Ibrutinib + Venetoclax for Leukemia

(TAILOR Trial)

Recruiting at 91 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Janssen Research & Development, LLC

Disqualifiers: Autoimmune anemia, Bleeding disorders, Stroke, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 15 cycles (each cycle = 4 weeks)

320 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two treatments, ibrutinib (Imbruvica) and venetoclax (Venclexta), used alone or together for individuals with chronic lymphocytic leukemia or small lymphocytic lymphoma. Researchers aim to determine if adjusting the ibrutinib dosage in response to side effects enhances safety and effectiveness. This trial suits individuals diagnosed with these types of leukemia or lymphoma who have noticeably enlarged lymph nodes. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants the opportunity to contribute to significant advancements in treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that ibrutinib is usually well-tolerated, but some patients have experienced serious side effects. Specifically, studies reported 25 cases of serious side effects leading to death, including pneumonia and heart failure. Additionally, about 33% of patients stopped taking ibrutinib due to side effects.

For the combination of ibrutinib and venetoclax, studies have shown promising results. Many patients experienced long-term benefits, and the combination proved effective. However, side effects can still occur. Most patients managed the treatment well and showed good progress without disease progression.

This trial is in Phase 2, indicating that earlier trials have demonstrated some safety. However, the treatment is still being tested to better understand its safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ibrutinib and venetoclax for leukemia because they offer a fresh approach compared to standard chemotherapy and targeted therapies like imatinib. Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which interferes with cancer cell signaling and helps prevent their growth and survival. Venetoclax targets B-cell lymphoma 2 (BCL-2) proteins, promoting cancer cell death. The combination of these two drugs could potentially enhance effectiveness and provide a more targeted treatment option, reducing the need for more invasive treatments. Moreover, the different dosing strategies explored in the trial may optimize their effectiveness and minimize side effects, offering a tailored approach to treatment.

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

Research shows that ibrutinib, which participants in this trial may receive as monotherapy, effectively treats leukemia. Studies in real-world settings have found that 89% to 93% of patients did not experience disease progression after 12 months, and 71% to 90% responded positively to the treatment. Among those taking ibrutinib for up to 10 years, 68% remained alive.

Another treatment option in this trial is the combination of ibrutinib and venetoclax, which has also demonstrated good results. In one study, 67% of patients did not experience disease progression after five years, and 96% remained alive. This combination is particularly effective for high-risk patients, with 67% in remission and 96% surviving. ^{1 6 7 8 9}

Who Is on the Research Team?

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Are You a Good Fit for This Trial?

This trial is for adults with untreated chronic lymphocytic leukemia who are not pregnant or breastfeeding, agree to use contraception, and have a certain level of physical function (ECOG status). They must have measurable disease by CT scan. People planning pregnancy soon after the study or those with other health conditions that could interfere are excluded.

Inclusion Criteria

A participant using oral contraceptives must use an additional contraceptive method

I have a lymph node that is at least 1.5 cm big, confirmed by a CT scan.

I am active and can care for myself, with little to no assistance.

Exclusion Criteria

I don't have worsening anemia or low platelets due to autoimmunity, nor need high-dose steroids.

My condition has not progressed to Richter's transformation or spread to my brain.

I have a known bleeding disorder like von Willebrand's or hemophilia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib and venetoclax with dosing adjustments based on cohort assignment

15 cycles (each cycle = 4 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Venetoclax

Trial Overview The study tests two treatment methods: Ibrutinib alone, and in combination with Venetoclax. It aims to see how effective they are and if adjusting Ibrutinib doses can reduce side effects while maintaining benefits.

How Is the Trial Designed?

Group I: Cohort 2b: Continuous Ibrutinib Monotherapy Experimental Treatment 1 Intervention

Participants will receive ibrutinib 420 mg QD for 1 cycle (1 cycle = 28 days) followed by Ibrutinib 280 mg QD (or last tolerated dose) and continue until disease progression or unacceptable toxicity.

Group II: Cohort 2a: Continuous Ibrutinib Monotherapy Experimental Treatment 1 Intervention

Participants will receive ibrutinib 420 mg QD (or last tolerated dose) until disease progression (PD) or unacceptable toxicity.

Group III: Cohort 1b: Ibrutinib Lead-in+Fixed Duration Ibrutinib+Venetoclax Experimental Treatment 2 Interventions

Participants will receive ibrutinib 420 mg capsule QD for a lead-in of 3 cycles (1 cycle = 28 days). From Cycle 4, venetoclax 400 mg tablet dose ramp-up (from 20 to 400 mg over 5 weeks) will begin and ibrutinib dose will be reduced to 280 mg and will be administered QD, venetoclax 400 mg tablets QD will be administered with ibrutinib 280 mg for 12 cycles through Cycle 15.

Group IV: Cohort 1a: Ibrutinib Lead-in+Fixed Duration Ibrutinib+Venetoclax Experimental Treatment 2 Interventions

Participants will receive ibrutinib 420 milligrams (mg) capsule every day (QD) for a lead-in of 3 cycles (1 cycle = 28 days). From Cycle 4, venetoclax 400 mg tablet dose ramp-up (from 20 to 400 mg over 5 weeks) will begin, and venetoclax 400 mg QD will be administered with ibrutinib 420 mg QD, orally for 12 cycles through Cycle 15.

