Impact of Bosutinib on Safety, Tolerability, Biomarkers and Clinical Outcomes in Dementia With Lewy Bodies
Condition: Dementia With Lewy Bodies
MeSH terms: Dementia; Lewy Body Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Placebo Oral Tablet; Bosutinib Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): 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) .
Other intervention name(s): Placebo; Bosutinib(Bosulif®, SKI-606, Pfizer)
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: We will evaluate the effects of 100 mg Bosutinib versus matching placebo taken daily by mouth for 12 weeks, followed by a 4 week wash-out period in individuals diagnosed with DLB. We will perform physiologically-based population pharmacokinetics (popPK) using a seamless random single dose (RSD) of Bosutinib, where participants (n=30) will be randomized to 3 groups (n=10) and take a single oral dose of 100mg, 200mg, Bosutinib or placebo (1;1;1) open label. Lumbar puncture will be performed between 1-4 hours after dosing. Participants will then be randomized double-blinded into 2 groups 1;1 using placebo(n=15) and 100mg (n=15) for 3 months.
Randomization and Registration will be performed by an internet based randomization module. Randomization of the subjects to the 2 treatment groups will be performed in a stratified manner. The chance for randomization to the groups is 1:1 for placebo: 100 mg Bosutinib.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment