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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of bosutinib, a type of medication, for individuals with mild cognitive impairment or dementia. Researchers seek to determine the safety of long-term use and its impact on symptoms. Those experiencing memory problems or a decline in thinking skills affecting daily life might be suitable for this study. Participants will take bosutinib daily, beginning with a low dose that increases if significant side effects do not occur. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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 there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that bosutinib is generally safe and well-tolerated by patients. Several studies found that bosutinib effectively enters the brain, which is crucial for treating conditions like dementia. Patients taking a 100 mg dose of bosutinib reported few side effects, and the treatment reduced certain harmful proteins in the brain. These findings suggest that bosutinib might be a promising option for those with memory and thinking problems. As with any treatment, monitoring for side effects and discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for dementia focus on managing symptoms or slowing progression through medications that target neurotransmitter systems, like cholinesterase inhibitors and NMDA receptor antagonists. However, bosutinib is unique because it is a tyrosine kinase inhibitor (TKI), which targets specific enzymes involved in cellular processes that may contribute to dementia. This novel mechanism of action holds promise for potentially altering the underlying disease process rather than just addressing symptoms. Researchers are excited about bosutinib because it could offer a new approach in treating dementia, providing hope for more effective management of the condition.

What evidence suggests that bosutinib might be an effective treatment for dementia?

Research suggests that bosutinib could be helpful in treating dementia. Studies have shown that it is safe, can enter the brain, and targets specific proteins important for brain health. One of these proteins, alpha-synuclein, can build up in the brain and is linked to dementia. In one study, patients who took bosutinib for a year experienced positive results, but their conditions worsened when they stopped taking it. Additionally, bosutinib has helped people with certain types of dementia improve their daily activities. These findings support the potential of bosutinib to help manage dementia symptoms. Participants in this trial will receive bosutinib, with the dosage progressively increased over the course of the study. ^{1 2 3 5 6}

Who Is on the Research Team?

Sheldon Jordan, MD

Principal Investigator

Neurological Associates of West Los Angeles

Are You a Good Fit for This Trial?

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

I have an advanced terminal illness or cancer needing chemotherapy.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8382351/

Treatment of Dementia With Bosutinib: An Open-Label Study ... The data suggest an overall positive outcome among participants after a year of bosutinib, with a worsening in condition following treatment discontinuation.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9157583/

Safety, target engagement, and biomarker effects of bosutinib ... Bosutinib is safe and well tolerated and penetrates the blood–brain barrier to inhibit Abelson and reduce CSF alpha‐synuclein and dopamine catabolism.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03888222

Impact of Bosutinib on Safety, Tolerability, Biomarkers and ... This study evaluates the effect of Bosutinib (Bosulif,Pfizer®) in the treatment of patients with Dementia with Lewy Bodies. Half participants will receive 100 ...

4. neurology.org neurology.org/doi/10.1212/WNL.98.18_supplement.2799

Safety, Target Engagement and Effects of Bosutinib in ... Bosutinib is safe and enters the brain. Bosutinib, 100mg, inhibited Abl/Src indicting dual target engagement, reduced brain alpha-synuclein and improved ...

5. conferences.medicom-publishers.com conferences.medicom-publishers.com/content/conference-reports/safety-and-effects-of-bosutinib-in-lewy-body-dementia/

Safety and effects of bosutinib in Lewy body dementia Bosutinib 100 mg inhibited Abl/Src in plasma, reduced brain alpha-synuclein, and improved activities of daily living. These outcomes will guide ...

6. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/trc2.12296

Safety, target engagement, and biomarker effects of bosutinib ... Bosutinib is safe and well tolerated and penetrates the blood–brain barrier to inhibit Abelson and reduce CSF alpha-synuclein and dopamine catabolism.