Ibrutinib + Fludarabine for Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must not be taking: Immunomodulatory, Chemotherapy, Radiotherapy, others

Disqualifiers: Transformed CLL, Autoimmune anemia, Hepatitis, HIV, others

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

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

Compensation: Varies

Number of Visits: 6

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, ibrutinib and fludarabine, to evaluate their safety and effectiveness in treating individuals with chronic lymphocytic leukemia (CLL) who have not undergone previous treatment. Participants take ibrutinib daily, while fludarabine is administered in specific cycles. Researchers aim to determine if this treatment can fully control the disease after six cycles and how many participants discontinue due to side effects. Suitable candidates include those with CLL or small lymphocytic lymphoma (SLL) who experience symptoms such as significant weight loss, extreme fatigue, or frequent fevers, and have not received prior CLL treatment. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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 take certain medications like strong CYP3A inhibitors or require anticoagulation with warfarin. 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 shows that ibrutinib, a key part of the treatment under study, has been used safely in other trials. In long-term studies lasting up to 8 years, many patients continued using ibrutinib without major issues. These studies indicate that ibrutinib can be well-tolerated over time.

Fludarabine, the other treatment in the study, has been used in cancer treatment for a while. It is known to have some side effects, but these are usually predictable and manageable. In this study, fludarabine is given in short courses, which may help reduce the risk of side effects.

Overall, previous research suggests that the combination of ibrutinib and short-course fludarabine is reasonably safe. However, since the study is in the early stages, ongoing research will provide a better understanding of the safety of this combination in people with chronic lymphocytic leukemia (CLL). ^{1 2 3 4 5}

Why are researchers excited about this study treatment for chronic lymphocytic leukemia?

Researchers are excited about the combination of Ibrutinib and Fludarabine for treating Chronic Lymphocytic Leukemia (CLL) because it introduces a novel approach to the current treatment landscape. Unlike the standard therapies like chemoimmunotherapy, Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that uniquely targets and disrupts specific signaling pathways essential for CLL cell survival. This targeted mechanism might offer a more precise attack on cancer cells with potentially fewer side effects. Additionally, combining Ibrutinib with short-course Fludarabine, a chemotherapy agent, could enhance the overall effectiveness by attacking the cancer cells from multiple angles, possibly leading to better outcomes for patients.

What evidence suggests that ibrutinib and fludarabine might be an effective treatment for chronic lymphocytic leukemia?

Research has shown that ibrutinib is promising for treating chronic lymphocytic leukemia (CLL). In one study, ibrutinib helped 92% of patients, with 18% achieving a complete response, meaning no detectable cancer. Additionally, long-term results indicate that ibrutinib can extend progression-free survival, the time patients live without their cancer worsening.

In this trial, participants will receive a combination of ibrutinib and fludarabine. Fludarabine, often used with other drugs to treat CLL, enhances their effectiveness. Combining ibrutinib with fludarabine might improve treatment outcomes by leveraging the strengths of both drugs. Although specific data on this combination is limited, the effectiveness of each drug alone supports the potential of this approach. ^{1 2 5 6 7}

Who Is on the Research Team?

Andy Itsara, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

This trial is for adults with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL), who have certain blood cell counts and are able to perform daily activities. They must not have had previous CLL treatments, be free from significant heart disease, active infections like Hepatitis B/C or HIV, and agree to use effective contraception.

Inclusion Criteria

I have CLL/SLL and have not received any treatment yet.

Agreement to use acceptable methods of contraception, negative pregnancy test for females of childbearing potential, and willingness to participate in all study procedures

I can perform daily activities with minimal assistance.

Exclusion Criteria

Psychiatric illness/social situations limiting patient's ability to comply with study requirements, inability to understand the study or give informed consent

I do not have severe liver, kidney, or other life-threatening health issues.

Major surgery within specific timeframe, currently active, clinically significant cardiovascular disease, subjects who received or require strong CYP3A inhibitors

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib daily and fludarabine during cycles 3 and 4

24 weeks

6 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine
• Ibrutinib

Trial Overview The study tests the combination of Ibrutinib taken daily until disease progression or side effects become intolerable, with Fludarabine given in short courses. The main goals are to see how many patients achieve a complete response after 6 cycles and monitor those who stop treatment due to side effects within the same period.

How Is the Trial Designed?

Group I: Ibrutinib and short-course fludarabine Experimental Treatment 2 Interventions

* Ibrutinib 420 mg PO daily for the duration of the study * Fludarabine 25 mg/m2/day IV on days 1-5 of cycles 3 and 4

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

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Mantle-cell lymphoma
• Non-Hodgkin's lymphoma

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Stem Cell Transplant Conditioning

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Ibrutinib has shown high effectiveness as a first-line treatment for chronic lymphocytic leukemia in real-world settings, with 12-month overall survival rates between 95% and 96% and progression-free survival rates ranging from 89% to 93% across various studies involving 112 to 2033 patients.

The treatment demonstrated a strong response rate, with 71% to 90% of patients responding positively, and a significant majority (91% at 12 months and 87% at 24 months) did not require new treatment, indicating its sustained efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Literature Review of Real-World Effectiveness Results Data for First-Line Ibrutinib in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. Lee, P., Kistler, KD., Douyon, L., 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]

Ibrutinib (Imbruvica) is an effective treatment for chronic lymphocytic leukemia, targeting specific pathways to inhibit cancer cell growth.

Tasimelteon (Hetlioz) is beneficial for individuals with non-24-hour sleep-wake disorder, helping to regulate sleep patterns, while anti-inhibitor coagulant complex (Feiba) is used to prevent or reduce bleeding episodes in patients with hemophilia A or B, demonstrating its efficacy in managing bleeding risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical approval update. Goldenberg, MM.[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]

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7153674/

Efficacy of Ibrutinib-Based Regimen in Chronic ... In a phase 3 trial (n = 136), the overall response rate (ORR) with ibrutinib was 92% whereas 18% patients had a complete response (CR). Progression free ...

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

Efficacy and Safety of Ibrutinib Therapy in Patients with ... Likewise, 3-year PFS in ibrutinib-treated CLL patients was reported to be 53% for patients with del(17p), 66% for those with del(11q), and 58% for patients ...

3. 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.

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

Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic ... A marked improvement in progression-free survival and overall survival among patients with CLL has been realized with the addition of anti-CD20 ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S000649712200516X

Long-term outcomes for ibrutinib–rituximab and ... Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers ...

6. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00144-4/fulltext

Ibrutinib and rituximab versus fludarabine ... This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 ...

7. 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 ... Additional findings from pooled analysis of three Phase 3 studies showed treatment with ibrutinib has the potential to achieve comparable overall survival ...