Study for the Use of TKIs for Treatment of Cognitive Decline Due to Degenerative Dementias

September 26, 2022 updated by: Sheldon Jordan, Neurological Associates of West Los Angeles

Open Label Study for the Use of Tyrosine Kinase Inhibitors for Treatment of Cognitive Decline Due to Degenerative Dementias

The present study is designed as an open label study of patients with mild cognitive impairment or dementia to evaluate longer term tolerability and potential efficacy of tyrosine kinase inhibitors. Baseline and outcome measures in this study utilize validated tests that are appropriate for repeated measures which are not affected by practice effects. Advantages of this study include the fact that the neuropsychological testing instruments and advanced MRI imaging protocols that have been in routine clinical deployment provide for a high degree of availability and reliability for diagnosis and for monitoring change of status. Quality assurance is tightly controlled. The study population is sufficiently broad and the conditions of interest are sufficiently prevalent so that recruitment of the projected numbers of subjects is not a limiting factor.

For a Phase I trial there is a proposed 150 patient sample to determine the frequency of common side effects in the population that is being studied. Subjects will be administered the initial dose of bosutinib, with dosage progressively increased over the course of the study. The initial dose of bosutinib is 100 mg tablet, once per day. The dose will be increased as tolerated up to 300 mg per day.

All subjects will be started at 100 mg/day and the dose will be increased by 100 mg each month if the lower dose is tolerated without significant side effects. That is to say, the subject will take 100 mg/day every day for the first month, 200 mg/day every day for the second month, and 300 mg/day every day for the third month and for the remainder of the study, provided that adverse reactions do not prohibit continuation at this dosage. The investigators will be using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 to monitor, evaluate, and report adverse reactions on an ongoing basis. Stopping and dose reduction rules for reported adverse reactions have been taken from the package insert of bosutinib.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

In order for a subject to be considered for this study, the following criterion is required:

• Cognitive decline with mild cognitive impairment (Clinical Dementia Rating Stage 0.5) through moderate dementia (CDR Stages 1 and 2)

All patients, according to routine best practices will have an evaluation including neurological interview and examination to screen for reversible causes of cognitive change such as depression, substance abuse, vitamin deficiency and systemic illness. All patients will have a Beck Depression scale and blood tests for B12 and thyroid hormone. Patients will have an EKG, in particular to screen for QT prolongation which is a relative counterindication for use of tyrosine kinase inhibitor therapy.

According to the package insert for bosutinib, the investigators are proposing to use an age range and dosage route that is comparable and overlapping with routine application of this drug. In addition, the investigators are proposing dosage ranges that are substantially lower than usually recommended for treatment of leukemia.

The QDRS scale will be given to all patients; a cut off score of 1.5 has been used qualify patients with a dementia score (CDR) of 0.5 (ref 19).

All patients will have a lumbar puncture for ABeta 42 and Tau proteins for Alzheimer's Spectrum. This spinal fluid examination has been shown to be both sensitive and specific for Alzheimer's disease (ref 20). Cerebrospinal fluid (CSF) tau levels are also elevated in alpha synucleinopathy and frontotemporal lobar degeneration (ref 21). The lumbar puncture is performed once at entry.

All patients will have an advanced MRI of the brain to include volume measurement of the hippocampus (ref 22), arterial spin labeling (ASL) perfusion scan (ref 23) and MRS of prefrontal, precuneus, hippocampus and occipital lobe. Patients with cognitive decline have decreased perfusion in temporal parietal or frontal regions of the brain with ASL perfusion, or show characteristic change in MRS or volumetric evaluation compared to aged matched control subjects. MRI will also demonstrate if patients have tumors, hydrocephalus, subdural hematomas and other structural etiologies of cognitive decline.

On entry, patients will have CDR stage of at least 0.5 and at least one abnormal imaging biomarker and none of the exclusion criteria below. Baseline, six months, twelve months, eighteen months and two year (completion) testing will include the Quick Dementia Rating System (QDRS) for staging and the following battery of tests:

  • the Repeatable Battery for Assessment of Neuropsychological Status (RBANS),
  • Standardized 25 foot timed gait test
  • the Nine Hole Pegboard Test,
  • Montreal Cognitive Assessment Test versions 1,2,3 (MOCA),
  • Brain imaging will be repeated at one year and two years. CSF studies have demonstrated good sensitivity and specificity for mild cognitive impairment (MCI) and dementia of the Alzheimer's type (ref 5). MRI volumetrics, perfusion scans and magnetic resonance spectroscopy (MRS) have shown to be of excellent discriminating value among Alzheimer's dementia (AD), Parkinson's spectrum degeneration (PDD/DLB) and frontal temporal lobar degeneration (FTLD) subgroups and is responsive to change as patient's progress from MCI to dementia (ref 6).

