Triple Therapy for CLL/SLL

Recruiting in Washington (>99 mi)

+2 other locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 7

Duration: Up to 12 cycles (28 days each)

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of lenalidomide when given together with ibrutinib and rituximab in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that has come back (relapsed), has not responded well to prior treatments (refractory), has spread to other parts of the body (metastatic), or cannot be removed by surgery. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving lenalidomide together with ibrutinib and rituximab may kill more cancer cells.

Will I have to stop taking my current medications?

The trial requires that you do not take any other approved anti-cancer therapies or investigational agents while participating. Additionally, you must not have taken chemotherapy within 21 days or monoclonal antibodies within 6 weeks before starting the trial. If you are on corticosteroids, you must reduce the dose to less than 20 mg per day of prednisone or equivalent at least 7 days before starting the trial.

What data supports the effectiveness of the drug combination Ibrutinib, Lenalidomide, and Rituximab for treating CLL/SLL?

Research shows that Ibrutinib, when combined with other drugs like bendamustine and rituximab, significantly improves the time patients live without their disease getting worse in CLL/SLL. Ibrutinib alone has also been effective in real-world settings for relapsed CLL, suggesting its potential benefit in combination therapies. ^{1 2 3 4 5}

Is the triple therapy for CLL/SLL safe for humans?

Ibrutinib, a part of the triple therapy, is generally well-tolerated, but some patients may experience side effects like atrial fibrillation (irregular heartbeat) and hypertension (high blood pressure). Rituximab, another component, is also used widely and is generally safe, though it can cause infusion reactions and infections. Lenalidomide, the third component, is known to cause side effects such as low blood counts and fatigue, but is considered safe when monitored properly. ^{6 7 8 9 10}

What makes the triple therapy of Ibrutinib, Lenalidomide, and Rituximab unique for treating CLL/SLL?

This triple therapy combines Ibrutinib, a targeted drug that helps restore the immune system, with Lenalidomide, which boosts the immune response, and Rituximab, an antibody that targets cancer cells, offering a novel approach that may improve outcomes compared to traditional treatments. ^{1 4 11 12 13}

Research Team

Kieron Dunleavy

Principal Investigator

MedStar Georgetown University Hospital

Eligibility Criteria

This trial is for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that's returned, spread, or can't be surgically removed. Eligible participants must not have severe allergies to the drugs being tested, no recent heart issues or strokes, and should not be pregnant. They need functioning major organs and cannot have used certain treatments recently.

Inclusion Criteria

My cancer is advanced, cannot be surgically removed, and standard treatments are not effective.

I have been treated for CLL or SLL and need further treatment.

I have not had major surgery in the last 28 days.

Exclusion Criteria

I do not have moderate or severe liver problems.

Serologic status reflecting active hepatitis B or C infection

I haven't had chemotherapy in the last 3 weeks or monoclonal antibody treatment in the last 6 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 12 cycles (28 days each)

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Every 6 months

Treatment Details

Interventions

• Ibrutinib
• Lenalidomide
• Rituximab

Trial Overview The trial tests a combination of lenalidomide with ibrutinib and rituximab to see how well they work together against cancer cells. It's in phase I to determine side effects and the best dose. The study includes collecting biospecimens, bone marrow biopsies, imaging tests like CT scans and MRIs.

Participant Groups

Group I: Treatment (lenalidomide, ibrutinib, rituximab) Experimental Treatment 8 Interventions

Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.

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

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In the phase 3 HELIOS trial involving 578 patients with previously treated chronic lymphocytic leukemia (CLL), the combination of ibrutinib and bendamustine-rituximab (BR) significantly improved progression-free survival (PFS) compared to placebo+BR, with a median PFS not reached for ibrutinib+BR versus 14.3 months for placebo+BR.

The treatment with ibrutinib+BR also resulted in a higher rate of minimal residual disease (MRD)-negative responses (26.3% vs. 6.2% for placebo+BR), indicating a deeper response to therapy, while the safety profile remained consistent with earlier reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Fraser, G., Cramer, P., Demirkan, F., et al.[2023]

Acalabrutinib, a selective BTK inhibitor, has been FDA approved for treating chronic lymphocytic leukemia (CLL) and shows improved efficacy and safety compared to standard treatments, including ibrutinib.

In multinational phase 1/2 and phase 3 studies, acalabrutinib demonstrated significant effectiveness in treatment-naïve and relapsed refractory CLL patients, with fewer treatment-limiting toxicities such as atrial fibrillation and bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data. Isaac, K., Mato, AR.[2020]

Ibrutinib and idelalisib, two B-cell receptor signaling inhibitors, have shown significant clinical activity in treating chronic lymphocytic leukemia (CLL), particularly in relapsed or refractory cases, and have been FDA-approved for this use.

Both drugs are generally well tolerated, even by older patients, with mild and self-resolving side effects; however, clinicians should be aware of specific adverse events that could limit their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. Falchi, L., Baron, JM., Orlikowski, CA., et al.[2020]

Acalabrutinib, a Bruton's tyrosine kinase inhibitor, has been shown to be effective and safe for treating chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with significant improvements in efficacy observed in both monotherapy and combination treatments.

In clinical studies, acalabrutinib demonstrated a high rate of molecular remission when combined with venetoclax, while maintaining an acceptable safety profile, although some adverse events occurred in over 20% of patients, including myelosuppression and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. Egyed, M., Lueff, S., Borbely, J., et al.[2022]

Zanubrutinib (zanu) has been shown to significantly improve progression-free survival compared to bendamustine-rituximab in treatment-naive patients with chronic lymphocytic leukemia (CLL), indicating its efficacy as a first-line treatment option.

In a direct comparison with ibrutinib, zanu demonstrated a better safety profile and enhanced clinical efficacy, leading to its approval by the FDA and EMA as a preferred treatment for CLL/SLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. Molica, S., Tam, C., Allsup, D., et al.[2023]

Chronic lymphocytic leukemia (CLL) is a complex B-cell cancer that often relapses after traditional treatments, highlighting the need for new therapeutic options.

Recent advancements in CLL treatment include a variety of novel drugs such as ibrutinib and idelalisib, which are showing promise in improving patient outcomes compared to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel agents for chronic lymphocytic leukemia. Wu, M., Akinleye, A., Zhu, X.[2021]

References

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

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. [2023]

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

The Real-World Experience With Single Agent Ibrutinib in Relapsed/Refractory CLL. [2022]

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

Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data. [2020]

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

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton's Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Comparison of ibrutinib and idelalisib plus rituximab in real-life relapsed/resistant chronic lymphocytic leukemia cases. [2021]

6. Italy pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. [2020]

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

Safety and efficacy analysis of long-term follow up real-world data with ibrutinib monotherapy in 58 patients with CLL treated in a single-center in Greece. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202. [2023]

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

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. [2023]

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

Novel agents for chronic lymphocytic leukemia. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Targeted therapies for CLL: Practical issues with the changing treatment paradigm. [2022]

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

Ibrutinib Restores Tumor-specific Adaptive Immunity in Chronic Lymphocytic Leukemia. [2022]