TKI Cessation for Chronic Myeloid Leukemia

(TOKIN Trial)

Recruiting at 3 trial locations

Overseen By Martha Mims, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Baylor College of Medicine

Must be taking: Tyrosine kinase inhibitors

Disqualifiers: Stem cell transplant, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 24

Duration: 36+ months

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether individuals with chronic myeloid leukemia (CML) can safely discontinue tyrosine kinase inhibitors (TKIs), a type of cancer drug, after achieving stable remission. The primary goal is to determine if patients can maintain remission without the medication. Suitable candidates for this trial have been on TKIs for over three years, show no signs of leukemia outside the bone marrow, and have maintained stable remission for at least two years. Participants will stop taking TKIs and undergo monthly monitoring for two years to assess if the leukemia remains in remission. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial is specifically about stopping tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia, so you will need to stop taking TKIs if you participate. The protocol does not mention other medications, so it's unclear if you need to stop any other current medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that stopping tyrosine kinase inhibitors (TKIs) like bosutinib, dasatinib, imatinib mesylate, and nilotinib can be safe for some patients with chronic myeloid leukemia (CML). Studies indicate that bosutinib works well and is generally easy to tolerate, with some patients safely stopping it after achieving a stable response. This suggests that stopping bosutinib might be safe for those who respond well to it.

For dasatinib and nilotinib, research shows that patients with strong and lasting responses can safely stop these treatments. This has been observed in patients who have maintained their response for a long time.

Regarding imatinib mesylate, some studies found that patients may relapse if they stop treatment. However, other studies show that some can maintain their response even after stopping the medication. Imatinib generally has mild side effects like swelling, muscle cramps, and nausea, making it a well-tolerated option while on treatment.

Overall, stopping these TKIs has been shown to be safe for patients with a stable and strong response to treatment. Each TKI has a safety profile that supports stopping it under the right conditions. Patients should work closely with their healthcare providers to determine if stopping their TKI is appropriate. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores the possibility of safely stopping treatment with tyrosine kinase inhibitors (TKIs) for patients with chronic myeloid leukemia (CML) who are in complete molecular remission. Current standard treatments for CML involve long-term use of TKIs like Imatinib, Dasatinib, or Nilotinib to keep the disease under control. However, continuous TKI therapy can lead to side effects and financial costs. This trial aims to determine if patients can maintain remission without ongoing medication, which could significantly improve their quality of life. If successful, it could redefine the approach to managing CML by reducing or eliminating the need for lifelong treatment.

What evidence suggests that TKI cessation might be an effective treatment for chronic myeloid leukemia?

Research has shown that stopping certain medications called tyrosine kinase inhibitors (TKIs), such as bosutinib, dasatinib, imatinib mesylate, and nilotinib, can be effective for many people with chronic myeloid leukemia (CML) who have responded well to treatment. In this trial, participants will stop taking their TKI medication, including bosutinib, dasatinib, imatinib mesylate, or nilotinib, to evaluate the effects of cessation. For bosutinib, some patients continue to do well after stopping, although some may see their condition return within months. Dasatinib has shown good results, with many patients responding well again if their condition returns. Imatinib mesylate has a nearly 47% success rate of staying in remission without treatment for 24 months, indicating it works well for some. Nilotinib shows similar results, with about 61% of patients staying in remission six months after stopping and 50% at 24 months. Overall, stopping TKIs can be safe and effective for CML patients who have had a strong, lasting response to the treatment. ^{1 3 4 5 6}

Who Is on the Research Team?

Martha Mims, MD, PhD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for adults with chronic myeloid leukemia (CML) who have been on TKI therapy for over 3 years and show a stable molecular response. They must have good blood counts, no signs of aggressive leukemia outside the bone marrow, and be expected to live more than a year without treatment. Participants need to understand the study's research nature and consent in writing.

Inclusion Criteria

Prior evidence of a quantifiable BCR-ABL1 transcript by RT-PCR

Contraception requirements will be as per routine clinical practice.

Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L

Exclusion Criteria

I have an ongoing liver condition like hepatitis or cirrhosis.

