Triple Drug Therapy for Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must not be taking: Steroids, Immunosuppressants, Anticoagulants, others

Disqualifiers: Autoimmune disease, Active infection, Cardiovascular 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: 3

Duration: 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a combination of three drugs—ibrutinib, fludarabine, and pembrolizumab—in treating high-risk chronic lymphocytic leukemia (CLL). Researchers are testing these drugs together to determine if they can more effectively reduce CLL cells and enhance the immune system's ability to fight cancer compared to ibrutinib alone. The trial seeks participants with active CLL who have either relapsed after treatment or possess certain high-risk genetic markers, such as specific mutations in their cancer cells. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are currently on certain treatments like systemic steroids or strong CYP3A inhibitors within 7 days before starting the trial. It's best to discuss your current medications with the trial team.

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

Research has shown that ibrutinib, fludarabine, and pembrolizumab have been used to treat chronic lymphocytic leukemia (CLL) with promising results. Ibrutinib effectively treats CLL and has been safely used in many patients, often showing better outcomes than some standard treatments. Fludarabine is also widely used for CLL and is generally well-tolerated, allowing most patients to take it without serious side effects. Pembrolizumab, an immune therapy, helps the body attack cancer cells and has been used in other types of cancer.

Regarding safety, studies have shown that these drugs can cause side effects, but they are often manageable. For example, ibrutinib can cause mild issues like diarrhea or tiredness in some people. Fludarabine might lead to low blood cell counts, which doctors monitor closely. Pembrolizumab can cause immune-related side effects, but these are usually mild and treatable.

Since this treatment is in an early study phase, researchers are closely monitoring the combination for safety. While the drugs are promising, researchers are still learning about any potential side effects when used together. It is important to discuss the risks and benefits with a doctor before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ibrutinib, Fludarabine, and Pembrolizumab for treating Chronic Lymphocytic Leukemia (CLL) because it brings together a unique mix of mechanisms. Ibrutinib is a targeted therapy that blocks a specific protein signaling pathway, which helps stop cancer cell growth. Fludarabine is a chemotherapy drug that interferes with the DNA of cancer cells, causing them to die. Pembrolizumab, an immunotherapy, boosts the immune system to better recognize and attack cancer cells. This triple-drug approach aims to enhance effectiveness by combining targeted, chemotherapeutic, and immune-based actions, potentially offering a powerful alternative to existing treatments like chemotherapy alone or standard immunotherapies.

What evidence suggests that this trial's treatments could be effective for CLL?

Research has shown that combining the drugs ibrutinib, fludarabine, and pembrolizumab, as studied in this trial, may effectively treat chronic lymphocytic leukemia (CLL), especially in high-risk patients. Ibrutinib often outperforms standard chemotherapy for patients with certain genetic changes, such as del17p. Long-term studies have found that ibrutinib can help patients live longer without disease progression. Fludarabine targets both cancer cells and the immune system, which can support cancer growth. Pembrolizumab aids the immune system in attacking cancer cells. Early results suggest that using these drugs together might reduce cancer cells more effectively than using ibrutinib alone. ^{1 3 4 6 7}

Who Is on the Research Team?

Adrian U Wiestner, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

This trial is for adults with active, high-risk or relapsed/refractory Chronic Lymphocytic Leukemia (CLL) who meet specific criteria including weight loss, presence of certain mutations, progressive symptoms, and adequate organ function. Participants must not have a history of certain infections or conditions that could affect the study's safety or outcomes.

Inclusion Criteria

My condition meets one of the required criteria for active disease.

Agreement to use acceptable methods of contraception during the study and for 90 days after the last dose of study drug if sexually active and able to bear or beget children

My organs are working well enough for the study.

Exclusion Criteria

Psychiatric illness/social situations that may limit compliance with study requirements

Known hypersensitivity to specific medications

I have not had major surgery in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Treatment

Ibrutinib is administered starting from cycle -3 and Fludarabine is administered on cycle -2

8 weeks

Multiple visits for drug administration

Treatment

Pembrolizumab is administered every 3 weeks starting from cycle 1 for 1 year

1 year

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine
• Ibrutinib
• Pembrolizumab

Trial Overview The trial tests a combination treatment for CLL using Ibrutinib continuously from cycle -3 until progression/intolerable side effects; Fludarabine on days 1-5 in cycle -2 only; Pembrolizumab every 3 weeks starting from cycle 1 for one year. The goal is to achieve greater reduction in CLL cells and restore immune response.

How Is the Trial Designed?

Group I: Ibrutinib, Fludarabine, and Pembrolizumab in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Experimental Treatment 3 Interventions

Ibrutinib, Fludarabine, and Pembrolizumab combination therapy will be administered in participants with High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Ibrutinib will be administered daily by mouth starting cycle -3 at 420 mg until end study or disease progression or intolerable side effects occur. Fludarabine will be administered intravenously only on cycle -2 at 25mg/m\^2 x5 days. Pembrolizumab will be administered intravenously every 3 weeks at 200 mg starting from cycle 1 through cycle 17 or 1 year of immunotherapy phase.

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

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Mantle-cell lymphoma
• Non-Hodgkin's lymphoma

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Stem Cell Transplant Conditioning

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

Chronic lymphocytic leukemia (CLL) treatment varies based on patient age and fitness, with younger patients typically receiving the FCR regimen and older, fit patients being treated with BR or bendamustine plus ofatumumab.

New oral medications like idelalisib and ibrutinib have shown impressive efficacy and tolerability in patients with high-risk genetic factors or relapsed CLL, indicating a shift in treatment strategies towards these novel agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chronic lymphocytic leukemia: current standards and novel approaches]. Tausch, E., Stilgenbauer, S.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03204188

Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or ... This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. Chronic lymphocytic leukemia and small lymphocytic ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7153674/

Efficacy of Ibrutinib-Based Regimen in Chronic ... Ibrutinib has shown to have better efficacy than standard chemoimmunotherapy in del17 positive chronic lymphocytic leukemia (CLL) patients; however its role ...

3. ashpublications.org ashpublications.org/bloodadvances/article/6/11/3440/484605/Up-to-8-year-follow-up-from-RESONATE-2-first-line

Up to 8-year follow-up from RESONATE-2: first-line ibrutinib ... Long-term RESONATE-2 data show sustained PFS and OS benefits (medians not reached) for first-line ibrutinib treatment in patients with CLL.

4. jnj.com jnj.com/innovativemedicine/emea/newsroom/oncology/findings-from-landmark-resonate-2-study-confirm-sustained-survival-benefit-of-imbruvica-ibrutinib-for-first-line-chronic-lymphocytic-leukaemia-treatment-with-up-to-10-years-follow-up

Findings from landmark RESONATE-2 study confirm ... Additional findings from pooled analysis of three Phase 3 studies showed treatment with ibrutinib has the potential to achieve comparable overall survival ...

5. academic.oup.com academic.oup.com/jimmunol/advance-article/doi/10.1093/jimmun/vkaf182/8232766

Activation and exhaustion of CD8 T cells in patients with ... Here, we report clinical and translational data on combination immunotherapy using ibrutinib, up to 2 cycles of fludarabine, and pembrolizumab ( ...

6. clinicaltrial.be clinicaltrial.be/en/details/8695?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or... This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. Chronic lymphocytic leukemia and small ...

7. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/ibrutinib?pn=1

Clinical Trials Using Ibrutinib - NCI NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying ibrutinib.