Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Ibrutinib and Vaccine Therapies in Treating Patients with Asymptomatic, High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Protocol: OSU-15012

Full Title

Early intervention trial of ibrutinib for patients with asymptomatic, high-risk chronic lymphocytic leukemia/small lymphocytic lymphoma


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.

Study Objective


I. To determine the 2-year progression-free survival of asymptomatic, high-risk genomic chronic lymphocytic leukemia (CLL) patients treated with ibrutinib.


I. To determine whether concurrent administration of ibrutinib with 2 doses of the pneumococcal vaccine (pneumococcal 13-valent conjugate vaccine) does not negatively impact the immune response compared to those who receive the pneumococcal vaccination with sequential therapy.

II. To determine if concurrent administration of ibrutinib with the DTaP vaccine (diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine adsorbed) will increase type 1 helper cell (Th1) cluster of differentiation (CD)4+ T-cell polarization and/or promote Th1 CD4+ T-cell polarization and enhance cellular response compared to administration of the DTaP vaccine alone, in asymptomatic, genomic high-risk CLL patients.

III. To determine the safety and toxicity associated with administering ibrutinib to asymptomatic, high-risk genomic CLL patients.

IV. To determine the response pattern (complete response [CR] minimal residual disease [MRD]-, CR, partial response [PR], PR with lymphocytosis, stable disease [SD]) in asymptomatic, genomic high-risk patients treated with ibrutinib.

V. To perform select pharmacodynamic studies to assess predictors of early response, features of CLL cells with delayed lymphocytosis and resistance to ibrutinib.

VI. To determine if response to vaccine covaries with patients’ self-reports of psychological stress.

VII. To determine changes in the stress, anxiety and depressive symptoms, and related quality of life indicators from patients treated with ibrutinib.


I. To determine whether concurrent administration of ibrutinib with the influenza vaccine does not negatively impact the immune response compared to those who receive the influenza vaccination with sequential therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A (CONCURRENT VACCINES + IBRUTINIB): Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Patients also receive pneumococcal 13-valent conjugate vaccine intramuscularly (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.

ARM B (SEQUENTIAL VACCINES + IBRUTINIB): 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.

After completion of study treatment, patients are followed up for 28 days, every 3 months for 1 year, and then every 6 months thereafter.

Are you eligible?

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)

Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification

Chronic Lymphocytic Leukemia Acute Lymphoblastic Leukemia Leukemia