This study evaluates the effect of Bosutinib (Bosulif,Pfizer®) in the treatment of patients with Dementia with Lewy Bodies. Half participants will receive 100 mg of Bosutinib , while the other half will receive placebo.
This proposal will evaluate the effects of Bosutinib (Bosulif, Pfizer®) treatment - an FDA-approved tyrosine kinase inhibitor that targets c-Abelson (Abl) and Src tyrosine kinases- in patients with DLB. Investigators have demonstrated safety and efficacy of this compound in pre-clinical animal models and others have shown similar benefits of Bosutinib on inflammation and neurotoxic protein clearance in neurodegeneration. Investigators have demonstrated that Bosutinib enters the brain (5% CSF:plasma ratio) and inhibits Abl at lower doses (5mg/kg) than the cancer dose (80mg/kg) in animals. Bosutinib also reduces the levels of neurotoxic proteins including alpha-synuclein, tau and beta-amyloid and improves motor and cognitive behavior in models of neurodegeneration. The use of Bosutinib is a novel strategy that promotes autophagy to clear neurotoxic protein aggregates in neurons. Bosutinib is FDA-approved for the treatment of chronic myelogenous leukemia (CML) at an oral dose of 400-600 mg daily. Based on our preclinical evidence, investigators used allometric conversion to extrapolate animal to human dose and estimated a human equivalent dose daily dose of 100mg Bosutinib in this clinical study to determine the safety and tolerability, pharmacokinetics and pharmacodynamics in patients with mild to moderate DLB.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
26
Fifteen (15) patients in group 1 will receive the matching placebo("sugar pill") one (1) tablet orally once daily for 3 months (90 days) .
Fifteen (15) patients in group 1 will receive the 100 mg of Bosutinib one (1) tablet orally once daily for 3 months (90 days) .
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, United States
Safety and Tolerability Go/NoGo (25% Discontinuations) Will be Determined Based on Any Emergent Adverse Events.
We will determine safety and tolerability using the occurrence of adverse events (AEs) of interest, including myelosuppression, urinary, pancreatic and hepatic disorders, QTc prolongation as per Bosutinib IB.
Time frame: 12 weeks
Determine Changes in Absorbance Levels (ABS) in DLB Related CSF and Plasma Tyrosine Kinases
Phospho-ABL(PanTyr) and phospho-SRC(Y416) are critical drivers in the pathogenesis of various neurodegenerative diseases. We will examine the changes in CSF and Plasma phospho-ABL(PanTyr) and phospho-SRC(Y416) absorbance (ABS) levels at baseline and 3 months. The magnitude of the absorbance is proportional to the quantity of tyrosine-phosphorylated protein.
Time frame: Change between baseline (BSL) and Week-12
Determine the Maximum Concentration (Cmax) (ng/ml) of Bosutinib in the CSF and Plasma.
To determine the Cmax (ng/ml), we will measure Bosutinib in both the CSF and Plasma using Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Time frame: 12 weeks
Determine the Maximum Concentration (Cmax) (nM) of Bosutinib in the CSF and Plasma.
To determine the Cmax (nM), we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Time frame: 12 weeks
Determine the Maximum Time (Tmax) Bosutinib Peaks in CSF and Plasma.
To determine the Tmax, we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Time frame: 12 weeks
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Determine the Area Under the Curve (AUC) (ng/ml*Hours) for Bosutinib in CSF and Plasma.
To determine the AUC (ng/ml\*hours) , we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Time frame: 12 weeks
Determine the Area Under the Curve (AUC) (nM*Hours) for Bosutinib in CSF and Plasma.
To determine the AUC (nM\*hours) , we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Time frame: 12 weeks
Changes in Dementia Lewy Body (DLB) Related CSF and Plasma Biomarkers
We will examine the changes in CSF and Plasma Abeta40, Abeta42, total tau, ptau181 and total and oligomeric alpha-synuclein at baseline, week-12, and the change between baseline and week-12.
Time frame: Change between baseline (BSL) and Week-12
Change in Ratios in Dementia Lewy Body (DLB) Related CSF and Plasma Biomarkers
We will examine the ratio changes in CSF and Plasma AB42 to AB40, ptau(181 )to AB42, pTau(181) to tTau, aggregated a-syn to total a-syn at baseline, 12 weeks, and between baseline and week-12.
Time frame: 12 weeks
Measure HVA and DOPAC in CSF and Plasma
We will measure the levels of DOPAC AND Homovanillic Acid (HVA) using liquid-liquid extraction and Liquid chromatography-tandem mass spectrometry (LC-MS/MS) in CSF and plasma samples at baseline (BSL), 12 weeks, and between baseline and 12 weeks (WK12).
Time frame: 12 weeks