A Phase IIa Multi-Center Study of 18F-FDG PET, Safety, and Tolerability of AZD0530 in Mild Alzheimer's Disease
Condition: Alzheimer's Disease
MeSH terms: Alzheimer Disease
Intervention: AZD0530 100mg daily; AZD0530 125mg daily; Placebo
Intervention description: All patients in experimental group (50%) will be started on 100mg AZD0530 daily; Patients with plasma drug level <100ng/ml after 2 weeks of 100mg AZD0530 daily will receive 125mg daily of AZD0530.; 50% of patients will receive placebo treatment for the duration of the study.
Intervention MeSH terms: Saracatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 159.0
Sex: All
Minimum age: 55 Years
Maximum age: 85 Years
Healthy volunteers: No

Summary:

      AZD0530 is an inhibitor of Src and Abl family kinases1. It has been developed as treatment
      for malignancies because these kinases play a role in tumor invasion and proliferation.
      However, the Src family kinases (SFKs) are highly expressed in brain and have major effects
      on synaptic plasticity2. Moreover, the investigators have recently shown that a specific SFK,
      namely Fyn, is aberrantly activated by specific conformations of the Amyloid Beta (Aß)
      peptide from Alzheimer's disease (AD). Genetic deletion of Fyn rescues AD deficits in
      preclinical models. This clinical trial will test the potential benefit of AZD0530 for
      Alzheimer's disease modification.
    

Eligibility criteria:

        Inclusion Criteria

          1. NIA-Alzheimer's Association core clinical criteria for probable AD

          2. 18F-Florbetapir scan with evidence of elevated Aβ (based on central review)

          3. Age between 55-85 (inclusive)

          4. MMSE score between 18 and 26 (inclusive)

          5. Stability of permitted medications for 4 weeks. In particular:

               -  Stable doses of antidepressants lacking significant anticholinergic side effects
                  (if they are not currently depressed and do not have a history of major
                  depression within the past 1 year)

               -  Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks
                  prior to screen

          6. Geriatric Depression Scale less than 6 [Note: a score ≥6 on this screening scale may
             be permissible, if the subject is examined by a site clinician and judged not to be
             depressed.]

          7. Study partner is available who has frequent contact with the subject (e.g., average of
             10 hours per week or more), and can accompany the subject to most visits to answer
             questions about the subject

          8. Visual and auditory acuity adequate for neuropsychological testing

          9. Good general health with no disease expected to interfere with the study

         10. Subject is not pregnant, lactating, or of childbearing potential (i.e., women must be
             two years post-menopausal or surgically sterile)

         11. Modified Hachinski less than or equal to 4

         12. Completed six grades of education or has a good work history

         13. Must speak English or Spanish fluently

        Exclusion Criteria

          1. Any significant neurologic disease other than AD, such as Parkinson's disease,
             multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain
             tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple
             sclerosis, or history of significant head trauma followed by persistent neurologic
             defaults or known structural brain abnormalities

          2. Screening/baseline MRI scan with evidence of infection, infarction, or other focal
             lesions or multiple lacunes or lacunes in a critical memory structure

          3. Subjects that have any contraindications for MRI studies, including claustrophobia,
             the presence of metal (ferromagnetic) implants, or cardiac pacemaker

          4. Major depression, bipolar disorder as described in DSM-IV within the past 1 year or
             psychotic features, agitation or behavioral problems within 3 months, which could lead
             to difficulty complying with the protocol

          5. History of schizophrenia (DSM V criteria)

          6. History of alcohol or substance abuse or dependence within the past 2 years (DSM V
             criteria)

          7. Clinically significant or unstable medical condition, including uncontrolled
             hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal,
             hepatic, endocrine, or other systemic disease in the opinion of the Investigator, may
             either put the subject at risk because of participation in the study, or influence the
             results, or the subject's ability to participate in the study.

          8. Has had a history within the last 5 years of a primary or recurrent malignant disease
             with the exception of non-melanoma skin cancers, resected cutaneous squamous cell
             carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ
             prostate cancer with normal prostate-specific antigen post-treatment

          9. Clinically significant abnormalities in B12 or TFTs that might interfere with the
             study. A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and
             methylmalonic acid (MMA)) indicate that it is not physiologically significant.

         10. Residence in skilled nursing facility.

         11. Use of any excluded medication as described in study protocol

         12. Current or recent participation in any procedures involving radioactive agents,
             including current, past, or anticipated exposure to radiation in the workplace, such
             that the total radiation dose exposure to the subject in a given year would exceed the
             limits of annual and total dose commitment set forth in the US Code of Federal
             Regulations (CFR) Title 21 Section 361.1. This guideline is an effective dose of 5 rem
             received per year.

         13. Neutropenia defined as absolute neutrophils count of <1,800/microliter

         14. Thrombocytopenia defined as platelet count <120x103/microliter

         15. For CSF sub-study participants, a current blood clotting or bleeding disorder, or
             significantly abnormal PT or PTT at screening

         16. Clinically significant abnormalities in screening laboratories, including:

               -  Aspartate aminotransferase (AST) >1.5 times ULN

               -  Alanine aminotransferase (ALT) > 1.5 times ULN

               -  Total bilirubin >1.5 times ULN

               -  Serum creatinine >2.0 times ULN

         17. History of interstitial lung disease

         18. Patients whom the PI deems to be otherwise ineligible