Impact of Bosutinib on Safety, Tolerability, Biomarkers and Clinical Outcomes in Dementia With Lewy Bodies

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.

Inclusion Criteria:

1. Written informed consent

2. Capable of providing informed consent and complying with study procedures. Subjects
who are unable to provide consent may use a Legally Authorized Representative (LAR)

3. Age of 25-90 years, medically stable

4. Clinical diagnosis of DLB according to McKeith et al (7) with both dementia MoCA≥18
and Parkinsonian defined as bradykinesia in combination with rest tremor, rigidity or
both UPDRS I-III ≤ 50 and UPDRS-III between 20-40.

5. Dementia and Parkinsonism must be present with at least one other symptom such as
fluctuation, visual hallucinations or REM sleep behavioral disorder (RBD)

6. Abnormal DaTScan

7. Stable on Levodopa no more than 800mg daily, acetylcholinesterase inhibitors, dopamine
agonists for at least 6 weeks

8. Stable on monoamine oxidase inhibitors (MOA-B) for at least 4 weeks before enrollment

9. Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI

10. QTc interval 350-480 ms, inclusive

11. Participants must be willing to undergo LP at baseline and 3 months after treatment.

Exclusion Criteria:

1. Medical history of liver or pancreatic disease, GI ulcers and Chron's disease, kidney,
GI, or blood problems

2. Abnormal liver function defined as AST and/or ALT > 100% the upper limit of the normal

3. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of
normal or proteinuria

4. History of HIV, clinically significant chronic hepatitis, or other active infection

5. hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥480 ms or concomitant drugs
known to prolong the QTc interval and history of any cardiovascular disease, including
myocardial infarction or cardiac failure, angina, arrhythmia

6. History or presence of significant cardiac conditions including: cardiovascular or
cerebrovascular event (e.g. myocardial infarction, unstable angina, or stroke),
congestive heart failure, first, second- or third-degree atrioventricular block, sick
sinus syndrome, or other serious cardiac rhythm disturbances, any history of Torsade
de Pointes.

7. Treatment with any of the following drugs at the time of screening or the preceding 30
days, and/or planned use over the course of the trial: Treatment with Class IA or III
antiarrhythmic drugs (e.g. quinidine), treatment with QT prolonging drugs
(www.crediblemeds.org)- excluding SSRIs (e.g. Citalopram, Escitalopram, Paroxetine,
Sertraline, Duloxetine, Trazodone, etc.), Strong CYP3A4 inhibitors (including
grapefruit juice). The concomitant use of strong CYP3A4 inhibitors (e.g.,
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) must be avoided.
Should treatment with any of these agents be required, therapy with Bosutinib should
be interrupted. Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin,
daltiparin, xeralto, etc. St. John's Wort and the concomitant use of strong other
CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,
rifapentine, phenobarbital) must be avoided since these agents may reduce the
concentration of Bosutinib

8. Females must not be lactating, pregnant or with possible pregnancy

9. Clinical signs indicating syndromes other than DLB including, Alzheimer's Disease (AD)
idiopathic PD, corticobasal degeneration, supranuclear gaze palsy, multiple system
atrophy, chronic traumatic encephalopathy, signs of frontal dementia, history of
stroke, head injury or encephalitis, cerebellar signs, early severe autonomic
involvement, Babinski sign

10. Current evidence or history in past two years of epilepsy, focal brain lesion, head
injury with loss of consciousness or DSM-IV criteria for any active major psychiatric
disorder including psychosis, major depression, bipolar disorder, alcohol or substance
abuse

11. Evidence of any significant clinical disorder or laboratory finding that renders the
participant unsuitable for receiving an investigational drug including clinically
significant or unstable hematologic, hepatic, cardiovascular, pulmonary,
gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory
abnormality.

12. Active neoplastic disease, history of cancer five years prior to screening, including
breast cancer (history of skin melanoma or stable prostate cancer are not
exclusionary)

13. Contraindications to LP: prior lumbosacral spine surgery, severe degenerative joint
disease or deformity of the spine, platelets < 100,000, use of Coumadin/warfarin, or
history of a bleeding disorder.

14. Must not be on any immunosuppressant medications

15. Must not be enrolled as an active participant in another clinical study.