Ibrutinib + Rituximab for Chronic Lymphocytic Leukemia

Recruiting at 879 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

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: 3

Duration: 6-7 months

529 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, 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. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. It is not yet known whether fludarabine phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on strong CYP3A inhibitors, warfarin, or other investigational agents. You also cannot be on systemic immunosuppressant therapy other than low-dose corticosteroids within 28 days of starting the study drug.

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

Research shows that Ibrutinib, alone or with Rituximab, improves outcomes for patients with Chronic Lymphocytic Leukemia (CLL) compared to traditional chemoimmunotherapy. In particular, Ibrutinib has been shown to extend the time patients live without the disease getting worse. ^{1 2 3 4 5}

Is the combination of Ibrutinib and Rituximab safe for treating chronic lymphocytic leukemia?

The combination of Ibrutinib and Rituximab has been studied for safety in treating chronic lymphocytic leukemia. It is generally well-tolerated, but some patients may experience side effects like diarrhea, infections, bleeding disorders, and heart issues such as atrial fibrillation. These side effects are consistent with those observed when Ibrutinib is used alone or with other treatments. ^{1 6 7 8 9}

What makes the drug combination of Ibrutinib and Rituximab unique for treating chronic lymphocytic leukemia?

The combination of Ibrutinib and Rituximab is unique because Ibrutinib, a BTK inhibitor (a type of drug that blocks a protein involved in cancer cell growth), when used with Rituximab, has shown improved outcomes like longer progression-free survival compared to traditional chemoimmunotherapy. This combination is considered a potential new standard treatment option for chronic lymphocytic leukemia. ^{1 2 5 8 9}

Research Team

Tait D Shanafelt

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Participants should have symptoms like night sweats, weight loss, or anemia and meet specific blood criteria. They must not have had prior treatments for CLL/SLL, active infections, other primary cancers requiring treatment within 2 years, or certain heart conditions.

Inclusion Criteria

I have been diagnosed with CLL or SLL.

I have a confirmed diagnosis of small lymphocytic lymphoma or CLL.

I meet the criteria for needing treatment.

Exclusion Criteria

Recent vaccination history

I need certain medications or treatments.

I have a specific condition affecting my digestive system.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ibrutinib and rituximab or fludarabine phosphate, cyclophosphamide, and rituximab. Treatment cycles repeat every 28 days.

6-7 months

Monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

10 years

Regular follow-up visits every 3 months for the first 2 years, then every 6 months

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine Phosphate
• Ibrutinib
• Rituximab

Trial Overview The study compares the effectiveness of Ibrutinib plus Rituximab against Fludarabine Phosphate with Cyclophosphamide and Rituximab in treating CLL/SLL. It aims to determine which combination works better at stopping cancer cell growth by either killing cells or helping the immune system attack them.

Participant Groups

Group I: Arm A (ibrutinib, rituximab) Experimental Treatment 5 Interventions

Patients receive ibrutinib PO QD on days 1-28. Beginning cycle 2, patients also receive rituximab IV over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD.

Group II: Arm B (rituximab, fludarabine phosphate, cyclophosphamide) Active Control 6 Interventions

Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

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]

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]

Ibrutinib, a BTK inhibitor, has been shown to significantly improve clinical outcomes for patients with chronic lymphocytic leukemia, as demonstrated in two phase III trials.

When used alone or in combination with rituximab, ibrutinib enhances progression-free survival compared to traditional chemoimmunotherapy regimens, suggesting it should be considered a standard treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Ibrutinib Confirmed for CLL. [2019]

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]

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]

References

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

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

2. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

3. 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]

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

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

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

First-Line Ibrutinib Confirmed for CLL. [2019]

6. France pubmed.ncbi.nlm.nih.gov

Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival. [2021]

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

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

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

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

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

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