I have been diagnosed with HIV.

Any medical condition that, in the opinion of the investigator, would exclude the patient from participating in this study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants continue TKI therapy for more than 36 months with a current status of complete molecular remission (CMR) before cessation

36+ months

Cessation

Participants stop taking TKI and undergo monthly BCR-ABL1 testing for 24 months

24 months

24 visits (monthly in-person)

Follow-up

Participants are monitored for progression-free survival and molecular relapse-free survival

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Bosutinib
• Dasatinib
• Imatinib Mesylate
• Imatinib Mesylate, Dasatinib, Nilotinib or Bosutinib Re-initiation
• Imatinib Mesylate, Dasatinib, Nilotinib or Bosutinib Withdrawal
• Nilotinib

Trial Overview

The study tests if patients with CML can safely stop taking their tyrosine kinase inhibitors (TKIs), which are drugs like Imatinib Mesylate, Dasatinib, Nilotinib or Bosutinib. If needed, it also looks at what happens when these drugs are restarted.

How Is the Trial Designed?

Group I: All Subjects Enrolled (stop taking TKI) Experimental Treatment 2 Interventions

Patients with a diagnosis of Philadelphia chromosome- or BCR-ABL1-positive CML (as determined by cytogenetics, FISH, or PCR), prior evidence of a quantifiable BCR-ABL1 transcript by RT-PCR, and whom have been taking TKI for \> 36 months with a current status of complete molecular remission (CMR). TKI cessation begins within 7 days of study registration. Patients undergo BCR-ABL1 test every month in 24 months.

Bosutinib is already approved in United States for the following indications:

Approved in United States as Bosulif for:

• Treatment of adult patients with chronic, accelerated or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy
• Treatment of adult patients with newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML)
• Treatment of pediatric patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML), newly-diagnosed or resistant or intolerant to prior therapy

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Published Research Related to This Trial

Bosutinib (Bosulif) received conditional marketing authorization in the EU for treating adult patients with Philadelphia chromosome positive chronic myelogenous leukemia (CML) who have previously been treated with other tyrosine kinase inhibitors and for whom standard treatments are not suitable.

The efficacy of bosutinib was primarily demonstrated in a subgroup analysis of a phase I/II study, focusing on patients with specific BCR-ABL mutations that indicate resistance to other treatments, highlighting its targeted mechanism of action as a kinase inhibitor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European medicines agency review of bosutinib for the treatment of adult patients with chronic myelogenous leukemia: summary of the scientific assessment of the committee for medicinal products for human use. Hanaizi, Z., Unkrig, C., Enzmann, H., et al.[2021]

In a study of 30 patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who had failed three previous tyrosine kinase inhibitors, bosutinib showed a 56.6% probability of maintaining or improving their complete cytogenetic response (CCyR) after a median follow-up of 11.1 months.

Bosutinib demonstrated a promising progression-free survival rate of 73% at 20 months, making it a viable treatment option for patients resistant or intolerant to prior therapies, although it was associated with higher rates of severe hematological and non-hematological toxicities, particularly in resistant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib shows low cross intolerance, in chronic myeloid leukemia patients treated in fourth line. Results of the Spanish compassionate use program. García-Gutiérrez, V., Martinez-Trillos, A., Lopez Lorenzo, JL., et al.[2022]

In a study of 293 Italian patients with chronic myeloid leukemia (CML) who discontinued tyrosine kinase inhibitors (TKI) after achieving deep molecular response, 62% maintained treatment-free remission (TFR) after a median follow-up of 34 months, indicating that stopping TKI can be safe and effective.

The study found no disease progression during the follow-up period, supporting the feasibility of TKI discontinuation in clinical practice, with the majority of patients stopping treatment due to shared decision-making with their physician.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Observational study of chronic myeloid leukemia Italian patients who discontinued tyrosine kinase inhibitors in clinical practice. Fava, C., Rege-Cambrin, G., Dogliotti, I., et al.[2020]

In a study of 584 patients with chronic myeloid leukaemia (CML), 23% successfully discontinued tyrosine kinase inhibitor (TKI) therapy after achieving a deep molecular response, indicating that TKI discontinuation is feasible in clinical practice.

