Rituximab + Bendamustine/Ibrutinib for Chronic Lymphocytic Leukemia

Recruiting at 1052 trial locations

Age: 65+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, CYP3A4/5 inhibitors

Disqualifiers: Heart failure, Recent stroke, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 12

Duration: 24 weeks

547 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must not be on active systemic anticoagulation with heparin or warfarin, and you should not require therapy with strong CYP3A4/5 inhibitors or inducers. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination of Rituximab, Bendamustine, and Ibrutinib for treating Chronic Lymphocytic Leukemia?

Research from the HELIOS trial shows that adding Ibrutinib to Bendamustine and Rituximab improves disease outcomes in patients with previously treated chronic lymphocytic leukemia compared to using Bendamustine and Rituximab alone. ^{1 2 3 4 5}

Is the combination of Rituximab, Bendamustine, and Ibrutinib safe for humans?

The combination of Rituximab, Bendamustine, and Ibrutinib has been studied for safety in patients with chronic lymphocytic leukemia. The studies show that this combination is generally well-tolerated, with no unexpected toxicities, and the safety profile is consistent with what is known for each drug individually. ^{1 2 4 6 7}

How is the drug combination of Rituximab, Bendamustine, and Ibrutinib unique for treating chronic lymphocytic leukemia?

This drug combination is unique because it adds Ibrutinib, which is an oral drug that blocks a specific protein (Bruton's tyrosine kinase) involved in cancer cell growth, to the standard treatment of Bendamustine and Rituximab. This combination has shown improved outcomes in patients who have already been treated for chronic lymphocytic leukemia, offering longer progression-free survival compared to the standard treatment alone. ^{1 2 5 8 9}

What is the purpose of this trial?

This randomized phase III trial studies rituximab with bendamustine hydrochloride or ibrutinib to see how well they work compared to ibrutinib alone in treating older patients with previously untreated chronic lymphocytic leukemia. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Chemotherapy drugs, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether rituximab with bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in treating chronic lymphocytic leukemia.

Research Team

Jennifer A Woyach

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

This trial is for older patients (65+) with untreated chronic lymphocytic leukemia who meet specific diagnostic criteria, have a certain level of physical fitness (ECOG 0-2), and organ function. They must not have had prior CLL treatment except for steroids or rituximab for autoimmune complications, no major surgery within 10 days before enrollment, and no active hepatitis B or uncontrolled infections.

Inclusion Criteria

My CLL cells show specific markers and lack a certain genetic change.

My CLL is at an intermediate or high-risk stage.

My condition is at an intermediate stage with enlarged lymph nodes and possibly an enlarged liver or spleen.

Exclusion Criteria

I take 20 mg or less of prednisone or its equivalent daily.

I am not currently on blood thinners like heparin or warfarin.

You should not have a known allergy to mannitol.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treatment according to their assigned arm: rituximab and bendamustine hydrochloride, ibrutinib, or ibrutinib with rituximab. Treatment cycles repeat every 28 days.

24 weeks

6 cycles of treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes bone marrow aspiration, biopsy, blood sample collection, and CT scans.

Up to 10 years

Every 6 months

Treatment Details

Interventions

• Bendamustine Hydrochloride
• Ibrutinib
• Rituximab

Trial Overview The study compares the effectiveness of rituximab combined with bendamustine hydrochloride or ibrutinib versus using just ibrutinib alone in treating CLL. It aims to determine which therapy works best at stopping cancer cell growth by either killing cells, preventing division, or blocking enzymes needed for cell growth.

Participant Groups

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

Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and biopsy, blood sample collection, and CT throughout the study.

Group II: Arm II (ibrutinib) Experimental Treatment 7 Interventions

Patients receive ibrutinib PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and biopsy, blood sample collection, and CT throughout the study.

Group III: Arm I (rituximab, bendamustine hydrochloride) Active Control 8 Interventions

Patients receive rituximab IV on day 1 (day 0 course 1) and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II. Additionally, patients undergo bone marrow aspiration and biopsy, blood sample collection, and CT throughout the study.

Bendamustine Hydrochloride is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin lymphoma (NHL)

Approved in European Union as Levact for:

• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin lymphoma (NHL)
• Multiple myeloma

Approved in Japan as Ribomustin for:

• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin lymphoma (NHL)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In the HELIOS trial involving 578 subjects, the combination of bendamustine/rituximab and ibrutinib (BR-I) resulted in significantly higher systemic exposure to rituximab compared to bendamustine/rituximab with placebo (BR), particularly in the initial treatment cycles.

The study found no significant safety differences between the BR-I and BR groups, suggesting that the enhanced efficacy of BR-I may be achieved without compromising patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Lavezzi, SM., de Jong, J., Neyens, M., et al.[2021]

In a phase 1b study involving patients with relapsed/refractory chronic lymphocytic leukemia, the combination of ibrutinib with bendamustine and rituximab (BR) showed a high overall response rate of 93.3%, with significant improvements in complete responses over time.

The study demonstrated that ibrutinib can enhance the efficacy of chemoimmunotherapy without adding prolonged hematologic toxicity, suggesting a promising treatment strategy for patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Brown, JR., Barrientos, JC., Barr, PM., et al.[2021]

Bendamustine hydrochloride has been associated with serious adverse events such as Stevens-Johnson syndrome and toxic epidermal necrolysis, leading to important label updates regarding its safety and administration.

Despite these risks, the long-term pharmacovigilance data suggest that bendamustine maintains a favorable risk-benefit profile, making it a valuable treatment option for patients with chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety experience with bendamustine for injection in a real-world setting. Martin, P., Barr, PM., James, L., et al.[2017]

In a study of 34 patients with relapsed/refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), maintenance therapy with lenalidomide after bendamustine and rituximab (BR) did not significantly improve progression-free survival (PFS), which was 18.3 months compared to 15.2 months without maintenance.

The study highlighted challenges with lenalidomide maintenance due to hematological and infectious toxicities, as only 6 out of 19 patients completed the intended 12 cycles, suggesting that lenalidomide may be more effective in earlier treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study. Chang, JE., Havighurst, T., Kim, K., et al.[2018]

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]

References

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

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. [2022]

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

Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. [2022]

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

Efficacy and Safety of Bendamustine and Ibrutinib in Previously Untreated Patients With Chronic Lymphocytic Leukemia: Indirect Comparison. [2021]

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

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Long-term safety experience with bendamustine for injection in a real-world setting. [2017]

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

Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study. [2018]

9. 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]