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

42 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Ibrutinib for high-risk CLL/SLL?

Ibrutinib has shown impressive results in treating chronic lymphocytic leukemia (CLL), especially in patients who have relapsed or have a specific genetic deletion (17p deletion). It is effective as a single agent and is well tolerated, even in older patients. ^{1 2 3 4 5}

Is ibrutinib safe for humans?

Ibrutinib is generally well tolerated by most patients, including older individuals, but some may experience side effects like atrial fibrillation (irregular heartbeat) or bleeding, which can lead to stopping the treatment. Most side effects are mild and resolve on their own, but it's important for doctors to monitor for any severe reactions. ^{2 3 6 7 8}

How is the drug ibrutinib unique for treating high-risk CLL/SLL?

Ibrutinib is unique because it is a targeted therapy that specifically inhibits Bruton tyrosine kinase, a key player in the growth of cancer cells in chronic lymphocytic leukemia (CLL). It is effective even for patients who are older or have other health issues, and it can be used when other treatments have failed. ^{1 2 4 5 9}

What is the purpose of this trial?

This randomized phase II trial studies how well ibrutinib works when given together with vaccine therapies in treating patients without clinical signs or indications that raise the possibility of a particular disorder or dysfunction (asymptomatic) who have high-risk 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. Vaccines, such as pneumococcal 13-valent conjugate vaccine, trivalent influenza vaccine, and diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine adsorbed, may help the body build an effective immune response to kill cancer cells. Giving ibrutinib together with vaccine therapies may be a better treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma.

Research Team

Jennifer Woyach, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

References

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

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

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

The Real-World Experience With Single Agent Ibrutinib in Relapsed/Refractory CLL. [2022]

3. Greece pubmed.ncbi.nlm.nih.gov

Long-term Efficacy of Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of the Polish Adult Leukemia Study Group Observational Study. [2021]

4. England pubmed.ncbi.nlm.nih.gov

The clinical safety of ibrutinib in chronic lymphocytic leukemia. [2021]

5. England 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. [2021]

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

Safety and efficacy analysis of long-term follow up real-world data with ibrutinib monotherapy in 58 patients with CLL treated in a single-center in Greece. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Bruton's tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL). [2021]

9. England pubmed.ncbi.nlm.nih.gov

Ibrutinib dose modifications in the management of CLL. [2021]