Senolytic Therapy to Modulate Progression of Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this pilot study is to evaluate whether a combination of two drugs, dasatinib (D) and quercetin (Q) [D+Q], penetrate the brain using cerebrospinal fluid (CSF) in older adults with early Alzheimer's disease (AD). This combination of drug therapy has been shown to affect dying cells in humans with other chronic illnesses and in Alzheimer's mice models. The study team want to know if this combination of medications will reach the brain in order to evaluate if this intervention may be effective for treating AD symptoms in future studies. This is also known as a proof of concept study.

Detailed Description
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Up to 40 potential candidates will be pre-screened to identify eligible men and women ages 65 years and over with a clinical diagnosis of early AD on a stable dose of cholinesterase inhibitors for at least 3 months (for example, Aricept). Eligible participants will undergo laboratory assessments of blood and urine, receive study medications over a twelve week period, and complete pre- and post-treatment testing including: an MRI for digital imaging of the brain; lumbar puncture to obtain cerebrospinal fluid; memory and thinking assessments; quality of life questionnaires; and tests of walking, balance and strength, all of which will be done for research purposes only. Participants must be accompanied by a Legally Authorized Representative and have no travel plans for 4-5 months that would interfere with study visits.

Official Title
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Pilot Study to Investigate the Safety and Feasibility of Senolytic Therapy to Modulate Progression of Alzheimer's Disease (SToMP-AD)

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Dasatinib + Quercetin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 65 years or above. Clinical diagnosis of AD (MoCA 10-20 and Clinical Dementia Rating Scale/CDR = 1) on a stable dose of cholinesterase inhibitors for at least three months Body Mass Index (BMI) within range of 19 - 35 kg/ m2 Labs: Normal blood cell counts without clinically significant excursions (WBCs: 4,500-10,500 cells/mcL; absolute neutrophil count: 1,800-8,700 cells/mcL; platelets: 140-450 K/uL; hemoglobin 12.0-17.5 grams/dL); liver and renal function (AST 10-40 IU/L, total bilirubin 0.1-1.4 mg/dl); cholesterol (<240 mg/dl), triglycerides (<300 mg/dl), and glucose control (HbA1c < 7%). PT/PTT/INR within normal limits Participants must be accompanied by a Legally Authorized Representative designated to sign informed consent and to provide study partner reported outcomes at all remaining visits Participants must have no plans to travel over the next 4-5 months that interfere with study visits following consent Exclusion Criteria: Hearing, vision, or motor deficits despite corrective devices; Alcohol or drug abuse; MRI contraindications; Myocardial infarction, angina, stroke or transient ischemic attack in the past 6 months; QT interval >440 on ECG will not be enrolled. Chronic heart failure will be exclusionary; Participants with coagulation disorders; Neurologic, musculoskeletal, or other condition that limits subject's ability to complete study physical assessments; Uncontrolled diabetes (HbA1c > 7% or the current use of insulin); Current or chronic history of liver disease, or known hepatic or biliary abnormalities; Use of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or anti-coagulant medication; Current use of quinolone antibiotics. Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg). Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and psychiatric disease. History of or MRI-positive for any space occupying lesion, including mass effect or abnormal intracranial pressure, which would indicate contraindication to lumbar puncture

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This study is an open-label pilot study of intermittent D+Q to measure its target engagement in CSF and blood, and to establish the feasibility and safety of D+Q treatment in older adults with early stage AD as initial proof-of-concept for a larger Phase 2 clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermittent D+Q<br>Senolytic treatment in 5 individuals with early AD to determine levels of drug that reach the central nervous system (CNS) by collecting cerebral spinal fluid (CSF), and begin collecting initial data on target engagement of senescent cells, AD-related markers, and AD-relevant outcomes for future trials. | Drug: Dasatinib + Quercetin<br>* Intermittent D+Q administered for 2 days on/14 days off for 12 weeks (6 cycles)<br>* Other names: D+Q;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Penetrance of Dasatinib (D) | Cerebrospinal Fluid (CSF) collected by lumbar puncture before and after 12 weeks of treatment to determine levels of drug that reach the central nervous system will be measured by high performance liquid chromatography/mass spectrometry (HPLC/MS) | Change from 0 to 12 weeks | 
| Brain Penetrance of Quercetin (Q) | CSF collected by lumbar puncture before and after 12 weeks of treatment to determine levels of drug that reach the central nervous system using HPLC/MS | Change from 0 to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alzheimer's Disease Marker - CSF Tau | Cerebrospinal Fluid collected by lumbar puncture analyzed for level of tau proteins present in CSF | Change from 0 to 12 weeks | 
| Alzheimer's Disease Marker - CSF Amyloid Beta | Cerebrospinal Fluid collected by lumbar puncture analyzed for level of amyloid beta proteins present in CSF | Change from 0 to 12 weeks | 
| Senescence Marker IL-6 in CSF | Laboratory measure of level of IL-6 found in CSF collected pre and post treatment | Change from 0 to 12 weeks | 
| Senescence Marker P16 in CSF | Laboratory measure of level of P16 found in CSF collected pre and post treatment | Change from 0 to 12 weeks | 
| Electronic Gait Mapping Under Single and Dual-task Conditions | Participants walk on a pressure-sensitive walkway to capture data on gait speed | Change from 0 to 12 weeks | 
| Montreal Cognitive Assessment (MoCA) | A test which scores the participant with score ranges between 0 and 30. A score of 26 or over is considered normal. Individuals with mild cognitive impairment score lower and individuals with Alzheimer's disease score even lower. | Change from 0 to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dementia, Alzheimer, Cognitive decline, dasatinib