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

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead Sponsor

Trials

1,022

Recruited

6,408,000+

Joaquin Duato

Janssen Research & Development, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Research & Development, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

Published Research Related to This Trial

In a safety run-in cohort of 21 patients with relapsed/refractory mantle cell lymphoma, the combination of ibrutinib and venetoclax showed an impressive overall response rate of 81%, with 62% achieving a complete response after a median follow-up of 31 months.

The study indicated that concurrent administration of ibrutinib and venetoclax is safe, with only three dose-limiting toxicities observed and no new safety concerns, allowing the trial to proceed without an ibrutinib lead-in.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. Wang, M., Ramchandren, R., Chen, R., et al.[2021]

Ibrutinib, idelalisib, and venetoclax are novel oral therapies for chronic lymphocytic leukemia that provide unique clinical benefits compared to traditional treatments, but they also come with specific safety concerns and logistical challenges.

Each of these agents has distinct adverse effects: ibrutinib can cause bleeding and atrial fibrillation, idelalisib may lead to hepatotoxicity, and venetoclax carries a risk of tumor lysis syndrome, necessitating careful monitoring and potential dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax. Waldron, M., Winter, A., Hill, BT.[2021]

The HOVON 141/VISION trial is investigating the combination treatment of ibrutinib and venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia (RR-CLL), focusing on the possibility of stopping ibrutinib in patients who achieve undetectable minimal residual disease (uMRD) after 12 cycles of treatment.

The primary goal of the study is to assess progression-free survival 12 months after randomization, providing insights into the long-term efficacy and safety of discontinuing ibrutinib in patients who have reached deep remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protocol description of the HOVON 141/VISION trial: a prospective, multicentre, randomised phase II trial of ibrutinib plus venetoclax in patients with creatinine clearance ≥30 mL/min who have relapsed or refractory chronic lymphocytic leukaemia (RR-CLL) with or without TP53 aberrations. Levin, MD., Kater, AP., Mattsson, M., et al.[2021]

In a phase 3 trial with 523 patients, the combination of ibrutinib and venetoclax significantly improved progression-free survival compared to the traditional FCR treatment, with only 12 patients experiencing disease progression or death in the ibrutinib-venetoclax group versus 75 in the FCR group.

The study also found that 65.9% of patients on ibrutinib-venetoclax achieved undetectable measurable residual disease (MRD) in bone marrow after 5 years, indicating effective disease control, although there was a higher incidence of serious cardiac adverse events in this group compared to FCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir, T., Cairns, DA., Bloor, A., et al.[2023]

Long-term treatment with the combination of venetoclax and ibrutinib in mantle cell lymphoma (MCL) patients led to significant changes in immune cell populations, particularly in CD4+ and CD8+ T cells and natural killer cells, indicating a potential for immune recovery.

Despite the restoration of normal immune subsets in patients who stopped treatment after achieving deep responses, certain myeloid gene expressions remained altered, suggesting that the combination therapy may have lasting effects on the immune system even after treatment cessation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy. Davis, JE., Handunnetti, SM., Ludford-Menting, 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]

In a study of 45 patients with chronic lymphocytic leukemia (CLL) who had been on ibrutinib for at least 12 months, adding venetoclax led to a high rate of undetectable measurable residual disease (U-MRD) in bone marrow, with 57% achieving U-MRD4 at 12 months.

The combination therapy resulted in 71% of patients achieving U-MRD by the end of the treatment, suggesting that this approach may allow some patients to stop ibrutinib and potentially achieve durable treatment-free remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD. Thompson, PA., Keating, MJ., Ferrajoli, A., et al.[2023]

In a retrospective study of 22 patients with chronic lymphocytic leukaemia (CLL) who progressed on ibrutinib, the combination of ibrutinib and venetoclax resulted in a median overall survival of 47.1 months, indicating potential efficacy in this challenging patient group.

For 11 patients with double-refractory CLL, the same combination therapy led to a median overall survival of 27.0 months, suggesting that this treatment may provide a valuable option for patients who have limited alternatives after failing standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. Hampel, PJ., Rabe, KG., Call, TG., et al.[2022]

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 ... Real-world studies have also confirmed the benefit of 1L ibrutinib treatment; specifically, real-world OS (rwOS) rates were reported to be 89% ...

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

Systematic Literature Review of Real-World Effectiveness ... Twelve-month progression-free survival rates ranged from 89% to 93%, and the overall response rate ranged from 71% to 90% across four studies.

3. 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.

4. targetedonc.com targetedonc.com/view/new-10-year-data-show-ibrutinib-s-lasting-efficacy-in-cll-sll

New 10-Year Data Show Ibrutinib's Lasting Efficacy in CLL ... Furthermore, the median overall survival (OS) for patients on ibrutinib was not reached, with a 9-year OS rate of 68% for all patients in the ...

5. 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 ...

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5927982/

Toxicities and outcomes of 616 ibrutinib-treated patients in ... The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In ...

8. 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 ... Overall, 25 AEs leading to death were noted in the ibrutinib arm, including pneumonia, cardiac failure, CLL, and death (supplemental Table 2), of which 2 events ...

9. jnj.com jnj.com/media-center/press-releases/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 ... AEs of any Grade led to discontinuation of ibrutinib in 33 percent of patients (n=44) over the whole study duration, in 13 percent of patients ( ...