Ibrutinib for High-risk CLL/SLL

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jennifer Woyach

Must not be taking: Corticosteroids, H2-blockers, Warfarin, others

Disqualifiers: Cardiovascular disease, Recent infection, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 28

Duration: 24-27 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of ibrutinib, a drug that may inhibit cancer cell growth, when combined with certain vaccines. It targets individuals with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who are asymptomatic. The trial will compare two groups: one receiving ibrutinib and vaccines simultaneously, and another receiving them sequentially. Individuals who have not yet received treatment for CLL/SLL and possess specific genetic markers in their cancer cells may be suitable candidates. As a Phase 2 trial, this 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 requires that you stop taking certain medications, such as corticosteroids above a certain dose, H2-blockers, and strong CYP3A4/5 inhibitors, before starting the study. If you are on these medications, you may need to discuss alternatives with your doctor.

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

Research has shown that ibrutinib is generally well-tolerated by patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In studies, patients using ibrutinib as their first treatment experienced long-lasting benefits, with their cancer not worsening for up to 8.9 years.

Although ibrutinib can cause side effects, various studies have demonstrated its general safety. Common side effects include mild to moderate issues like tiredness, diarrhea, and minor infections, while serious side effects are less common.

Overall, evidence suggests that ibrutinib, when used with vaccines, could be a safe treatment option for high-risk CLL or SLL, although researchers are still studying the exact combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ibrutinib for high-risk chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) because it works differently from traditional chemotherapy treatments. Ibrutinib specifically targets and inhibits Bruton's tyrosine kinase (BTK), an enzyme crucial for cancer cell survival and proliferation. This targeted approach can lead to fewer side effects compared to broad-spectrum chemotherapy. Additionally, incorporating vaccines alongside ibrutinib in different sequences may enhance the immune response against CLL/SLL, providing a more comprehensive treatment strategy.

What evidence suggests that this trial's treatments could be effective for high-risk CLL/SLL?

Research has shown that ibrutinib works well for people with high-risk chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In real-world settings, 89% of patients treated with ibrutinib survived after 30 months. Even patients with high-risk genetic traits had similar survival rates to those without these traits when treated with ibrutinib. Long-term studies also show that treatments with ibrutinib remain effective for at least four years. In this trial, participants will receive ibrutinib either concurrently with vaccines or sequentially after vaccines. These findings suggest that ibrutinib could be a promising option for managing CLL and SLL. ^{1 2 3 6 7}

Who Is on the Research Team?

Jennifer Woyach, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma who haven't had previous treatment. They should have certain genetic markers, a life expectancy over 24 months, and be in relatively good health (ECOG <=2). Participants must not show signs needing immediate CLL/SLL treatment, have other serious illnesses or infections, or be on conflicting medications.

Inclusion Criteria

Patients must have histologically identified chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) as defined by the World Health Organization (WHO) classification of hematopoietic neoplasms

CLL/SLL cells must demonstrate one or more of the following high-risk genomic features: Del17p13.1(tumor protein p53 [TP53]) as detected by fluorescence in-situ hybridization (FISH), Del11q22.3 ataxia telangiectasia mutated (ATM) as detected by FISH, Complex karyotype (>= 3 cytogenetic abnormalities on stimulated karyotype), Unmutated immunoglobulin variable region heavy chain (IgVH) ( >= 98% sequence homology compared with germline sequence), Zeta-chain (TCR) associated protein kinase 70kDa (ZAP-70) gene promoter hypomethylation < 20%, No prior therapy for CLL/SLL, including chemotherapy and/or radiotherapy is allowed, Estimated life expectancy of greater than 24 months, Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%), Total bilirubin =< 1.5X upper limit of normal (ULN) unless secondary to Gilbert's disease, Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5X institutional upper limit of normal, Serum creatinine =< 2 md/dL or estimated creatinine clearance (CrCl) > 50ml/min/body surface area (BSA), Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN, Able to swallow capsules without difficulty and no history of malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or active ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female subjects of childbearing potential must have a negative serum pregnancy test upon study entry, Male and female subjects who agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug

Exclusion Criteria

Patients meeting any of the following consensus criteria for initiating treatment for their CLL: Progressive symptomatic splenomegaly and/or lymphadenopathy identified by physical examination, Anemia ( < 11g/dL) or thrombocytopenia ( < 100,000/uL) due to bone marrow involvement, Presence of unintentional weight loss > 10% over the preceding 6 months, National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 3 fatigue, Fevers > 100.5°F or night sweats for > 2 weeks without evidence of infection, Patients who have had any treatment for their CLL/SLL, including but not limited to chemotherapy, radiotherapy, or immunotherapy, prior to entering the study, No corticosteroid use will be permitted within two weeks prior to study, except for maintenance therapy for a non-malignant disease; maintenance therapy dose may not exceed 20 mg/day prednisone or equivalent, Patients may not be receiving any other investigational agents, History of allergic reactions attributable to compounds of similar chemical or biologic composition to ibrutinib or any component of pneumococcal, influenza and DTaP vaccines, Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject is considered by his or her physician to have a less than 2-year survival expectation, Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection and/or psychiatric illness/social situations that would limit compliance with study requirements, Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization, Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration [> 14 days] of > 20mg/day of prednisone) within 14 days of the first dose of study drug, Patients must discontinue treatment with H2-blockers (cimetidine, ranitidine, etc.) prior to beginning protocol therapy, Vaccinated with any of the vaccines planned for administration in the trial within 8 weeks of starting treatment on the study, Recent infection requiring systemic treatment that was completed =< 14 days before starting treatment on the study, Concomitant use of warfarin or other vitamin K antagonists, Patients who require treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor, Known bleeding disorders (eg, von Willebrand's disease) or hemophilia, History of stroke or intracranial hemorrhage within 6 months prior to enrollment, Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV); patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded, Major surgery within 4 weeks of starting trial, Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk, Lactating or pregnant, Unwilling or unable to participate in all required study evaluations and procedures, Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib and vaccines according to their assigned arm. Arm A receives concurrent vaccines and ibrutinib, while Arm B receives sequential vaccines followed by ibrutinib.

