Overview
The goal of this clinical trial is to learn whether extracellular vesicles (EVs) in the blood can be used as biomarkers to predict chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer patients receiving chemotherapy with taxanes, platinum compounds, or antimitotic drugs. The main questions the study aims to answer are whether blood levels of EVs change in patients who develop CIPN during and after chemotherapy and whether specific features of EVs, including lipids and microRNAs, are associated with the development and severity of CIPN. Participants will be followed from before the start of chemotherapy until six months after treatment ends to evaluate how changes in EVs relate to nerve damage caused by chemotherapy. During the study, participants will provide blood samples before chemotherapy, at the end of treatment, and six months later for measurement and molecular analysis of EVs, will complete questionnaires about neuropathy symptoms, and will undergo simple, non-invasive nerve function tests using a tuning fork (diapason) and a Neuropen device. This study does not test cancer drugs; instead, it aims to identify biological markers in blood that may help predict which patients are at higher risk of developing CIPN, with the goal of improving monitoring and care during cancer treatment.
Description
CIPN is a frequent and often long-lasting complication of treatment with several commonly used antineoplastic agents, including taxanes, platinum compounds, and antimitotic drugs. The condition primarily affects sensory neurons of the dorsal root ganglia and peripheral nerve fibers, leading to symptoms such as numbness, tingling, pain, and loss of vibration or tactile sensation. The severity and persistence of CIPN vary markedly between individuals, and currently there are no validated biological markers that allow early identification of patients at increased risk or objective monitoring of neurotoxicity during treatment. As a result, CIPN is usually detected only after clinical symptoms appear, at a stage when nerve damage may already be established and difficult to reverse.
EVs are membrane-bound particles released by virtually all cell types and present in large numbers in biological fluids, including blood. They contain proteins, lipids, and nucleic acids that reflect the physiological and pathological state of their cells of origin. Because EVs can originate from neural and glial cells and can cross biological barriers, they provide a potential window into otherwise inaccessible tissues such as the peripheral nervous system. Changes in EV concentration, membrane composition, and RNA cargo have been reported in several neurological and neurodegenerative conditions, supporting their potential role as circulating indicators of neuronal injury and dysfunction.
This study is designed to evaluate whether longitudinal changes in circulating EVs are associated with the development of CIPN in patients undergoing chemotherapy. Blood samples collected at predefined time points will be used to isolate and quantify EVs and to characterize selected molecular components of their cargo, including membrane lipids and microRNAs. These EV-based measurements will be evaluated in relation to standardized clinical and neurophysiological assessments of peripheral neuropathy performed over the course of treatment and follow-up. By integrating biological and clinical data, the study aims to explore whether EV-derived markers reflect early neurotoxic effects of chemotherapy and whether they may capture individual susceptibility to CIPN.
The study uses a single-group, longitudinal design in which each participant serves as their own reference over time. This approach allows the evaluation of intra-individual changes in EV-related parameters across the different phases of chemotherapy exposure and recovery. It is particularly suited for biomarker discovery in conditions such as CIPN, where baseline inter-individual variability is high and where the key biological signal of interest is the change from an individual's pre-treatment state. This design also avoids the need for a concurrent untreated control group, which would not be ethically or clinically appropriate in this setting.
EVs will be isolated from plasma using standardized protocols designed to preserve vesicle integrity and minimize contamination from non-vesicular particles. Quantitative analysis will be performed to determine the concentration of circulating EVs, expressed as vesicles per microliter, at each study time point. In addition, qualitative analyses will be carried out to investigate specific components of EV cargo that may be relevant to nerve injury and inflammation. These include selected classes of membrane lipids, such as phosphatidylcholine, sphingomyelin, and cholesterol, which are known to influence membrane stability and signaling, as well as microRNAs involved in neuronal function, stress responses, and neuroinflammatory pathways. The combination of quantitative and molecular profiling is intended to provide a multidimensional view of EV dynamics in relation to chemotherapy exposure.
Clinical evaluation of CIPN will be performed using validated symptom-based questionnaires and objective bedside tests of peripheral nerve function. These assessments capture both patient-reported experience and physician-based measures of sensory impairment, allowing a more comprehensive characterization of neurotoxicity than either approach alone. By relating EV-based measurements to these clinical data over time, the study will explore whether changes in EV concentration or composition precede, accompany, or follow the onset of neuropathic symptoms.
Individual susceptibility to CIPN is influenced by multiple factors, including demographic characteristics, pre-existing neuropathy, and genetic background. Although the primary focus of this study is on EV-derived biomarkers, relevant clinical and demographic information will be collected to allow exploratory analyses of how these factors may interact with EV patterns. This will help to distinguish EV changes that are primarily driven by chemotherapy-induced nerve damage from those that reflect underlying patient-specific characteristics.
Because the study does not modify or assign cancer treatments, all oncologic care will proceed according to standard clinical practice. The additional procedures introduced by the study are limited to blood sampling and non-invasive neurological assessments. These procedures are intended solely to support biomarker analysis and phenotypic characterization of CIPN and are not expected to interfere with therapeutic decisions or outcomes.