The rationale behind this criterion is supported by the importance that the subject is cognitively able to effectively speak, listen, and read in English, and has the cognitive capacity to give informed consent.

All subjects will be started at 100 mg/day and the dose will be increased by 100 mg each month if the lower dose is tolerated without significant side effects. Adverse reactions will be scaled according to the CTCAE v.5. If the subject experiences severe adverse reactions at any dose, or if the subject requires dose reduction for toxicity from a dose of 100 mg/day, the subject will be removed from the study. If the subject experiences moderate adverse reactions at a dose >100 mg/day, the dose will be reduced by 100 mg and maintained at the lower dose for 1 month. If the subject experiences moderate or severe adverse reactions at this lower dose, the subject will be removed from the study. After 1 month, the dose will again be increased by 100 mg. If the subject does not experience any adverse reactions at this elevated dose, he/she will resume with the original up-titration schedule (i.e. increase by 100 mg every month up to 300 mg/day). If the subject experiences moderate symptoms at this elevated dose, the dose will again be reduced by 100 mg and will be maintained at this lower dose as the maximally tolerated dose.

The duration of treatment is 1 year. To minimize risk, subjects will be seen regularly for toxicity monitoring during the first month of treatment, and biweekly during the second month of treatment. On weeks when the subject is not in for a visit, subject status will be assessed on the basis of phone calls with the respective care taker. The care taker will be determined during the QDRS staging at the time of the initial consultation. The care taker is an individual who is intimately familiar and in close contact with the subject. After the first two months, visits will be on a monthly basis. Mild, moderate, and severe adverse reactions will be reported on an ongoing basis. The rationale for such extended administration is to allow for a more reliable assessment of tolerability. The primary endpoint in evaluating tolerability will be how many of the initial 20 subjects are discontinued due to adverse reactions. Subjects will be discontinued if they have moderate or severe adverse reaction ratings according to the CTCAE, which are not remediable by dosage reduction.

Study Type

Interventional

Enrollment (Anticipated)

150

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Santa Monica, California, United States, 90403
        • Neurological Associates of West LA

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

43 years to 87 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Cognitive decline with mild cognitive impairment (Clinical Dementia Rating Stage 0.5) through moderate dementia (CDR Stages 1 and 2)

Exclusion Criteria:

  • Subjects with a history of hypersensitivity to bosutinib
  • Subjects with contraindications for lumbar puncture, such as bleeding abnormalities, use of anticoagulant medications, and local skin or spine abnormalities
  • Reversible causes of cognitive impairment that explains the clinical status entirely, such as hypothyroidism, depression
  • Advanced stages of any terminal illness or any active cancer that requires chemotherapy
  • Pre-existing renal impairment
  • Pre-existing hepatic impairment
  • QT prolongation
  • Significant cytopenia
  • Cardiovascular, cerebrovascular, and peripheral vascular arterial thrombosis
  • Women who are pregnant, may become pregnant, or are breastfeeding
  • Women of child-bearing potential and male participants with female partners who are of child-bearing potential
  • Subjects unable to give informed consent or in vulnerable categories, such as prisoners

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Bosutinib Treatment Arm
Subjects will be administered the initial dose of bosutinib, with dosage progressively increased over the course of the study. The initial dose of bosutinib is 100 mg tablet, once per day. The dose will be increased as tolerated up to 300 mg per day. The dose will be increased by 100 mg each month if the lower dose is tolerated without significant side effects. That is to say, the subject will take 100 mg/day every day for the first month, 200 mg/day every day for the second month, and 300 mg/day every day for the third month and for the remainder of the study, provided that adverse reactions do not prohibit continuation at this dosage. Stopping and dose reduction rules for reported adverse reactions have been taken from the package insert of bosutinib. The duration of treatment is 1 year.
Drug: bosutinib
Other Names:
  • TKI
  • bosulif

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients who are discontinued due to tolerability issues related to treatment
Time Frame: 1 year
Outcome goal to determine safety and tolerability of study medication
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Neurological Associates of West Los Angeles

Collaborators

Pfizer

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2016

Primary Completion (Anticipated)

December 31, 2023

Study Completion (Anticipated)

December 31, 2025

Study Registration Dates

First Submitted

September 28, 2016

First Submitted That Met QC Criteria

September 30, 2016

First Posted (Estimate)

October 3, 2016

Study Record Updates

Last Update Posted (Actual)

September 28, 2022

Last Update Submitted That Met QC Criteria

September 26, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 062016

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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