Antineoplastic Agents

All Drugs and Chemicals

Immune Checkpoint Inhibitors

Patients who receive ICI but no develop kidney injury

Patients who receive ICI and develop kidney injury

In the urine samples of these patients, a series of biomarkers of early kidney damage and / or predisposition to kidney damage will be measured.

Early kidney damage biomarkers

In the urine samples of these patients, a series of biomarkers of predisposition to kidney damage will be measured.

Predisposition to kidney injury biomarkers

Ana Isabel Morales Martín, PhD

Laura Vicente Vicente, PhD

Edel del Barco Morillo

Milagros Hijas Villahizán

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.

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.

In this project, only urine samples will be collected. This will be centrifuged, aliquoted and stored at -80 degrees Celsius until its determination

Immune Checkpoint Inhibitors Nephrotoxicity

Application of Biomarkers of Renal Damage in Patients Treated With Immune Checkpoint Inhibitors

It is a biomarker of early kidney damage. It is able to detect kidney damage in the early stages, before the clinical markers creatinine and plasma urea. There are no reference values for humans, so the means of non-smoking patients without risk factors (group 1) should be compared with the rest of the groups. This biomarker will be measured at different times to evaluate its evolution and compare it against the baseline value.

It is an enzyme whose urinary excretion is elevated in case of kidney damage. It is capable of detecting damage before the classic plasma creatinin and urea markers. There are no reference values for humans, so the means of non-smoking patients without risk factors (group 1) should be compared with the rest of the groups. This biomarker will be measured at different times to evaluate its evolution and compare it against the baseline value.

It is a group of markers that are in patent phase so their names can not be mentioned. They are able to detect the susceptibility to kidney damage before administering a nephrotoxic agent. There are no reference values for humans, so the means of non-smoking patients without risk factors (group 1) should be compared with the rest of the groups. This biomarker will be measured at different times to evaluate its evolution and compare it against the baseline value.

Body weight will be measured to each patient and expressed in kilograms

The height will be measured to each patient and expressed in meters

Weight and height will be combined to report BMI in kg/m\^2

Through the year of birth, the patient's age will be calculated, which will be expressed in years.

Patients will be classified in Male or Female

From the analytical biochemistry performed on the patient as part of his usual procedure, the plasma urea data will be obtained in mg/dL units.

Instituto de Investigación Biomédica de Salamanca

Hospital Clínico Universitario de Valladolid

University of Salamanca

R. Laura Vicente Vicente

University professor

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Urinary Bladder Neoplasms

Pregnancy Complications

Urologic Neoplasms

Urogenital Diseases

Urinary Bladder Diseases

Urogenital Neoplasms

Male Urogenital Diseases

Female Urogenital Diseases

Female Urogenital Diseases and Pregnancy Complications

Urologic Diseases

Nivolumab

Relatlimab

Antineoplastic Agents, Immunological

1 cycle of intravenous nivolumab on day 1 and 1 cycle of intraveous nivolumab on day 29. Total administration frequency is twice.

1 cycle of intravenous nivolumab and relatlimab on day 1 and 1 cycle of intraveous nivolumab and relatlimab on day 29. Total administration frequency is twice.

Induction with immune checkpoint blockade nivolumab on day 1. Nivolumab will also be administered on day 29. Response evaluation will be after the last cycle of checkpoint inhibition.

Induction with immune checkpoint blockade nivolumab and relatlimab on day 1. Nivolumab and relatlimab will also be administered on day 29. Response evaluation will be after the last cycle of checkpoint inhibition.

Michiel Van der Heijden, PhD

Hamza Ali, MSc

Michiel van der Heijden, Dr.

This is a non-blinded phase 2 trial in Stage II-IIIa urothelial cancer randomizing pre-operative nivolumab with or without relatlimab to assess whether bladder preservation after dual immunotherapy would be a viable treatment option for patients responding to treatment

This is a phase 2 study in which ninety adult patients with cT2-4aN0 or cT1-4aN1urothelial bladder cancer will be included.

Included patients will be treated with two cycles of checkpoint inhibition with nivolumab or two cycles of nivolumab+relatlimab every 28 days.

Response of this induction therapy will be evaluated by cystoscopy, mpMRI and a CT scan.

The primary endpoint is efficacy, defined as pathological complete response (pCR) defined as pT0N0 or pTisN0 at cystectomy.

Secondary end-points consist of feasibility analysis, defined as percentage of patients completing cystectomy within 12 weeks of start of treatment. Other key secondary end points are drug safety and overall and event-free survival. Events consist of death by any cause; disease recurrence inside or outside the urinary tract and switching to other treatments.

