Ruxolitinib + TKI for CML

Recruiting at 7 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must be taking: Tyrosine kinase inhibitors

Must not be taking: JAK inhibitors

Disqualifiers: Accelerated CML, TKI resistance, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 24

24 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine if adding Ruxolitinib to a Tyrone Kinase Inhibitor (TKI), prior to a second attempt at stopping a TKI will lead to prolonged treatment free remission (TFR).

Do I have to stop my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you must stay on the same TKI you were on before your first treatment-free remission attempt.

Will I have to stop taking my current medications?

The trial requires that you stay on your current TKI medication for at least 12 months during the combination treatment phase. You do not need to stop taking your current TKI, but you must continue with the same one you were on before your first treatment-free remission attempt.

What data supports the idea that Ruxolitinib + TKI for CML is an effective treatment?

The available research shows that using BCR-ABL tyrosine kinase inhibitors (TKIs) like imatinib has significantly improved the outcomes for patients with chronic myeloid leukemia (CML). Imatinib was the first drug to make a big difference, but some patients developed resistance to it. Newer drugs like dasatinib and nilotinib have been developed to overcome this resistance and have shown better results in patients who didn't respond well to imatinib. These newer drugs are more powerful and can help patients achieve a deeper response, meaning the disease is less detectable in their bodies. While the research doesn't specifically mention Ruxolitinib combined with TKIs, the success of these newer TKIs suggests that combining them with other treatments like Ruxolitinib could potentially be effective. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Ruxolitinib + TKI for CML?

Research shows that BCR-ABL tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib have significantly improved outcomes for patients with chronic myeloid leukemia (CML) by targeting the cancer-causing protein. These drugs have been effective in patients who are resistant to initial treatments, suggesting that combining them with Ruxolitinib could potentially enhance treatment effectiveness. ^{1 2 3 4 5}

What safety data is available for Ruxolitinib + TKI treatment in CML?

The safety data for TKIs used in CML treatment, such as imatinib, nilotinib, dasatinib, and bosutinib, indicates that these drugs have differing safety profiles. Common adverse events include cardiovascular toxicity, myelosuppression, fluid retention, gastrointestinal toxicity, and dermatologic toxicity. Cardiovascular events are a significant concern, especially with long-term use. Most adverse events are mild to moderate and manageable, but long-term safety, particularly with newer TKIs, is not fully understood. Bosutinib, for example, has shown an acceptable safety profile with primarily manageable grade 1/2 gastrointestinal events and rash. Ruxolitinib's safety profile in combination with TKIs is not specifically detailed in the provided research, but understanding the safety profiles of individual TKIs can help inform treatment decisions. ^{6 7 8 9 10}

Is the combination of Ruxolitinib and TKI safe for treating CML?

TKIs like imatinib, nilotinib, dasatinib, and bosutinib are generally safe but can cause side effects such as cardiovascular issues, fluid retention, and gastrointestinal problems. Ruxolitinib, often used for other conditions, has its own safety profile, but specific safety data for the combination with TKIs in CML is not detailed in the available research. ^{6 7 8 9 10}

Is the drug BCR-ABL Tyrosine Kinase Inhibitor (TKI) a promising treatment for CML?

Yes, BCR-ABL Tyrosine Kinase Inhibitors (TKIs) are promising drugs for treating Chronic Myeloid Leukemia (CML). They are effective in reducing the activity of the BCR-ABL1 enzyme, which is responsible for CML. TKIs like imatinib, dasatinib, and nilotinib have improved patient outcomes and are well-tolerated. They also help overcome resistance to earlier treatments, making them a valuable option for CML patients. ^{4 11 12 13 14}

What makes the drug Ruxolitinib + TKI unique for treating CML?

The combination of Ruxolitinib with a Tyrosine Kinase Inhibitor (TKI) for treating chronic myeloid leukemia (CML) is unique because it explores the potential benefits of combining a JAK inhibitor (Ruxolitinib) with TKIs, which are already effective in targeting the BCR-ABL1 kinase responsible for CML. This approach may offer a new strategy to overcome resistance seen with TKIs alone. ^{4 11 12 13 14}

Research Team

Javier Pinilla-Ibarz, MD, PhD

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Eligibility Criteria

This trial is for individuals with chronic phase Chronic Myeloid Leukemia (CML) who have tried to stop taking their Tyrosine Kinase Inhibitor (TKI) once before but saw their disease return. They must be in stable condition, not resistant to TKIs, and meet specific criteria regarding previous treatment responses and current health status.

Inclusion Criteria

I've been on a TKI for at least 1 year after my first treatment failure and plan to stay on it.

Must have met ALL the following criteria prior to first attempt to discontinue their TKI:

I have chronic phase CML with specific genetic variants.

Exclusion Criteria

My cancer has not responded to TKI treatment.

You cannot have taken any other experimental drugs in the 4 weeks leading up to the study.

