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

15 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Chronic lymphocytic leukemia and small lymphocytic lymphoma (hereby referred as CLL) are tumors of B cells. A subset of patients categorized as high-risk CLL has a poor clinical outcome when treated with conventional chemotherapy. This single-arm, phase II study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. Ibrutinib is an orally administered therapy for CLL. Fludarabine is a well-tolerated drug that has been widely used to treat CLL. Also, fludarabine can modulate CLL cells as well as immune cells that support the growth of CLL cells. Pembrolizumab recruits immune cells to attack CLL cells. With this approach we hope to achieve a greater reduction in CLL cells than with single agent ibrutinib and to restore healthier immune system that could contribute to durable responses. Objective: To investigate the rate of complete response to ibrutinib, short course fludarabine and pembrolizumab. Eligibility: Patients with active CLL meeting treatment indications defined by 2008 International Workshop on CLL (IWCLL) consensus guideline. High-risk CLL defined by one of the following: * Relapsed/refractory disease status, or * Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53 mutation, NOTCH1 mutation, SF3B1 mutation, MYC aberration, or complex cytogenetics. Design: This is a single-arm, open-label phase II study. Timeline: Treatment on this study is given in cycles from cycle -3 to 17, then in months beyond cycle 17. Cycles -3 to -1 are 28-day cycles. Cycles 1 to 17 are 21-day cycles. After completion of 1 year of pembrolizumab, the time on study is by chronological months on study from starting pembrolizumab. Treatment plan: * Ibrutinib is given starting from cycle -3 and continuously until disease progression or intolerable side effects occur. * Fludarabine is given on D1-D5 on cycle -2 only * Pembrolizumab is given every 3 weeks starting from cycle 1 for 1 year. * Minimal residual disease will be measured at 2 years from cycle 1 to determine the need for long- term treatment with ibrutinib. * Previously-untreated patients who achieve minimal residual disease negativity will stop ibrutinib. * Patients who do not achieve minimal residual disease negativity or who has Relapsed/refractory CLL will continue ibrutinib.

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.

What data supports the effectiveness of the drug combination including Fludarabine, Ibrutinib, and Pembrolizumab for treating Chronic Lymphocytic Leukemia?

Research shows that Ibrutinib, when combined with other drugs like rituximab, has been effective in improving progression-free survival in patients with Chronic Lymphocytic Leukemia. Additionally, Ibrutinib has shown impressive results in treating relapsed or refractory CLL, especially in patients with high-risk genetic factors. ^{1 2 3 4 5}

What makes the triple drug therapy for chronic lymphocytic leukemia unique?

The triple drug therapy for chronic lymphocytic leukemia is unique because it combines fludarabine, ibrutinib, and pembrolizumab, which target different aspects of the cancer cells. Fludarabine is a chemotherapy drug, ibrutinib blocks signals that help cancer cells survive, and pembrolizumab is an immunotherapy that helps the immune system attack cancer cells, offering a multi-faceted approach to treatment. ^{6 7 8 9 10}

Research Team

Adrian U Wiestner, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

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

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

Known hypersensitivity to specific medications

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

References

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

Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. [2023]

2. Czech Republic pubmed.ncbi.nlm.nih.gov

[Therapeutic Options for "Slow go" Patients with Chronic Lymphocytic Leukemia]. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

[Chronic lymphocytic leukemia: current standards and novel approaches]. [2018]

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

Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. [2023]

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

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. [2021]

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

Old and new therapies in chronic lymphocytic leukemia: now is the time for a reassessment of therapeutic goals. [2013]

7. Italy pubmed.ncbi.nlm.nih.gov

Fludarabine, ara-C, novantrone and dexamethasone (FAND) in previously treated chronic lymphocytic leukemia patients. [2013]

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

Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Fludarabine and epirubicin in the treatment of chronic lymphocytic leukaemia: a German multicenter phase II study. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Future prospects for fludarabine-containing regimens in the treatment of hematological cancers. [2016]