The first evaluation after completion of both treatment cycles will be after six months. Further follow-up visits will take place at 12 and 24 months after completion of the treatment. During these visits, focused physical examination, cystoscopy and a CT chest-abdomen will be performed, combined with registration of treatment-related adverse events and a questionnaire for evaluating QoL, bladder function and long-term effects of immunotherapy on QoL.

Stage II-IIIa Urothelial Cancer Randomizing Pre-operative Nivolumab With or Without Relatlimab

A Phase 2 Trial in Stage II-IIIa Urothelial Cancer Randomizing Pre-operative Nivolumab With or Without Relatlimab

Pathological complete response defined as pT0N0 or pTisN0 in all evaluable patients

Safety in terms of immunotherapy-related adverse events according to CTCAE 5.0 criteria

Percentage of patients that completes cystectomy within 12 weeks of start of treatment. Patients who elect to not undergo surgery or have a delay due to logistical reasons not related to study treatment will be excluded from this analysis.

PD-L1 expression of tumor tissue (obtained pre-treatment) will be determined using immunohistochemistry of tissue slides. For PD-L1, tumor proportion score (TPS) will be determined. Pathological complete response will be related to PD-L1 expression

RNA sequencing and multiplex immunofluorescence will be carried out on TUR and cystectomy tumor tissue. Methods may include RNA expression profiling and multiplex immunofluorescence.

Event-free survival is a composite endpoint, defined by the time from randomization to occurrence of any of the events below:

* Disease recurrence outside the urinary tract (distant metastases, pelvic recurrence).
* Disease progression precluding surgery.
* Muscle invasive recurrence in the bladder or distal ureters in case surgery is not performed for other reasons than progression.
* Switch to other treatments pre- or post-surgery directed at systemic UC (e.g. platinum-based chemotherapy combinations, antibody-drug conjugates etc.). In case adjuvant chemotherapy or immunotherapy is administered without evidence of residual disease, patients will be censored at the start of adjuvant therapy. Locoregional therapy to the bladder, such as (chemo)radiotherapy will not be considered an event in the absence of progressive disease.

OS is defined as the time between the date of enrollment and the date of death

Bristol-Myers Squibb

The Netherlands Cancer Institute

Heart and Blood Diseases

Symptoms and General Pathology

Substance Related Disorders

Wounds and Injuries

Heart Failure

Cardiotoxicity

Heart Diseases

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Radiation Injuries

Tin Fluorides

Angiotensin Receptor Antagonists

Adrenergic beta-Antagonists

Enzyme Inhibitors

Angiotensin-Converting Enzyme Inhibitors

Fluorides

Protective Agents

This group will stop their heart failure medication(s) under the supervision of the study team. The investigators expect most participants in the STOP group to only be on beta-blockers and/or angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). The ACEi or ARB will be stopped first. The ACEi or ARB will be reduced by 50% every 7 days and stopped 7 days after 25% of maximal recommended dose for HF is reached. At this point (or at baseline if only on BB), the BB dose will be reduced by 50% every 7 days then stopped once 25% of the maximal dose is reached.

This group with continue with their heart failure medication(s) for at least 1 year.

This group will stop their heart failure medication(s) under the supervision of the study team.

Stopping Heart Failure Medication(s)

Paaladinesh Thavendiranathan, MD

Anju Nohria, MD

Tom Marwick, MD

James White, MD

Edith Pituskin, PhD

Davinder Jassal, MD

Darryl Leong, MD

Ian Paterson, MD

Kim Connelly, MD

Charlotte Manisty, MD

Cancer therapy-related cardiac dysfunction (CTRCD) is when the heart's ability to pump oxygenated blood to the body is compromised. It is a side effect of cancer therapy which can occur as commonly as in 1 in 5 patients. When this occurs, heart failure medications are started to protect the heart from progressing to heart failure. With early detection and treatment, heart function recovers to normal in \>80% of patients. Unfortunately, heart failure medications are associated with an undesirable long-term pill burden, financial costs, and side-effects (e.g., dizziness and fatigue). As a result, cancer survivors frequently ask if they can safely stop their heart failure medications once their heart function has returned to normal. Currently there is no scientific evidence in this area of Cardio-Oncology.

To address this knowledge gap, the investigators have designed a randomized control trial to assess the safety of stopping heart failure medication in patients with CTRCD and recovered heart function. The investigators will enrol patients who have completed their cancer therapy and are on heart medications for their CTRCD, which has now normalized. The investigators will randomize patients with no other reasons to continue heart failure medications (e.g., kidney disease) to continuing or stopping their heart medications safely. All patients will undergo a cardiac MRI at baseline, 1 and 5 years with safety assessments at 6-8 weeks, 6 and 9 months and 3 and 5 years. The investigators will determine if stopping medications is non-inferior to continuing medications by counting the numbers of patients who develop heart dysfunction by 1 year in each group.