I do not have any serious health or mental conditions that could stop me from completing the treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Combination Therapy

Participants receive Ruxolitinib in combination with BCR-ABL Tyrosine Kinase Inhibitors for 12 cycles

12 months

Monthly visits for each cycle

Treatment Free Remission (TFR)

Participants discontinue BCR-ABL TKI and are monitored off treatment

36 months

Regular PCR testing during the first 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BCR-ABL Tyrosine Kinase Inhibitor (TKI)
• Ruxolitinib

Trial Overview The study aims to see if adding Ruxolitinib to a patient's current TKI therapy can help them achieve a prolonged period where they don't need any treatment at all after stopping the TKI for the second time.

Participant Groups

Group I: Combination Therapy + Remission Phase Experimental Treatment 2 Interventions

Combination therapy followed by treatment free remission (TFR) phase. Combination Therapy: Ruxolitinib plus BCR-ABL Tyrosine Kinase Inhibitors (TKIs). All eligible patients will begin ruxolitinib in combination with their BCR-ABL TKI on cycle 1 day 1 of the combination phase. For cycle 2 and beyond, if day 1 of a cycle is delayed, day 1 procedures should be repeated if out of the specified window and day 1 of the cycle is considered the day study drug is restarted. They will continue combination therapy for a total of 12 cycles. Each cycle will be approximately 28 days. At the end of 12 cycles ruxolitinib will be discontinued and any patient who has met the criteria for the treatment free remission (TFR) screening phase will enter into the TFR phase. Once in the TFR phase, participants will discontinue their BCR-ABL TKI and be monitored off treatment.

BCR-ABL Tyrosine Kinase Inhibitor (TKI) is already approved in European Union, United States for the following indications:

Approved in European Union as Imatinib for:

• Chronic myeloid leukemia (CML)
• Gastrointestinal stromal tumors (GIST)

Approved in United States as Imatinib for:

• Chronic myeloid leukemia (CML)
• Gastrointestinal stromal tumors (GIST)
• Acute lymphoblastic leukemia (ALL)

Approved in European Union as Dasatinib for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in United States as Dasatinib for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in European Union as Nilotinib for:

• Chronic myeloid leukemia (CML)

Approved in United States as Nilotinib for:

• Chronic myeloid leukemia (CML)

Approved in European Union as Bosutinib for:

• Chronic myeloid leukemia (CML)

Approved in United States as Bosutinib for:

• Chronic myeloid leukemia (CML)

Approved in European Union as Ponatinib for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in United States as Ponatinib for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in European Union as Asciminib for:

• Chronic myeloid leukemia (CML)

Approved in United States as Asciminib for:

• Chronic myeloid leukemia (CML)

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

H. Jean Khoury Cure CML Consortium

Collaborator

Trials

3

Recruited

80+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

Patients with chronic myeloid leukemia (CML) who had a warning response (BCR-ABL transcript level >0.1% and ≤1%) after 12 months of treatment with tyrosine kinase inhibitors (TKIs) had significantly poorer long-term outcomes compared to those with a best response (BCR-ABL ≤0.1%).

The size of the spleen was identified as an independent risk factor affecting prognosis, with larger spleen size correlating with a slower achievement of deep molecular response (DMR) and a poorer long-term prognosis, suggesting that early intervention may be necessary for patients with warning responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Relationship between BCR-ABLIS and Prognosis and Affecting Factors for Prognosis in CML Patients Treated with TKI for 12 Months]. Hu, CY., Yu, D., Zhan, B., et al.[2019]

Imatinib, the first BCR-ABL1 tyrosine kinase inhibitor, has set a foundation for treating chronic myeloid leukemia (CML), and newer, more potent TKIs are enhancing treatment expectations.

Molecular monitoring is crucial for improving patient outcomes in CML, as achieving an early molecular response to TKI therapy is linked to better long-term prognoses and the potential for treatment-free remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: importance of achieving treatment-free remission. Erba, HP.[2015]

Imatinib mesylate (Gleevec) has significantly improved the prognosis and survival rates for Chronic Myeloid Leukemia (CML) patients by targeting the BCR-ABL tyrosine kinase, which is present in over 90% of cases.

Resistance to imatinib, primarily due to mutations in the ABL kinase domain, has led to the development of second-generation TKIs like nilotinib and dasatinib, which are effective for patients who are intolerant or resistant to imatinib, although they are not effective against the T315I mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. An, X., Tiwari, AK., Sun, Y., et al.[2022]

Imatinib, the first tyrosine kinase inhibitor (TKI) approved for chronic myelogenous leukemia (CML), has greatly improved patient outcomes, but resistance occurs in 40% to 50% of cases due to mutations affecting its binding to the Bcr-Abl kinase.

Novel TKIs, such as dasatinib and nilotinib, have been developed to overcome resistance mechanisms, and combination therapies are being explored to enhance treatment efficacy by targeting multiple pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance. Jabbour, E., Cortes, J., O'Brien, S., et al.[2022]

In a study of 16 chronic-phase chronic myeloid leukemia (CP-CML) patients who had been on imatinib for at least two years, switching to dasatinib resulted in a significant increase in deep molecular response (DMR) rates, reaching 75% by 12 months.

