Venetoclax and Ibrutinib in Patients With Relapsed/Refractory CLL or SLL
Condition: Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence
Intervention: Ibrutinib; Venetoclax
Intervention description: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1.; Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Intervention MeSH terms: Venetoclax
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is an open-label non-randomized two-center phase 2 study evaluating the safety and
      efficacy of concurrent therapy with ibrutinib and venetoclax in subjects with relapsed or
      refractory CLL/SLL.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject must voluntarily sign and date an informed consent approved by the
             Institutional Review Board prior to initiation of any study specific procedures

          -  Subject must have a diagnosis of CLL that meets International Workshop on Chronic
             Lymphocytic Leukemia (IWCLL)/National Cancer Institute (NCI)-Working Group (WG)
             criteria

          -  Subject must have relapsed/refractory disease with an indication for treatment
             according to the 2008 IWCLL/NCI WG criteria

          -  Measurable nodal disease by computed tomography (CT)

          -  Absolute neutrophil count > 750 cells/mm^3 (0.75 x 10^9/L)

          -  Platelet count > 30,000 cells/mm^3 (30 x 10^9/L)

          -  Hemoglobin > 8.0 g/dL

          -  Serum aspartate transaminase (AST) or alanine transaminase (ALT) =< 2.5 x upper limit
             of normal (ULN)

          -  Estimated creatinine clearance >= 30 mL/min (Cockcroft-Gault)

          -  Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
             non-hepatic origin)

          -  Prothrombin time/international normalized ratio (PT/INR) < 1.5 x ULN and partial
             thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          -  Female subjects who are of non-reproductive potential (ie, 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 must 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 90 days after the last dose of study drug

        Exclusion Criteria:

          -  Subject has previously received either venetoclax or ibrutinib

          -  Subject has received a live virus vaccine within 28 days prior to the initiation of
             study treatment

          -  Subject has undergone an allogeneic stem cell transplant in the past 1 year and must
             not have active chronic graft versus host disease (cGVHD) if over 1 year post
             allogeneic transplant

          -  Subject has developed Richter's transformation confirmed by biopsy

          -  Chemotherapy =< 21 days prior to first administration of study treatment and/or
             monoclonal antibody =< 6 weeks prior to first administration of study treatment

          -  History of other malignancies, except:

               -  Malignancy treated with curative intent and with no known active disease present
                  for >= 3 years before the first dose of study drug and felt to be at low risk for
                  recurrence by treating physician

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated carcinoma in situ without evidence of disease

          -  Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc, or
             chronic administration [> 14 days] of > 20 mg/day of prednisone) within 28 days of the
             first dose of study drug

          -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug

          -  Recent infection requiring systemic treatment that was completed =< 14 days before the
             first dose of study drug

          -  Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
             to Common Terminology Criteria for Adverse Event (CTCAE, version [v]4), grade =< 1, or
             to the levels dictated in the inclusion/exclusion criteria with the exception of
             alopecia

          -  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 with hepatitis C virus
             (HCV) or hepatitis B virus (HBV); subjects 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

          -  Any uncontrolled active systemic infection

          -  Major surgery within 4 weeks of first dose of study drug

          -  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

          -  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

          -  Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
             gastrointestinal function, or resection of the stomach or small bowel, symptomatic
             inflammatory bowel disease or ulcerative colitis, or partial or complete bowel
             obstruction

          -  Concomitant use of warfarin or other vitamin K antagonists

          -  Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor

          -  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)