Pembrolizumab + TKI for Chronic Myeloid Leukemia

Recruiting at 318 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: ECOG-ACRIN Cancer Research Group

Must be taking: TKIs

Must not be taking: Corticosteroids, Monoclonal antibodies

Disqualifiers: Active infection, Autoimmune disease, 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: 48

Duration: 54 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well pembrolizumab and dasatinib, imatinib mesylate, or nilotinib work in treating patients with chronic myeloid leukemia and persistent detection of minimal residual disease, defined as the levels of a gene product called bcr-abl in the blood. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Dasatinib, imatinib mesylate, and nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and dasatinib, imatinib mesylate, or nilotinib may work better in treating patients with chronic myeloid leukemia.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must have been on a stable dose of your current TKI (like dasatinib, imatinib mesylate, or nilotinib) for at least 3 months before joining. You should not be using strong CYP3A4 inducers or inhibitors within 7 days before starting the trial.

What data supports the effectiveness of the drug combination Pembrolizumab + TKI for Chronic Myeloid Leukemia?

Research shows that dasatinib and nilotinib are effective options for patients with chronic myeloid leukemia who do not respond well to imatinib, improving their quality of life and turning the disease into a chronic condition. Additionally, second-generation tyrosine kinase inhibitors like nilotinib and dasatinib have been shown to improve survival in patients when imatinib therapy fails. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and TKIs like Dasatinib or Imatinib safe for humans?

Dasatinib and Imatinib, both used for treating chronic myeloid leukemia, have been studied for safety. Dasatinib may cause pleural effusion (fluid around the lungs) and low platelet counts, while Imatinib may lead to fluid retention and muscle pain. Safety profiles vary, so treatment should be tailored to individual health conditions. ^{1 5 6 7 8}

What makes the drug combination of Pembrolizumab and TKIs unique for treating chronic myeloid leukemia?

This treatment combines Pembrolizumab, an immunotherapy drug that helps the immune system fight cancer, with tyrosine kinase inhibitors (TKIs) like Dasatinib, Imatinib, and Nilotinib, which are standard treatments for chronic myeloid leukemia. The combination aims to enhance the effectiveness of TKIs by also engaging the body's immune response, offering a potentially novel approach compared to using TKIs alone. ^{3 5 9 10 11}

Research Team

Amer Zeidan

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for chronic myeloid leukemia patients who've been on first-line TKI therapy for at least 2 years, are in MMR for over a year but haven't achieved complete molecular remission. They must have no active hemolytic anemia or other cancers, not be pregnant or breastfeeding, and agree to use contraception. Participants should have stable organ function and can't be on steroids or immunosuppressants.

Inclusion Criteria

I am scheduled for a bone marrow biopsy within the next week.

I have chronic myeloid leukemia and have been on a first-line treatment for at least 2 years.

I haven't reached complete molecular response since starting TKI therapy.

Exclusion Criteria

I have another cancer that is getting worse or needs treatment.

I have cancer that has spread to my brain or spinal cord.

I have a history of lung inflammation not caused by an infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab IV and dasatinib, imatinib mesylate, or nilotinib orally every 21 days for up to 18 courses

54 weeks

Every 21 days

Extended Treatment

Participants with detectable MRD continue treatment for an additional 18 courses

54 weeks

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

6 years

Every 6 months

Treatment Details

Interventions

• Dasatinib
• Imatinib Mesylate
• Nilotinib
• Pembrolizumab

Trial Overview The study tests if pembrolizumab combined with dasatinib, imatinib mesylate, or nilotinib is more effective than current treatments alone in chronic myeloid leukemia patients with minimal residual disease. It examines the effects of adding a monoclonal antibody (pembrolizumab) to existing enzyme-blocking cancer therapies.

Participant Groups

Group I: Treatment (pembrolizumab, dasatinib, imatinib, nilotinib) Experimental Treatment 5 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1 and dasatinib, imatinib mesylate, or nilotinib PO as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity.

Dasatinib is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Sprycel for:

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

Approved in European Union as Sprycel for:

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

Approved in Canada as Sprycel for:

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

Who Is Running the Clinical Trial?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

Patients with chronic myeloid leukemia who switched to second-generation tyrosine kinase inhibitors (like nilotinib or dasatinib) after failing imatinib therapy showed significantly longer overall survival compared to those who did not receive these inhibitors, with a relative risk of 0.28.