The treatment switch also led to an increase in immune cell populations, specifically natural killer and cytotoxic T cells, while reducing regulatory T cells, indicating a potential enhancement in immune response alongside the efficacy of dasatinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy. Shiseki, M., Yoshida, C., Takezako, N., 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]

BCR-ABL tyrosine kinase inhibitors (TKIs) have significantly improved outcomes for patients with chronic myeloid leukemia (CML), but the presence of comorbidities can negatively impact prognosis.

Recent studies indicate that cardiovascular events (CVE) may occur as a late toxicity of TKIs, necessitating a collaborative approach between hematologists and cardiologists to manage these risks effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The importance of taking late cardiovascular toxicity induced by TKI into consideration in patients with CML. Takahashi, N.[2017]

In a study of 3,722 patients with chronic myeloid leukemia (CML), those treated with imatinib had a higher risk of adverse cardiovascular and cerebrovascular events (ACE) compared to those on dasatinib, but a lower risk compared to nilotinib.

Patients on imatinib also showed a higher risk of heart failure compared to those on dasatinib, although the difference was not significant when compared to nilotinib, indicating varying cardiac safety profiles among BCR-ABL tyrosine kinase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year cardiovascular outcomes in patients with chronic myeloid leukemia treated with imatinib, dasatinib, or nilotinib: A cohort study using data from a large multinational collaborative network. Nunes, RAB., Neves, PDMM., da Costa, LMA., et al.[2023]

Tyrosine kinase inhibitors (TKIs) have significantly improved long-term survival rates for patients with chronic myeloid leukemia (CML), but treatment must be carefully managed due to potential adverse events that can occur, especially early in therapy.

While TKIs generally have a favorable safety profile, new-generation TKIs may pose long-term risks to vital organs like the heart and lungs, particularly in patients with existing health issues, necessitating a careful selection of treatment based on individual patient factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia. Rea, D.[2022]

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]

In a study of 150 chronic myeloid leukemia (CML) patients treated sequentially with tyrosine kinase inhibitors (TKIs) over an average follow-up of 8.3 years, 88.6% achieved complete cytogenetic response (CCyR) and 58.0% achieved major molecular response (MMR), indicating effective treatment outcomes.

The 10-year overall survival (OS) and event-free survival (EFS) rates were 81.33% and 79.33%, respectively, with factors such as high ELTS score, poor ECOG performance status, and delayed achievement of MMR or CCyR linked to poorer survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes with Sequential Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients. Towachiraporna, S., Punnachet, T., Hantrakun, N., et al.[2023]

Bosutinib is an effective second-line treatment for patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who are resistant or intolerant to other tyrosine kinase inhibitors (TKIs), showing durable hematologic and cytogenetic responses in clinical trials.

While bosutinib is not superior to imatinib for newly diagnosed CML, it is safe for use, with common side effects like diarrhea and nausea being generally mild and self-limiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib for the treatment of chronic myeloid leukemia. Doan, V., Wang, A., Prescott, H.[2019]

Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) that effectively targets BCR-ABL1 and other kinases, showing similar response rates in patients with chronic myeloid leukemia (CML) who were previously resistant or intolerant to imatinib, comparable to nilotinib and dasatinib.

The ongoing phase III BELA study is evaluating bosutinib against imatinib in newly diagnosed CML patients, which could further establish its efficacy as a frontline treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib for the treatment of chronic myeloid leukemia in chronic phase. Quintás-Cardama, A., Kantarjian, H., Cortes, J.[2023]

Tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib are crucial for treating Chronic Myeloid Leukemia (CML) due to their ability to effectively reduce BCR-ABL1 tyrosine kinase activity, with proven bioavailability and stable blood concentrations in humans.

The pharmacokinetics of TKIs are influenced by various factors such as daily dosage, diet, individual variability, drug interactions, resistance, and withdrawal, which are essential for optimizing clinical treatment outcomes in CML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insight to Pharmacokinetics of TKIs: Optimizing Practical Guidelines for Individualized Therapy. Wang, R., Zhong, C., Zhang, C., et al.[2018]

References

1. China pubmed.ncbi.nlm.nih.gov

[Relationship between BCR-ABLIS and Prognosis and Affecting Factors for Prognosis in CML Patients Treated with TKI for 12 Months]. [2019]

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

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: importance of achieving treatment-free remission. [2015]

3. England pubmed.ncbi.nlm.nih.gov

BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. [2022]

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

New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance. [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy. [2018]

6. 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]

7. Japan pubmed.ncbi.nlm.nih.gov

The importance of taking late cardiovascular toxicity induced by TKI into consideration in patients with CML. [2017]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Five-year cardiovascular outcomes in patients with chronic myeloid leukemia treated with imatinib, dasatinib, or nilotinib: A cohort study using data from a large multinational collaborative network. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia. [2022]

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

Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. [2022]

11. Thailand pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes with Sequential Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Bosutinib for the treatment of chronic myeloid leukemia. [2019]

13. Spain pubmed.ncbi.nlm.nih.gov

Bosutinib for the treatment of chronic myeloid leukemia in chronic phase. [2023]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Insight to Pharmacokinetics of TKIs: Optimizing Practical Guidelines for Individualized Therapy. [2018]