cases
limit their use. Although nephrotoxicity is less common than other complications (liver,
gastrointestinal, skin, and lung toxicity), kidney effects have been shown to worsen
prognosis in cancer patients who develop kidney dysfunction. In addition, therapies based on
ICI combinations have recently been promoted to avoid the resistance acquired by the tumor to
treatment, and have even been associated with chemotherapy, which has improved the response,
but has increased the risk of nephrotoxic adverse events.
Kidney injury due to immunotherapy treatment is characterized by acute kidney damage,
proteinuria, electrolyte disturbances, tubular injuries, glomerular injuries, and more
frequently acute tubulointerstitial nephritis, the toxic mechanisms underlying these events
are largely unknown. The usual clinical procedure when kidney damage appears is to suspend
immunotherapy treatment and administer systemic corticosteroids. However, discontinuation of
treatment may not be appropriate without diagnostic confirmation of the progression of kidney
damage, but continuation of treatment if the diagnosis is subsequently confirmed may lead to
definitive and irreversible kidney damage.
At present, the diagnosis of kidney injury based on clinical findings and laboratory tests is
insufficient to predict the underlying kidney injury and identify the type of damage, since
serum markers such as creatinine or urea only provide information when the damage is already
established. In addition, it must be taken into account that kidney injuries, such as
ischemic and / or nephrotoxic tubular injury, paraneoplastic kidney injury, glomerular
injuries, and tubular obstruction can occur in cancer patients as a consequence of their
pathology and associated therapy. . Therefore, a careful evaluation of the possible causes
should be made to make the correct diagnosis in patients undergoing treatment with ICI (for
example, interstitial nephritis due to ICI versus other types of damage by other drugs) and
based on that, proceed to the management of the patient optimally. In this scenario, renal
biopsy is presented as the only alternative to definitively diagnose the lesion and
potentially guide therapy. Although it is the definitive diagnostic method, it is an invasive
technique, not without complications, therefore the possibility of using biomarkers capable
of identifying the type of damage (differential diagnosis biomarkers) would represent a
highly relevant diagnostic advance.
Another important approach in diagnosis is the identification of damage early, since
creatinine levels (a commonly used marker) do not show a significant increase until kidney
function has already decreased by 50%. Currently, the usefulness of biomarkers of early
kidney damage associated with drug treatment has been described. These markers are components
or metabolic derivatives, degradation compounds or remains of them that appear in the urine
as a consequence of damage to kidney structures, showing subclinical damage.
A significant advance in the management of kidney injury would be to find markers capable of
identifying subjects at risk, that is, in a stage prior to damage (risk biomarkers). It has
been defined that different drugs and kidney toxins, in completely subtoxic doses, are
capable of predisposing, or making experimental animals more sensitive to acute kidney
damage. The relevance of this situation is that individuals apparently unaffected by the
adverse effects of a treatment, or by exposure to a substance, could be, without knowing it
and therefore unable to do anything to prevent it, exposed to developing kidney damage acute
in situations, or under certain circumstances (other treatments, radiological contrasts,
environmental toxins, etc.) that do not produce any harm in non-predisposed individuals.
Associated with this condition, it have been identified and patented, and are clinically and
technologically developing urinary markers related to this acquired hypersensitivity. Their
clinical application would allow, not only to detect this predisposition, but also to
stratify patients in a preventive and personalized way, according to the individual risk they
acquire as a consequence of apparently innocuous pharmacological treatments or other
circumstances inherent to their pathology. On this basis, it is proposed in this project to
explore possible biomarkers that can be detected by patients at risk before starting
treatment with ICI.
For all the above, this project will be carried out through preclinical and clinical studies.
The main objective proposed in clinical setting is to validate biomarkers as diagnostic tools
for kidney damage in patients treated with immune checkpoint inhibitors:
1.1. Before starting treatment to detect patients at risk (risk markers) 1.2. During
treatment, in a first phase to detect early lesions (early biomarkers)
With this objective, it is intended to study whether these biomarkers can be a valid tool in
the management of kidney damage in patients treated with ICI, responding to an unresolved
diagnostic need.
PATIENT DATA COLLECTION
A database will be prepared that collects the following variables for each patient: age, sex,
family history, personal history, tumor type, antitumor treatment regimen, clinical
characteristics of the case, comorbidity factors, allergies, usual medication, occasional
drugs and follow-up data.
Urine Sampling
The study times, in which urine samples will be taken, will be as follows:
- Before each antineoplastic cycle (Pre ICI)
- One week after each antineoplastic cycle (Post ICI)
Processing and storage of urine samples In the case of samples from the Salamanca University
Hospital, the samples will be handled and kept in the Sample Bank of the Salamanca University
Clinical Hospital. The samples from the Valladolid University Clinical Hospital will be
handled and kept in the Oncology Service itself. After collection, the samples will be
centrifuged to remove possible sediments and later frozen in several aliquots at -80 degrees
Celsius.
Study of kidney function using clinical parameters At all times of the study, the plasma
concentration of creatinine, urea and electrolytes will be extracted from the analytics
issued by the Biochemistry Service of the respective hospitals. These tests are prescribed by
doctors as part of the patient care process.
Study of early markers and risk markers of acute kidney damage The rest of the analytical
determinations necessary for the study will be carried out in the laboratory of the
"Theranostic Unit of Renal and Cardiovascular Diseases" of IBSAL. They are the following:
urinary creatinine concentration (commercial kit), creatinine clearance (using conventional
mathematical formulas), proteinuria, (Bradford technique), urinary NAG excretion (using
colorimetric kit), KIM-1, NGAL, albumin, transferrin and GM2AP (by ELISA or Western blot).
STATISTICAL ANALYSIS Data analysis will be done with "SPSS 25.0". A significance level of
0.05 will be used. Different contrasts will be applied depending on the association to be
studied in each case, and the type of variables, such as: normality test (Kolmogorov-Smirnov,
Shapiro-Wilk), frequency comparison (χ2), correlation test (Pearson, Spearman), comparison of
means for independent data (ANOVA and Kruskal-Wallis) and ANOVA for repeated measures and
Wilcoxon test for paired data. Finally, to simultaneously study data sets with several
variables measured for each individual or parameter collected, techniques with Multivariate
Analysis will be used, such as: regression analysis, general linear models, binary logistic
regression and correspondence analysis.
STUDY LIMITATIONS The variables included are biomarkers of early kidney damage and of
predisposition to acute kidney damage induced by certain kidney toxins. It is possible that
there are other (unknown) markers, not analyzed, and which can predict, diagnose earlier or
allow a differential etiological diagnosis of kidney damage associated with treatment with
immunotherapy or immunotherapy / chemotherapy.