The survival benefit was particularly pronounced in patients who achieved a complete cytogenetic response with the second-generation inhibitors, while those who did not achieve this response had survival rates similar to the control group, indicating that achieving this response is crucial for maximizing treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-generation tyrosine kinase inhibitors improve the survival of patients with chronic myeloid leukemia in whom imatinib therapy has failed. Ibrahim, AR., Clark, RE., Holyoake, TL., et al.[2021]

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]

Imatinib (Gleevec) has significantly improved survival rates for patients with chronic myeloid leukemia in chronic phase (CML-CP), transforming a previously poor prognosis into one comparable to that of healthy individuals of similar age.

While newer TKIs like nilotinib (Tasigna) and dasatinib (Sprycel) offer faster responses and are effective for patients who cannot tolerate or are resistant to imatinib, they have not demonstrated a survival advantage over long-term imatinib treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is imatinib still an acceptable first-line treatment for CML in chronic phase? Goldman, JM., Marin, D.[2017]

Dasatinib demonstrated a higher rate of major molecular response (MMR) at 18 months compared to imatinib (76% vs 37%), indicating it may be more effective in achieving deeper responses in newly diagnosed chronic phase chronic myeloid leukemia (CML-CP) patients.

Both dasatinib and imatinib were well-tolerated with mostly mild side effects, but dasatinib was associated with specific adverse events like pleural effusion and thrombocytopenia, while imatinib had more cases of hypophosphatemia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preliminary comparison of efficacy and safety of dasatinib and imatinib in newly diagnosed chronic myeloid leukemia]. Zhou, L., Wang, JX., Huang, XJ., et al.[2022]

Tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia have similar effectiveness but vary in safety, making it crucial to choose treatments based on individual patient tolerability and adverse event profiles.

Specific TKIs like nilotinib and ponatinib should be avoided in patients with cardiovascular risks, while dasatinib is not recommended for those with lung damage, highlighting the need for personalized treatment plans based on patient comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of comorbidities on the choice of tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Saydam, G., Ali, R., Demir, AM., et al.[2022]

In the phase 3 DASISION trial involving 519 patients with newly diagnosed chronic-phase CML, dasatinib demonstrated superior efficacy over imatinib after 24 months, with higher rates of complete cytogenetic response (86% vs. 82%) and major molecular response (64% vs. 46%).

Dasatinib was associated with fewer instances of side effects like fluid retention and myalgia compared to imatinib, although it had a higher frequency of pleural effusion and severe thrombocytopenia, indicating a favorable safety profile overall for first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Kantarjian, HM., Shah, NP., Cortes, JE., et al.[2021]

In a study of 519 patients with newly diagnosed chronic-phase CML, dasatinib resulted in a higher rate of complete cytogenetic response at 12 months compared to imatinib (77% vs. 66%), indicating its greater efficacy as a first-line treatment.

Dasatinib not only achieved higher response rates but also did so more quickly than imatinib, with a major molecular response rate of 46% compared to 28%, suggesting that dasatinib may lead to better long-term outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. Kantarjian, H., Shah, NP., Hochhaus, A., et al.[2023]

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]

In a study of 163 newly diagnosed patients with chronic-phase chronic myeloid leukemia (CML), dasatinib and nilotinib showed significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared to imatinib after 3 and 12 months of treatment.

The safety profiles of dasatinib, nilotinib, and imatinib were similar, indicating that while dasatinib and nilotinib are more effective, they do not present additional safety concerns compared to imatinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Dasatinib, Nilotinib and Imatinib in Newly Diagnosed Patients with Chronic-Phase Chronic Myeloid Leukemia: A Three-year Retrospective Analysis]. Wang, YY., Zhao, HG., Cui, ZG., 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]

References

1. England 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. [2022]

2. Italy pubmed.ncbi.nlm.nih.gov

Second-generation tyrosine kinase inhibitors improve the survival of patients with chronic myeloid leukemia in whom imatinib therapy has failed. [2021]

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

Is imatinib still an acceptable first-line treatment for CML in chronic phase? [2017]

5. China pubmed.ncbi.nlm.nih.gov

[Preliminary comparison of efficacy and safety of dasatinib and imatinib in newly diagnosed chronic myeloid leukemia]. [2022]

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

The effect of comorbidities on the choice of tyrosine kinase inhibitors in patients with chronic myeloid leukemia. [2022]

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

Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). [2021]

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

Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. [2023]

9. Thailand pubmed.ncbi.nlm.nih.gov

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

10. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Dasatinib, Nilotinib and Imatinib in Newly Diagnosed Patients with Chronic-Phase Chronic Myeloid Leukemia: A Three-year Retrospective Analysis]. [2022]

11. England pubmed.ncbi.nlm.nih.gov

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