Ibrutinib + Rituximab for Chronic Lymphocytic Leukemia

Recruiting at 895 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, Warfarin

Disqualifiers: Congestive heart failure, Hepatitis B, 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: 3

Duration: 6-7 months

529 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two different treatment combinations to determine which is more effective for individuals with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. One group will receive ibrutinib (a Bruton's tyrosine kinase inhibitor) and rituximab, while the other group will receive fludarabine phosphate, cyclophosphamide, and rituximab. The trial aims to identify which method better stops cancer cell growth and aids the immune system in fighting cancer. Individuals diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma who have not received prior treatments may be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking cancer 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, 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.

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

Research has shown that the combination of ibrutinib and rituximab is generally well-tolerated by people with chronic lymphocytic leukemia (CLL). Studies have found this treatment to be a safe option for CLL, with many patients experiencing manageable side effects. Some individuals might feel mild fatigue or nausea, but these symptoms are usually not severe.

The treatment using rituximab, fludarabine phosphate, and cyclophosphamide is a standard chemotherapy approach. These drugs have a well-known safety record and are commonly used to treat various cancers. However, they can lead to side effects like low blood cell counts and an increased risk of infections.

Previous research has studied both treatment options, providing a level of safety assurance. Participants should still consult their healthcare provider about any concerns to better understand the risks and benefits based on their personal health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer new ways to tackle Chronic Lymphocytic Leukemia (CLL). Unlike standard treatments such as chemotherapy, the combination of Ibrutinib and Rituximab in Arm A includes Ibrutinib, which is a Bruton's tyrosine kinase (BTK) inhibitor. This targets a specific protein in cancer cells, potentially leading to better outcomes with fewer side effects. Arm B uses a more traditional approach with Rituximab, Fludarabine Phosphate, and Cyclophosphamide, which are known to be effective but can have challenging side effects. The hope is that by comparing these approaches, researchers can identify more effective and tolerable treatments for CLL.

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

Studies have shown that using ibrutinib with rituximab effectively treats chronic lymphocytic leukemia (CLL). In this trial, participants in one arm will receive this combination. Research indicates that it helps patients live longer without disease progression compared to traditional treatments. Long-term studies have found that ibrutinib and rituximab work well for patients with various genetic types of CLL. Ibrutinib blocks certain enzymes that cancer cells need to grow, while rituximab helps the immune system find and destroy cancer cells. These findings suggest that the ibrutinib-rituximab combination is a promising treatment option for CLL. ^{4 6 7 8 9}

Who Is on the Research Team?

Tait D Shanafelt

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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

Specific medical criteria met including ECOG performance status, life expectancy, ability to tolerate therapy, specific lab values within normal range, and absence of certain medical conditions

I have been diagnosed with CLL or SLL.

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

Exclusion Criteria

Recent vaccination history

I need certain medications or treatments.

I have a specific condition affecting my digestive system.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35427411/

updated results of the E1912 trial - PubMed - NIH Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 Jul 14;140(2):112 ...

2. ashpublications.org ashpublications.org/blood/article/140/2/112/484957/Long-term-outcomes-for-ibrutinib-rituximab-and

Long-term outcomes for ibrutinib–rituximab and ... After a median follow-up of 6 years, IR led to superior PFS relative to FCR in patients with both IGHV muted and IGHV unmutated CLL.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02007044

NCT02007044 | Ibrutinib With or Without Rituximab in ... This phase II trial studies ibrutinib with or without rituximab in treating patients with chronic lymphocytic leukemia that has come back after treatment.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1817073

Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic ... Data regarding the efficacy of treatment with ibrutinib–rituximab, as compared with standard chemoimmunotherapy with fludarabine, ...

5. nature.com nature.com/articles/s41375-023-01891-3

Ibrutinib in combination with rituximab is highly effective in ... Ibrutinib in combination with rituximab is highly effective in treatment of chronic lymphocytic leukemia patients with steroid refractory and ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25150798/

Safety and activity of ibrutinib plus rituximab for patients with ... Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study · Authors · Affiliations.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8656120/

Efficacy and Safety of Ibrutinib Therapy in Patients with ... This study aimed to retrospectively evaluate the efficacy, safety, and survival outcome of single-agent ibrutinib therapy in chronic lymphocytic leukemia ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02232386

NCT02232386 | Phase 2 Study to Assess Activity & Safety ... The combined administration of Ibrutinib and Rituximab could be an effective and safe front-line treatment schedule for unfit patients with CLL. The current ...

9. ashpublications.org ashpublications.org/bloodadvances/article/6/11/3440/484605/Up-to-8-year-follow-up-from-RESONATE-2-first-line

Up to 8-year follow-up from RESONATE-2: first-line ibrutinib ... Long-term RESONATE-2 data show sustained PFS and OS benefits (medians not reached) for first-line ibrutinib treatment in patients with CLL.