24-27 months

Monthly visits for each 28-day course

Follow-up

Participants are monitored for safety, effectiveness, and adverse events after treatment

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine Adsorbed
• Ibrutinib
• Pneumococcal 13-valent Conjugate Vaccine
• Trivalent Influenza Vaccine

Trial Overview The study tests if the drug Ibrutinib combined with vaccines (pneumococcal, influenza, diphtheria/tetanus/pertussis) can help treat asymptomatic high-risk CLL/SLL by enhancing the immune response to fight cancer cells. It's a phase II trial where participants are randomly assigned to receive this combination therapy.

How Is the Trial Designed?

Group I: Arm B (sequential vaccines and ibrutinib) Experimental Treatment 7 Interventions

Patients receive pneumococcal 13-valent conjugate vaccine IM on day 1 of courses 1 and 3 and trivalent influenza IM and DTaP vaccine IM on day 1 of course 2. Beginning in course 4, patients receive ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 27 courses in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (concurrent vaccines and ibrutinib) Experimental Treatment 7 Interventions

Patients receive ibrutinib PO QD on days 1-28. Patients also receive pneumococcal 13-valent conjugate vaccine IM on day 1 of courses 3 and 5 and trivalent influenza vaccine IM and DTaP vaccine IM on day 1 of course 4. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

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?

Jennifer Woyach

Lead Sponsor

Trials

4

Recruited

100+

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

Ibrutinib is an effective treatment for chronic lymphocytic leukemia (CLL) and is generally well tolerated, even in older patients or those unable to undergo traditional chemotherapy.

However, adverse events, such as lymphocytosis and potential drug interactions, can lead to treatment interruptions and complications like major hemorrhage and atrial fibrillation, highlighting the need for careful monitoring and possible dose adjustments when used with certain medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Keeping a balance in chronic lymphocytic leukemia (CLL) patients taking ibrutinib: ibrutinib-associated adverse events and their management based on drug interactions. Cho, HJ., Baek, DW., Kim, J., et al.[2021]

Ibrutinib and idelalisib, two B-cell receptor signaling inhibitors, have shown significant clinical activity in treating chronic lymphocytic leukemia (CLL), particularly in relapsed or refractory cases, and have been FDA-approved for this use.

Both drugs are generally well tolerated, even by older patients, with mild and self-resolving side effects; however, clinicians should be aware of specific adverse events that could limit their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. Falchi, L., Baron, JM., Orlikowski, CA., et al.[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]

Ibrutinib is a targeted therapy that has significantly improved treatment outcomes for patients with chronic lymphocytic leukemia (CLL), particularly for those who have previously undergone therapy or have a specific genetic marker (17p deletion).

The drug is generally well-tolerated, with discontinuation due to side effects being rare, although some patients may experience specific toxicities like lymphocytosis, major bleeding, and atrial fibrillation, which require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical safety of ibrutinib in chronic lymphocytic leukemia. Molica, S.[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/PMC12311590/

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% at 30 months ...

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. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123098804

Overall Survival Outcomes in Chronic Lymphocytic ... CLL/SLL patients with high-risk molecular-cytogenetic features (del[17p], or del[11q], or unmutated IGHV) treated with 1L ibrutinib had similar OS compared to ...

5. news.abbvie.com news.abbvie.com/2020-12-06-Combined-Data-from-Multiple-Phase-3-Studies-of-IMBRUVICA-R-ibrutinib-Show-Efficacy-and-Safety-in-High-Risk-Previously-Untreated-Chronic-Lymphocytic-Leukemia-CLL-and-Real-World-Data-Indicating-Low-Biomarker-Testing-Rates-for-These-Patients

Combined Data from Multiple Phase 3 Studies of ... First-line treatment with IMBRUVICA-based therapies resulted in sustained, long-term efficacy with high 4-year PFS rates in high-risk CLL patients.

6. 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 ... After a median follow-up of 9.6 years for the ibrutinib arm, the final analysis revealed a median progression-free survival of 8.9 years for ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40353821/

Real-world survival outcomes in first-line ibrutinib-treated ... Of 1242 patients included, 969 and 273 had high- and non-high-risk CLL/SLL, with a mean age of 70.0 and 70.8 years, and a median follow-up of 32 ...