Rituximab + Bendamustine/Ibrutinib for Chronic Lymphocytic Leukemia

Not currently recruiting at 1078 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of different medication combinations for treating chronic lymphocytic leukemia (CLL), a cancer affecting the blood and bone marrow. The trial compares rituximab with either bendamustine or ibrutinib, and ibrutinib alone, to determine which is more effective. Rituximab targets cancer cells, bendamustine is a chemotherapy drug, and ibrutinib blocks enzymes that help cancer cells grow. The study seeks participants who have not yet received treatment for CLL and are experiencing symptoms such as worsening anemia, large lymph nodes, or significant fatigue. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that the treatments in this trial have promising safety records from past studies.

For the combination of rituximab and bendamustine, studies have found it effective and generally safe for people with chronic lymphocytic leukemia (CLL). However, about 8.6% of patients experienced serious infections, which is important to consider.

Ibrutinib, when used alone, has been well tolerated as a long-term treatment for CLL. Research indicates that no new safety concerns have appeared even after many years of use. Common side effects include mild to moderate issues like diarrhea and tiredness.

The combination of ibrutinib and rituximab has also been studied. This combination is considered safe for patients, including those with higher-risk genetic features, and has shown good long-term results without major safety problems.

Overall, these treatments have been studied extensively, and while they are generally well-tolerated, it's important to be aware of some potential side effects. Always consult with a healthcare provider for personalized advice. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for chronic lymphocytic leukemia because they combine or modify existing therapies in new ways to potentially enhance effectiveness. Unlike traditional treatments, which often rely on chemotherapy alone, these approaches integrate targeted therapies like ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, to disrupt cancer cell signaling and growth. Additionally, rituximab, an antibody that targets the CD20 protein on cancer cells, is paired with either bendamustine or ibrutinib, offering a unique combination that could improve patient outcomes by attacking the cancer cells through different mechanisms. This multi-pronged attack strategy could lead to better disease control and give patients more options, especially for those who might not respond well to standard chemotherapy treatments.

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

Research has shown that using bendamustine with rituximab, which participants in this trial may receive in Arm I, effectively treats chronic lymphocytic leukemia (CLL). One study found that 78.6% of patients using this combination did not experience disease progression for at least 12 months. Ibrutinib, administered in Arm II, also demonstrated strong results, with about 96.8% of patients responding well and 40.7% achieving complete remission. When combined with rituximab, as in Arm III, ibrutinib becomes even more powerful, helping patients recover faster and reducing the amount of remaining disease. These findings suggest that all three treatment options—rituximab with bendamustine, ibrutinib alone, and ibrutinib with rituximab—effectively manage CLL. ^{1 6 7 8 9}

Who Is on the Research Team?

Jennifer A Woyach

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

Citations

1. ashpublications.org ashpublications.org/bloodadvances/article/9/15/3801/537228/Real-world-survival-outcomes-in-first-line

Real-world survival outcomes in first-line ibrutinib-treated ... The mean time from first observed diagnosis to 1L ibrutinib initiation was 38.0 (SD, 45.3) months among patients with high-risk CLL/SLL and 68.3 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11971162/

Final results on effectiveness and safety of Ibrutinib in patients ... 3). By 60 months, 96.8% of the retrospective patients had a response to ibrutinib treatment: 40.7% had a complete response and 56.1% a partial ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36534239/

Systematic Literature Review of Real-World Effectiveness ... This systematic literature review confirms the benefit of ibrutinib as a first-line treatment in patients with chronic lymphocytic leukemia in real-world ...

4. ashpublications.org ashpublications.org/blood/article/146/18/2168/546415/Final-analysis-of-the-RESONATE-2-study-up-to-10

Final analysis of the RESONATE-2 study: up to 10 years of ... Key PointsIn the final analysis of RESONATE-2, survival and PFS benefits of ibrutinib treatment were sustained, with median PFS reached at 8.9 years.Ibruti.

5. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2024.2402814

Real-world outcomes following ibrutinib dose reduction in ... Systematic literature review of real-world effectiveness results data for first-line ibrutinib in chronic lymphocytic leukemia and small lymphocytic lymphoma.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40413564/

Real-World Safety Profile of Ibrutinib in Chronic ... The overall response rate was 82.2%, with 42.2% achieving complete remission. Multivariate analysis identified age and comorbidities as ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38342972/

Outcomes with ibrutinib in patients with chronic lymphocytic ... The REALITY study provides further evidence of the effectiveness and safety of ibrutinib in patients with CLL in a real-world setting, particularly in earlier ...

8. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/6550/501342/Real-World-Effectiveness-and-Safety-of-Ibrutinib

Real-World Effectiveness and Safety of Ibrutinib in Patients ... In this Belgian real-world study, ibrutinib was found to be an effective treatment for patients with CLL, including those with higher risk mutations, several ...

9. 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 ... Ibrutinib was well tolerated as a long-term treatment and no new safety signals emerged. 1 Rates of adverse events (AEs) of interest during years 8–9 and 9–10 ...