Nilotinib in Parkinson's Disease

The purpose of this study is to determine if nilotinib is safe, if it can be tolerated by
patients with Parkinson's disease (PD) and to learn if nilotinib has the possibility of
effectively treating PD symptoms. Nilotinib has been approved by the Food and Drug
Administration (FDA) to treat certain types of cancer (leukemia) but is considered
investigational in this study because it has not been approved for treating PD. Twenty-five
sites will enroll participants into 2 cohorts,approximately 75 in Cohort 1 and 60 in Cohort
2. Participants with moderate to advanced PD symptoms will be enrolled in Cohort 1, randomly
assigned to take nilotinib (150 mg or 300mg) or placebo, and will complete 13 in-person study
visits over 8.5 months.

The results from Cohort 1 will determine if either dose of nilotinib (150mg or 300 mg) is
safe and tolerable enough to move forward and evaluate in Cohort 2. If either dose is found
to be safe and tolerable, participants with early PD will be enrolled into Cohort 2.

Participants in Cohort 2 will be randomly assigned to either nilotinib (dose to be determined
from Cohort 1 results) or placebo and will complete 17 in-person visits over 14.5 months. For
both cohorts, the study visits will include clinical assessment of motor, neuropsychiatric
and cognitive testing as well as collection of blood and cerebral spinal fluid, collected by
lumbar puncture.

This study will also evaluate if nilotinib can help improve motor symptoms associated with
PD. All participants in Cohort 1 and participants in Cohort 2 who have started PD medications
will have an assessment of the motor exam (Part III) in a practically defined OFF state (12
hours post dose) and ON state (at least one-hour post dose).

Inclusion Criteria; Cohort 1 and 2:

1. Idiopathic PD based on the UK Brain Bank diagnostic criteria.

2. Any race and either gender, age 40-79

3. Able to read and understand English with the capacity to provide voluntary informed
consent by signing the informed consent form (ICF)

4. Willing to comply with all study procedures including multiple multiple lumbar
punctures (LP)

5. Must be on a stable regimen of central nervous system acting medications (if
applicable) for at least 30 days prior to the baseline visit (e.g., benzodiazepines,
antidepressants, hypnotics)

Inclusion criteria specific for Cohort 1:

6a. Diagnosis of PD duration > 5 year

7a. Hoehn & Yahr scale (H&Y) stage > 2 and < 4 in the ON state

8a. Must be on a stable regimen of PD medications, that includes levodopa, for at least 30
days prior to the screening visit A. Treatment with monoamine oxidase B (MAO-B) inhibitors
will be allowed provided the dose has been stable for 60 days prior to baseline

Inclusion criteria specific for Cohort 2:

6b. Diagnosis of PD duration < 3 years

7b. H&Y stage ≤ 2 8b. Participants who are currently NOT receiving symptomatic therapy (ST)
(levodopa,dopamine agonists and monoamine oxidase B (MAO-B) inhibitors) and NOT projected
to require ST for at least 3 months from enrollment.

a. Treatment with amantadine or an anticholinergic agent will be allowed provided the dose
has been stable for 30 days prior to screening and will remain stable for the duration of
the study

Exclusion Criteria; Cohorts 1 and 2:

1. Diagnosis of atypical parkinsonism

2. History of bipolar disorder or major depression, or presence of active depression
defined as a Beck Depression Inventory II (BDI-II) score >17

3. History of a suicide attempt within the last 5 years or active suicidal ideations

4. History of schizophrenia or schizophrenia spectrum disorders

5. History of uncontrolled hypokalemia or hypomagnesaemia, or laboratory evidence of such
on screening

6. History of cardiac arrhythmia, long QT syndrome, or a corrected QT interval (QTcF)
≥450ms at screening visit 1

7. Treated within 30 days prior to randomization, or planned use during the trial with
any of the following classes of Concomitant drugs:

1. Class IA or III antiarrhythmic drugs

2. QT prolonging drugs

3. Strong CYP3A4 inhibitors or inducers

4. Anticoagulants

5. Proton pump inhibitors

8. A clinical history, or the active presence of a cardiovascular condition including:

1. Myocardial infarction, known cardiac ischemia, or angina

2. Cerebrovascular event (e.g. embolic stroke)

3. Congestive heart failure, symptomatic first degree atrioventricular (AV) block or
PR interval > 220msec and all second and third degree AV block, second- or
third-degree atrioventricular block, sick sinus syndrome, or other serious
cardiac rhythm disturbances

4. History of Torsade de Pointes

5. Other cardiovascular history that, in the opinion of the Site Investigator, will
preclude study participation

9. History of hepatic disease, including abnormal liver function defined as Total
Bilirubin > 1.5 times upper limit, Aspartate Aminotransferase (AST) and/or Alanine
Aminotransferase (ALT) > 2 times the upper limit of the normal, or coagulopathy with
INR > 1.4

10. History of epilepsy or a seizure within the last 6 months

11. Active malignancy, or history of a neoplasm in the prior 5 years (excluding
basal/squamous cell carcinoma)

12. Prior history of pancreatitis or total gastrectomy or evidence of abnormal pancreatic
function defined as elevated amylase and/or lipase > 2 times upper limit of normal

13. Diagnosis of human immunodeficiency virus (HIV), clinically significant chronic
hepatitis such as hepatitis B (HBV) or hepatitis C (HCV), or clinical history or signs
of an active infection

14. History of drug or alcohol abuse ≤ 5 years

15. Active medical or psychiatric condition that in the opinion of the Site Investigator
should preclude study participation

16. Previous surgical management for PD

17. Participants participating in any drug or device clinical investigation concurrently
or within 30 days prior to screening for this study

18. Severe lactose and galactose intolerance

19. Participants with evidence of other significant laboratory abnormalities which in the
opinion of the site investigator or clinical monitor should preclude study
participation

20. Known hypersensitivity or contraindication to study drugs (nilotinib or matching
placebo) or their components.

21. Female participants of child-bearing potential. Female participants must be
post-menopausal, post-hysterectomy, or have a documented infertility based on a known
medical or surgical condition

22. Participants with a history of bone marrow suppression or evidence of persistent
myelosuppression defined as absolute neutrophil count <1.8 X 109/L, significant
anemia, or thrombocytopenia defined as platelet count < 100 X 109/L

Exclusion criteria specific for Cohort 1:

22a. Diagnosis of dementia based on the clinician's assessment, or a Montreal Cognitive
Assessment (MoCA) score < 21 at baseline

Exclusion criteria specific for Cohort 2:

22b.MoCA score < 26 at baseline

23b. Treated within 60 days prior to randomization or expected to require treatment within
3 months from randomization with any ST (including levodopa and dopamine agonists )

a. Treatment with amantadine or an anticholinergic agent will be allowed provided the dose
has been stable for 30 days prior to screening and will remain stable for the duration of
the study