The STOP-MED CTRCD Trial

A Multi-Centre Non-Inferiority Randomized Controlled Trial of STOPping Cardiac MEDications in Patients With Normalized Cancer Therapy Related Cardiac Dysfunction: The STOP-MED CTRCD Trial

Differences between the two groups in the following measures.

1. Changes in CMR LVEF as a continuous parameter.
2. Proportion of participants with increased CMR indexed LV volumes by ≥10% to higher-than-normal limits.
3. Proportion of participants with decline in CMR LVEF to \<50% with a \>10% absolute fall compared to pre-HF medication withdrawal.
4. CMR peak systolic global longitudinal strain (GLS) worsening by \>15%.

Proportion of participants with new diastolic dysfunction or worsening diastolic function ≥1 grade by echocardiography between the two study groups.

Difference in proportion of participants with clinical HF between the two groups.

Difference in patient questionnaires scores between the two groups using the following patient questionnaires:

1. Kansas City Cardiomyopathy Questionnaire
2. SF-36
3. EQ-5D-5L

Differences in the GENESIS-PRAXY score between groups

Incidence of novel biomarkers and genomic factors that may determine the risk of developing the primary endpoint between the two groups.

To compare the proportion of those that develop by 1 year of follow-up one or both of the following (i) left ventricular ejection fraction \<50% by cardiac magnetic resonance (CMR) (ii) new heart failure signs (at least two physical findings or one physical finding and one laboratory finding) AND symptoms (at least one) with the initiation of qualifying heart failure therapy.

Proportion of participants with non-adherence of heart failure medication(s) by 1 year between the two study groups. Non-adherence is defined in the STOP group as the proportion of participants in whom successful cessation of all medications used to treat CTRCD was not possible or re-addition of the same medications used in that participant for HF was necessary for non-HF indications (e.g., palpitations). In the standard of care (SOC) group non-adherence is defined as the proportion of participants who stopped all HF medications used to treat CTRCD.

Doubling of NT-pro BNP compared to pre-HF therapy cessation between the two study groups.

Difference in patient questionnaires scores between the two groups using the following patient questionnaires:

1. Kansas City Cardiomyopathy Questionnaire
2. Short Form (SF) Survey -36
3. EQ-5D-5L

We will compare the cost per quality adjusted life years between the two study groups.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immune Checkpoint Inhibitors Nephrotoxicity	NCT04902846	Kidney Injury Antineoplastics...	Early kidney da... Predisposition ...	18 Years - 100 Years	Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León
Immune Checkpoint Inhibitors Nephrotoxicity	NCT04902846	Kidney Injury Antineoplastics...	Early kidney da... Predisposition ...	18 Years - 100 Years	Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León
Stage II-IIIa Urothelial Cancer Randomizing Pre-operative Nivolumab With or Without Relatlimab	NCT06237920	Urologic Neopla... Urogenital Neop... Neoplasms by Si... Neoplasms Female Urogenit... Female Urogenit... Urogenital Dise... Urinary Bladder... Male Urogenital... Urinary Bladder... Antineoplastics...	Nivolumab Relatlimab	18 Years -	The Netherlands Cancer Institute
The STOP-MED CTRCD Trial	NCT06183437	Heart Failure Cardiotoxicity Cardiac Toxicit... Antineoplastics... Cancer	Stopping Heart ...	18 Years -	University Health Network, Toronto
Stage II-IIIa Urothelial Cancer Randomizing Pre-operative Nivolumab With or Without Relatlimab	NCT06237920	Urologic Neopla... Urogenital Neop... Neoplasms by Si... Neoplasms Female Urogenit... Female Urogenit... Urogenital Dise... Urinary Bladder... Male Urogenital... Urinary Bladder... Antineoplastics...	Nivolumab Relatlimab	18 Years -	The Netherlands Cancer Institute
The STOP-MED CTRCD Trial	NCT06183437	Heart Failure Cardiotoxicity Cardiac Toxicit... Antineoplastics... Cancer	Stopping Heart ...	18 Years -	University Health Network, Toronto
Immune Checkpoint Inhibitors Nephrotoxicity	NCT04902846	Kidney Injury Antineoplastics...	Early kidney da... Predisposition ...	18 Years - 100 Years	Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León

Spots Global Cancer Trial Database for antineoplastics toxicity