Pembrolizumab + TKI for Chronic Myeloid Leukemia

Not currently recruiting at 322 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining pembrolizumab with either dasatinib, imatinib mesylate, or nilotinib in treating chronic myeloid leukemia (CML) in patients who still exhibit traces of the disease despite treatment. Pembrolizumab, a monoclonal antibody, may help stop cancer cells from growing, while the other medications, known as tyrosine kinase inhibitors (TKIs), block enzymes that cancer cells need to grow. The study seeks participants who have been on the same first-line treatment for CML for at least two years but still show signs of the disease. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings in CML treatment.

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.

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

Research has shown that pembrolizumab, when combined with other treatments, generally does not cause serious harm. One study confirmed that pembrolizumab is safe and manageable for most patients.

Long-term research on dasatinib indicates it is mostly safe, but about 20% of people stopped using it due to side effects. While generally safe, some individuals might experience problems.

Imatinib mesylate is another treatment with a good track record. Studies have shown it helps people live longer, suggesting it is well-tolerated over time.

Nilotinib is usually safe, with most side effects being mild or moderate. It has been effective for many patients, though some might experience more serious side effects like heart issues.

Overall, each treatment has undergone extensive study and is safe for most people. However, some might experience side effects, so discussing any concerns with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using pembrolizumab in combination with TKIs like dasatinib, imatinib mesylate, and nilotinib for Chronic Myeloid Leukemia (CML) because pembrolizumab is an immune checkpoint inhibitor that may enhance the body's immune response against cancer cells. While standard treatments for CML, such as imatinib, dasatinib, and nilotinib, primarily target specific proteins to stop cancer cell growth, pembrolizumab targets the PD-1 pathway, potentially boosting the immune system's ability to fight the leukemia. This combination approach could lead to deeper and more sustained remissions by attacking the cancer from multiple angles. Researchers are hopeful that this strategy might improve outcomes for patients who have detectable minimal residual disease (MRD) after initial treatment.

What evidence suggests that this trial's treatments could be effective for chronic myeloid leukemia?

Research has shown that pembrolizumab helps patients live longer without their cancer worsening. In this trial, participants will receive pembrolizumab combined with either dasatinib, imatinib mesylate, or nilotinib. These combinations have demonstrated few additional side effects, making them a promising option for chronic myeloid leukemia. For dasatinib, studies indicate that up to 83% of patients reach key treatment goals, such as a major reduction in cancer markers in the blood. Imatinib mesylate has demonstrated a 97.8% survival rate over 10 years, with significant reductions in cancer markers, highlighting its long-term effectiveness. Nilotinib also proves effective, helping many patients maintain low levels of cancer markers over time. These treatments block specific enzymes that cancer cells need to grow. ^{2 3 6 7 8}

Who Is on the Research Team?

Amer Zeidan

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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.

Women of childbearing potential and sexually active males must use contraception

Exclusion Criteria

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

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10388268/

Insights into dasatinib use and outcomes in real-world ... Over 30% of patients failed to achieve deep molecular response (DMR) and 20% experienced adverse drug reactions (ADR) necessitating treatment discontinuation ...

2. sprycel-hcp.com sprycel-hcp.com/efficacy-newly-diagnosed

SPRYCEL® (dasatinib) Efficacy - Newly Diagnosed Patients 77% of SPRYCEL patients achieved the cCCyR 12-month treatment milestone. 83% achieved the Year 5 treatment milestone.1. IMPORTANT INFORMATION ABOUT ADVERSE ...

3. news.bms.com news.bms.com/news/details/2010/Four-Year-Follow-Up-Data-for-SPRYCEL-dasatinib-Demonstrate-82-Percent-Overall-Survival-in-Patients-with-Chronic-Myeloid-Leukemia-Who-Failed-Gleevec1/default.aspx

Four-Year Follow-Up Data for SPRYCEL® (dasatinib) ... At four years, for all patients administered SPRYCEL 100 mg once daily, overall survival was 82% (95% CI: 76%-88%) and progression-free survival was 66% (95% ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38135632/

Real-World Effectiveness of Dasatinib Versus Imatinib in ... Results: The dasatinib cohort (n = 309) experienced higher rates of MMR (n = 304, 79% vs. 65%, P < .001) and DMR (44% vs. 25%, P < .001) vs. the imatinib cohort ...

5. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6614/528020/Real-World-Data-of-Molecular-Response-Using

Real-World Data of Molecular Response Using Different ... After 3 months of therapy, CHR was achieved in overall 96% patients (98% with dasatinib 70 mg & 96% with dasatinib 100 mg dose). Early molecular ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31999839/

Long-term Results of Frontline Dasatinib in Chronic Myeloid ... Conclusions: After this long-term follow-up, dasatinib continues to show an excellent safety profile and produces rapid cytogenetic responses ...

7. sprycel-hcp.com sprycel-hcp.com/safety-newly-diagnosed

SPRYCEL® (dasatinib) Safety Profile - Newly Diagnosed ... SPRYCEL had a well-established and consistent safety profile through Year 5 · 1618 adult patients with chronic phase CML was 29 months (range 0–92.9 months) · 324 ...

8. nature.com nature.com/articles/s41408-018-0122-3

Long-term efficacy and safety of dasatinib in patients with ... The best response of CHR at any time within 5 years was reached in 51% and 54% of patients in the QD and BID arms, respectively. Fig. 1: ...