Ibrutinib and Pembrolizumab in Treating Patients with High Risk Chronic Lymphocytic Leukemia
- Have high risk CLL which includes one or more of the following characteristics: * 17p deletion by fluorescence in situ hybridization (FISH) or TP53 by next generation sequencing (NGS). * 11q deletion or ATM mutation by NGS. * Immunoglobulin heavy chain locus variable region mutation (IgVH) unmutated or IgVH mutated 3.21 phenotype by NGS assay.
- Have documented previously untreated CLL according to IWCLL criteria. * Monoclonal B cells that are clonally co-expressing at least 1 B-cell marker on flow cytometry: ** CD19 ** CD20 ** CD5 * Prolymphocytes may comprise no more than 55% of blood lymphocytes.
- Be willing and able to provide written informed consent/assent for the trial.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale.
- Absolute neutrophil count (ANC) >= 1,500 /mcL.
- Platelets >= 100,000/mcL.
- Hemoglobin >= 11 g/dL.
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 25 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]). * Creatinine clearance should be calculated per institutional standard.
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN.
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants.
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
- Negative serum pregnancy test within 3 days prior to receiving the first dose of study medication for a female subject of childbearing potential. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Women who are pregnant or breastfeeding are ineligible for this study.
- Female subjects of childbearing potential must be willing to use 2 methods of highly effective contraception, be surgically sterile, or abstain from heterosexual activity for the course of the study through 30 days and 90 days after the last dose of study medication for ibrutinib and pembrolizumab, respectively. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy. Men must agree to not donate sperm during and after the study.
- Is able to take oral medication and is willing to adhere to the medication regimen.
- Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
- Has had any treatment for CLL including any investigational agent, chemotherapy, monoclonal antibody (mAb), anti-PD-1, anti-PDL-1, or anti-CTLA-4.
- Meets iwCLL criteria to start therapy.
- Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (Richter’s transformation or pro-lymphocytic leukemia).
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents including subjects with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be excluded from the study.
- Has history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- Subjects with a history of a different malignancy are ineligible unless they have been disease free for 1 year and considered low risk for relapse, except for: cervical cancer in situ, ductal carcinoma in situ, localized prostate cancer with no detectable disease by imaging studies, and non-melanoma skin cancers which are eligible at any time.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 90 days after the last dose of trial treatment.
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected).
- Has received a live vaccine within 30 days prior to the first dose of trial treatment. Patients who had pneumococcal vaccination within 6 months from starting trial will not be eligible for the study.
- Major surgery or a wound that has not fully healed within 4 weeks of first dose.
- History of stroke or intracranial hemorrhage within 6 months prior to first dose.
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon).
- Requires chronic treatment with strong CYP3A inhibitors.
- Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
I. Assessment of the complete response (CR) of chronic lymphocytic leukemia (CLL) to therapeutic intervention (defined per current International Workshop on CLL [iWCLL] 2008 response criteria).
II. Time to response of CLL to therapeutic intervention (defined as time to achievement of response according to iWCLL 2008 criteria).
I. Assessment of the overall response rate (ORR) [CR + partial response [PR]) per iWCLL 2008 response criteria.
II. Restoration of immune response as measured by:
IIa. Decreased markers of T-cell exhaustion.
IIb. Increased of quantitative immunoglobulin levels and subtype.
III. Safety and toxicity of the combination.
IV. Progression free survival (PFS).
V. Incidence of Richter’s transformation (defined as transformation of CLL into an aggressive lymphoid/histiocytic histology including well defined World Health Organization 2008 subtypes).
I. Alterations in T lymphocyte function, including changes in:
Ia. TH1:TH2 polarization, and regulatory T cells (TReg):TH17 distributions.
Ib. Markers of T cell exhaustion and/or inhibition.
Ic. Alterations in distribution of naive versus (vs.) memory.
Id. Cellular activation and cell-mediated cytotoxic capacity.
II. Alterations in B lymphocyte function, including changes in:
IIa. Serum anti-pneumococcal antibody titers in response to Prevnar vaccination.
IIb. Quantitative serum immunoglobulin levels and subtyping.
IIc. Fc-receptor (FcR) expression patterns.
III. Alterations in global systemic cytokine patterns: Includes IFN-gamma, TNF-alpha, IL-2, IL-4, IL-10, IL-6, IL-17A, allowing discrimination between TH1, TH2, and TH17 profiles.
Patients receive pembrolizumab intravenously (IV) on day 1 and ibrutinib orally (PO) once daily (QD) beginning at week 6. Cycles repeat every 21 days for up to 51 weeks in the absence of disease progression or unacceptable toxicity. Patients may receive pembrolizumab for up to 1 additional year if there is clinical benefit per the investigator.
After completion of study treatment, patients are followed up at 30-35 days and then every 12 weeks for 12 months.
Trial Phase Phase II
Trial Type Treatment
Moffitt Cancer Center
Julio C. Chavez
- Primary ID MCC-19199
- Secondary IDs NCI-2019-02457
- Clinicaltrials.gov ID NCT03514017