TKIs for Dementia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Neurological Associates of West Los Angeles

Must not be taking: Anticoagulants

Disqualifiers: Hypersensitivity to bosutinib, Renal impairment, Hepatic impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 year

150 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are using anticoagulant medications, you may be excluded from the trial.

Is bosutinib safe for use in humans?

Bosutinib, a type of tyrosine kinase inhibitor (TKI), has been used to treat chronic myeloid leukemia and is generally considered safe, but it can cause side effects like diarrhea and liver issues. These side effects often occur early in treatment and need to be managed properly to ensure safety and effectiveness. ^{1 2 3 4 5}

How is the drug bosutinib unique for treating dementia?

Bosutinib is a tyrosine kinase inhibitor (TKI) that may offer a novel approach for treating dementia by targeting specific pathways involved in the disease. Unlike many existing treatments, TKIs like bosutinib have shown potential in crossing the blood-brain barrier, which is crucial for treating brain-related conditions. ^{6 7 8 9 10}

Research Team

Sheldon Jordan, MD

Principal Investigator

Neurological Associates of West Los Angeles

Eligibility Criteria

This trial is for people with mild to moderate dementia or cognitive decline, who can handle a lumbar puncture and don't have allergies to bosutinib. It's not for those with reversible cognitive issues, severe illnesses like advanced cancer, kidney or liver problems, heart rhythm issues, blood disorders, recent thrombosis, pregnant or breastfeeding women, and those unable to consent.

Inclusion Criteria

I have mild to moderate memory or thinking problems.

Exclusion Criteria

I have an advanced terminal illness or cancer needing chemotherapy.

I cannot have a lumbar puncture due to bleeding issues, medication, or spine problems.

My cognitive issues are not due to reversible causes like thyroid problems or depression.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive bosutinib with dosage progressively increased from 100 mg to 300 mg per day over the course of the study

1 year

Weekly visits for the first month, biweekly for the second month, then monthly

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• bosutinib

Trial Overview The study tests the drug bosutinib on patients with dementia. Starting at 100 mg daily and potentially increasing monthly up to 300 mg if tolerated without serious side effects. The goal is to see how well it works over time using brain scans and memory tests that are reliable and widely available.

Participant Groups

Group I: Bosutinib Treatment Arm Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Neurological Associates of West Los Angeles

Lead Sponsor

Trials

26

Recruited

4,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

The review highlights that the four available BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML)—imatinib, nilotinib, dasatinib, and bosutinib—have different safety profiles, which are influenced by their specificity and selectivity in targeting the BCR-ABL1 protein.

Understanding the mechanisms behind adverse events, such as cardiovascular toxicity and gastrointestinal issues, is crucial for clinicians when selecting the most appropriate TKI for patients, especially in first-line treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-, patient-, and disease-related factors and the emergence of adverse events with tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. Irvine, E., Williams, C.[2022]

Bosutinib is an effective treatment for chronic myeloid leukemia (CML) and is particularly useful for patients who have developed resistance or intolerance to other tyrosine kinase inhibitors (TKIs).

While bosutinib has a unique side effect of early and transient diarrhea, its overall adverse event profile is similar to other TKIs, with fewer cardiovascular issues, highlighting its potential as a safer option for long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of Bosutinib for the treatment of chronic myeloid leukemia. Kong, JH., Khoury, HJ., Kim, AS., et al.[2017]

Bosutinib is an effective second-generation tyrosine kinase inhibitor for treating chronic myeloid leukemia, showing efficacy in pivotal clinical trials with dosages of 400mg daily for first-line treatment and 500mg daily for later lines of treatment.

Management of bosutinib-related adverse events, particularly gastrointestinal symptoms and liver toxicity, is crucial for maintaining patient safety and treatment effectiveness, prompting expert recommendations for optimal management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Optimizing the use of bosutinib in patients with chronic-phase chronic myeloid leukemia: Recommendations of a panel of experts from the Fi-LMC (French CML working group)]. Rea, D., Cayssials, E., Charbonnier, A., et al.[2023]

Alectinib is an effective first-line treatment for patients with metastatic ALK+ non-small cell lung cancer (NSCLC), showing significant improvements in survival rates, even for those with brain metastases.

The review highlights alectinib's ability to target ALK gene rearrangements specifically, positioning it as a crucial therapy in the treatment course for ALK+ NSCLC patients, especially after prior treatment with crizotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of alectinib for the treatment of ALK-positive non-small cell lung cancer (NSCLC): patient selection and perspectives. Karachaliou, N., Fernandez Bruno, M., Bracht, JWP., et al.[2020]

Dovitinib, an oral multi-tyrosine kinase inhibitor, was found to be safe for patients with recurrent glioblastoma, with only 16.7% of adverse events classified as severe (grade 3) toxicity, primarily involving liver and blood-related issues.

The trial showed a progression-free survival rate of 16.7% at 6 months, indicating some efficacy, but this was not linked to the presence of the FGFR-TACC gene fusion in tumors, suggesting that further personalized trials are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. Schäfer, N., Gielen, GH., Kebir, S., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment-, patient-, and disease-related factors and the emergence of adverse events with tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Tofacitinib and Risk of Malignancy: Results From the Safety of Tofacitinib in Routine Care Patients With Rheumatoid Arthritis (STAR-RA) Study. [2023]

3. France pubmed.ncbi.nlm.nih.gov

Bosutinib. Chronic myeloid leukaemia in treatment failure: major toxicity. [2014]

4. England pubmed.ncbi.nlm.nih.gov

The safety of Bosutinib for the treatment of chronic myeloid leukemia. [2017]

5. France pubmed.ncbi.nlm.nih.gov

[Optimizing the use of bosutinib in patients with chronic-phase chronic myeloid leukemia: Recommendations of a panel of experts from the Fi-LMC (French CML working group)]. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance? [2017]

8. New Zealand pubmed.ncbi.nlm.nih.gov

EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data. [2020]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Profile of alectinib for the treatment of ALK-positive non-small cell lung cancer (NSCLC): patient selection and perspectives. [2020]

10. Germany pubmed.ncbi.nlm.nih.gov

Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. [2018]