By focusing on EVs as circulating indicators of peripheral nerve injury, this study aims to generate data that may support the future development of minimally invasive tools for monitoring neurotoxicity in patients receiving chemotherapy. If specific EV-based patterns are found to be associated with CIPN, this could open the way to earlier identification of at-risk individuals and to more personalized management of neurotoxic side effects, with the ultimate goal of improving quality of life for cancer survivors.
Eligibility
Inclusion Criteria:
- Age 60-85, all races/ethnicities, and both sexes are eligible;
- Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia; based on clinical judgment, may be rescreened in ≥ 7 days;
- Individuals with SBP ≥ 130 and SBP ≤ 180 if on 0 or 1 antihypertensive medications; ≥130 and ≤170 on up to 2 medications; ≥130 and ≤160 on up to 3 medications; ≥130 and ≤150 on up to 4 medications. Those on antihypertensives are eligible. If an individual, not treated for hypertension (HTN), has a SBP ≥ 125 mmHg, consider rescreening after 24 hours;
- Willingness to be randomized into the treatment groups and ability to return to clinic for follow-up visits over 24 months;
- Fluency in English or Spanish or both, adequate visual and auditory acuity to allow neuropsychological testing;
- Participants must have a regular healthcare provider.
Exclusion Criteria:
- Clinically documented history of stroke, focal neurological signs or other major cerebrovascular diseases based on clinical judgment or MRI/CT scans such as evidence of infection, infarction, or other brain lesions;
- Diagnosis of AD or other type of dementia, or significant neurologic diseases such as Parkinson's disease, seizure disorder, multiple sclerosis, history of severe head trauma or normal pressure hydrocephalus;
- Evidence of severe major depression (GDS ≥ 12, may be rescreened after 12 weeks or longer if evidence of reactive depression or temporary mood disturbances) or clinically significant psychopathology, (e.g., psychosis and schizophrenia); if hospitalized in past year, can be rescreened in 6 months; or presence of a major psychiatric disorder that in the investigator's opinion, could interfere with adherence to research assessments or procedures.
- Unstable heart disease based on clinical judgment (e.g., heart attack/cardiac arrest, cardiac bypass procedures within previous 6 months and congestive heart failure), or other severe medical conditions;
- History of atrial fibrillation and evidence on ECG with any of the following: active symptoms of persistent palpitation, dizziness, history of syncope, chest pain, dyspnea, orthopnea, shortness of breath at rest, or paroxysmal nocturnal dyspnea within the past 6 months; resting heart rate of \< 30 or \> 110 bpm; taking class I or III antiarrhythmic drugs including flecainide, propafenone, dronedarone, sotalol, dofetilide, and amiodarone; or clinical concerns for safely participating in lowering blood pressure.
- Systolic BP equal or greater than 180 mmHg and/or diastolic BP equal or greater than 110 mmHg, may be rescreened in 1 week.
- Orthostatic hypotension, defined as the third standing SBP \< 100mmHg, may be rescreened after 2 weeks;
- History of significant autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis or polymyalgia rheumatica;
- Significant history of alcoholism or drug abuse within the last five years;
- Uncontrolled diabetes mellitus, defined as hemoglobin A1C \> 7.5%, or requiring insulin treatment;
- Regularly smoking cigarettes within the past year;
- Pacemaker or other medical device of metal that precludes performing MRI;
- Women with a potential for pregnancy, lactation/childbearing (2 year post-menopausal or surgically sterile to be considered not childbearing potential);
- Participant enrolled in another investigational drug or device study, either currently or within the past 2 months;
- Severe obesity with BMI \> 40 ; clinical judgment should be applied in all cases to assess patient safety and anticipated compliance;
- Allergy to angiotensin receptor blockers (ARBs), i.e., drugs that have a suffix "-sartan"; allergy to amlodipine;
- Abnormal screening laboratory tests (e.g., liver ALT and AST \> 3 x ULN, GFR \< 30 or Hct \< 28%); may be rescreened after 2 weeks or longer;
- A medical condition likely to limit survival to less than 3 years;
- Participant has any condition(s) judged by the study investigator to be medically inappropriate, risky or likely to cause poor study compliance. For example:
- Plans to move outside the clinic catchment area in the next 2 years;
- Significant concerns about participation in the study from spouse, significant other, or family members;
- Lack of support from primary health care provider;
- Residence too far from the study clinic site such that transportation is a barrier including persons who require transportation assistance provided by the study clinic funds for screening or randomization visits;
- Residence in a nursing home; persons residing in an assisted living or retirement community are eligible if they meet the other criteria;
- Other medical, psychiatric, or behavioral factors that, in the judgment of the site PI or clinician, may interfere with study participation or the ability to follow the study Protocol.
- Couples or significant partners who live together cannot be enrolled or participate simultaneously in the study.