Ruxolitinib + Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Recruiting at 551 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: SWOG Cancer Research Network

Must be taking: Tyrosine kinase inhibitors

Must not be taking: Investigational agents

Disqualifiers: Pregnancy, Nursing, 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

Compensation: Varies

Number of Visits: 10

Duration: 12 months

84 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase II trial studies how well ruxolitinib phosphate, and bosutnib, dasatinib, imatinib or nilotinib, work in treating patients with chronic myeloid leukemia. Chronic myeloid leukemia cells produce a protein called BCR-ABL. The BCR-ABL protein helps chronic myeloid leukemia cells to grow and divide. Tyrosine kinase inhibitors, such as bosutinib, dasatinib, and nilotinib, stop the BCR-ABL protein from working, which helps to reduce the amount of chronic myeloid leukemia cells in the body. Ruxolitinib is a different type of drug that helps to stop the body from making substances called growth factors. Chronic myeloid leukemia cells need growth factors to grow and divide. The addition of ruxolitinib to the tyrosine kinase inhibitor may or may not help reduce the amount of chronic myeloid leukemia cells in the body.

Will I have to stop taking my current medications?

The trial requires that you continue taking your current tyrosine kinase inhibitor medication, such as bosutinib, nilotinib, dasatinib, or imatinib, for the duration of the study.

What data supports the effectiveness of the drug combination Ruxolitinib and Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia?

Research shows that tyrosine kinase inhibitors like nilotinib, dasatinib, and imatinib have improved the quality of life for patients with chronic myeloid leukemia, turning it into a manageable chronic condition. Bosutinib, another tyrosine kinase inhibitor, has demonstrated durable effectiveness and manageable side effects in patients who did not respond well to imatinib, with high survival rates over five years. ^{1 2 3 4 5}

What is the safety profile of Bosutinib for chronic myeloid leukemia?

Bosutinib is generally safe for treating chronic myeloid leukemia, but it can cause side effects like diarrhea, nausea, and liver issues. These side effects are usually manageable with dose adjustments or temporary treatment breaks. ^{4 6 7 8 9}

What makes the drug combination of Ruxolitinib and Tyrosine Kinase Inhibitors unique for treating chronic myeloid leukemia?

This treatment combines Ruxolitinib, which targets the JAK-STAT pathway, with tyrosine kinase inhibitors like Bosutinib, which is effective against most imatinib-resistant mutations in chronic myeloid leukemia. This combination may offer a novel approach by addressing different pathways involved in the disease, potentially benefiting patients who are resistant or intolerant to other treatments. ^{2 6 8 10 11}

Research Team

Kendra L Sweet

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for chronic myeloid leukemia patients who've been on tyrosine kinase inhibitors (TKI) like bosutinib, dasatinib, imatinib or nilotinib for at least a year. They should have stable vital signs and organ function, not be pregnant or breastfeeding, agree to use contraception, and not have HIV with detectable viral loads. Prior cancer is okay if no active treatment is needed.

Inclusion Criteria

My BCR-ABL levels are between 0.0032% and 1.0% as confirmed by a recent test.

I am currently on treatment with specific targeted cancer drugs.

My heart's electrical activity is normal as per my recent EKG.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a tyrosine kinase inhibitor alone or in combination with ruxolitinib for up to 12 months, with treatment cycles repeating every 90 days

12 months

4 cycles of 90 days each

Follow-up

Participants are monitored for safety, effectiveness, and survival outcomes after treatment completion

Up to 5 years

Every 6 months for 2 years, then annually

Treatment Details

Interventions

• Bosutinib
• Dasatinib
• Imatinib
• Nilotinib Hydrochloride Monohydrate
• Ruxolitinib Phosphate

Trial Overview The study tests adding Ruxolitinib—a drug that blocks growth factors necessary for leukemia cells—to the usual TKI treatments. It's a phase II randomized trial aiming to see if this combination better reduces leukemia cell counts compared to TKI alone.

Participant Groups

Group I: Arm II (ruxolitinib phosphate, dasatinib, nilotinib, imatinib) Experimental Treatment 5 Interventions

Patients receive ruxolitinib phosphate PO BID on days 1-90, and bosutinib PO daily or dasatinib PO daily or nilotinib PO BID or imatinib PO daily on days 1-90. Treatment repeats every 90 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (bosutinib, dasatinib, nilotinib, imatinib) Active Control 5 Interventions

Patients receive bosutinib PO daily or dasatinib PO daily or nilotinib PO BID or imatinib PO daily on days 1-90. Treatment repeats every 90 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

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?

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

In a cost-effectiveness analysis involving 100 patients with chronic myeloid leukemia, nilotinib was found to provide more progression-free life-years saved (15.21) compared to imatinib (12.64) and dasatinib (14.91), indicating its superior efficacy as a first-line treatment.

Nilotinib was also shown to be more cost-effective than dasatinib, with a lower incremental cost-effectiveness ratio of US$ 33,120.36 per progression-free life-year saved, making it the preferred option for treatment in Colombia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of nilotinib, dasatinib and imatinib as first-line treatment for chronic myeloid leukemia in Colombia, 2012. Romero, M., Chávez, D., De Los Ríos, M., 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]

Bosutinib is an effective treatment for chronic myeloid leukemia, particularly in patients who have developed resistance or intolerance to other tyrosine kinase inhibitors, demonstrating sustained efficacy in the chronic phase of the disease.

The safety profile of bosutinib includes distinct but manageable side effects, and it can be used without absolute contraindications in most patients, except those with specific mutations (T315I and V299L).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib: a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia. Rassi, FE., Khoury, HJ.[2021]

Bosutinib is a newly approved tyrosine kinase inhibitor for chronic myeloid leukemia that is effective even in the presence of most kinase domain mutations, making it a valuable treatment option.

The primary side effects of bosutinib are gastrointestinal issues, which should be considered when selecting it as a treatment in the appropriate clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical advances in the management of chronic myelogenous leukemia: focus on bosutinib and patient considerations. Sweet, K., Pinilla-Ibarz, J., Zhang, L.[2021]

Ruxolitinib is a well-absorbed tyrosine kinase inhibitor with 95% bioavailability, primarily metabolized in the liver, and its pharmacokinetics can vary based on factors like gender and body weight.

The drug's effectiveness can be influenced by liver and renal function, necessitating dose adjustments, and while model-informed precision dosing could enhance treatment personalization, more research is needed before it can be routinely implemented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review. Appeldoorn, TYJ., Munnink, THO., Morsink, LM., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Bosutinib for Chronic Myeloid Leukemia. [2020]

3. Colombia pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of nilotinib, dasatinib and imatinib as first-line treatment for chronic myeloid leukemia in Colombia, 2012. [2022]

4. 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]

5. Italy 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. [2019]

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

Bosutinib: a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia. [2021]

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

Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. [2022]

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

Clinical advances in the management of chronic myelogenous leukemia: focus on bosutinib and patient considerations. [2021]

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

Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. [2022]

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

Profile of bosutinib and its clinical potential in the treatment of chronic myeloid leukemia. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review. [2023]