Among those who stopped TKI treatment, nearly half (49%) had to restart therapy within about 4.8 months, suggesting that while discontinuation can be successful, some patients may still require ongoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful tyrosine kinase inhibitor discontinuation outside clinical trials - data from the population-based Swedish chronic myeloid leukaemia registry. Flygt, H., Sandin, F., Dahlén, T., et al.[2021]

In a study of 118 chronic myeloid leukemia (CML) patients who were resistant or intolerant to previous treatments, bosutinib showed significant efficacy with a 32% major cytogenetic response and a 73% complete hematologic response after a median follow-up of 28.5 months.

Bosutinib demonstrated an acceptable safety profile, with mostly manageable side effects like gastrointestinal issues and rash, making it a promising treatment option for CML patients who have failed multiple prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Khoury, HJ., Cortes, JE., Kantarjian, HM., et al.[2022]

Bosutinib shows equivalent efficacy to nilotinib and dasatinib in treating newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML), based on an unanchored matching-adjusted indirect treatment comparison using patient-level data from the BFORE trial and aggregated data from other studies.

While there were no statistically significant differences in major molecular response (MMR) or disease progression between bosutinib and the other two drugs, bosutinib demonstrated a trend towards better outcomes in achieving deeper molecular responses (MR4 and MR4.5) compared to nilotinib and dasatinib after 24 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia. Muresan, B., Mamolo, C., Cappelleri, JC., et al.[2022]

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]

In a phase I/II study involving 284 patients with chronic myeloid leukemia who had previously failed imatinib treatment, bosutinib showed durable efficacy, with 54% of patients remaining on treatment at 2 years and 40% at 5 years.

Bosutinib demonstrated a cumulative major cytogenetic response rate of 60% and a complete cytogenetic response rate of 50% by year 5, with manageable side effects primarily consisting of gastrointestinal issues, confirming its role as an effective second-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Gambacorti-Passerini, C., Cortes, JE., Lipton, JH., et al.[2019]

In a study of 117 patients with chronic myeloid leukemia, dasatinib showed higher adherence to treatment (91%) compared to nilotinib (82%) over two years.

Both dasatinib and nilotinib demonstrated similar efficacy in terms of progression-free survival (PFS) at 92%, indicating that while dasatinib may be better adhered to, both drugs are equally effective in preventing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adherence, persistence and efficacy of dasatinib and nilotinib in the treatment of patients resistant or intolerant to imatinib with chronic myeloid leukemia in chronic phase: an Italian multicenter study over two years in real life. Santoleri, F., Ranucci, E., La Barba, G., et al.[2022]

In a study of 60 patients with chronic myeloid leukemia (CML) who discontinued second-generation tyrosine kinase inhibitors (TKIs) after achieving a stable molecular response, 63.33% maintained treatment-free remission (TFR) at 12 months, indicating promising efficacy of TKI discontinuation.

Despite a 43.3% relapse rate within the first year, all patients who relapsed were able to regain their previous molecular response upon restarting therapy, suggesting that discontinuation is safe and manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Rea, D., Nicolini, FE., Tulliez, M., et al.[2022]

In a phase III study involving 536 patients with newly diagnosed chronic-phase CML, bosutinib demonstrated significantly higher rates of major molecular response (47.2% vs. 36.9%) and complete cytogenetic response (77.2% vs. 66.4%) compared to imatinib after 12 months.

While bosutinib was more effective, it also had a higher incidence of gastrointestinal side effects and liver enzyme elevations, indicating a need for monitoring but suggesting it may be a strong first-line treatment option for CML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. Cortes, JE., Gambacorti-Passerini, C., Deininger, MW., et al.[2022]

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Many patients were, in the end, treated successfully and durably with doses lower than the planned 400 mg daily dose (median dose 393.6 mg/d).

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At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8–92.6); there were 17 deaths, including 2 that were considered CML ...

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