Phase 2 Study of the Combination of Bruton's Tyrosine Kinase Inhibitor PCI-32765 and Rituximab in High-Risk Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients
Condition: Leukemia
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Rituximab; PCI-32765
Intervention description: 375 mg/m2 intravenously on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6.; 420 mg (3 * 140-mg capsules) orally started on Day 2 of cycle 1 once daily and will be continued daily.
Intervention MeSH terms: Rituximab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Leukemia; Chronic Lymphocytic Leukemia; CLL; Small Lymphocytic Lymphoma; SLL; Rituximab; Rituxan; PCI-32765

Summary:

      The goal of this clinical research study is to learn if PCI-32765 (Ibrutinib) combined with
      rituximab can help to control CLL and SLL. The safety of this combination will also be
      studied.

      Ibrutinib is designed to stop a protein from working in the cells, which may cause the cancer
      cells to die or stop growing.

      Rituximab is designed to attach to cancer cells and damage them, which may cause the cells to
      die.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 1.Patients must have a diagnosis of high-risk CLL/SLL and be previously treated with
             up to 3 lines of prior therapy. High-risk CLL and high-risk SLL is defined by the
             presence of a 17p deletion or 11q deletion or TP53 mutation. Any CLL and SLL patient
             who has a short remission duration of less than 3 years after prior first-line
             chemo-immunotherapy, such as the FCR regimen, also fulfills criteria of high-risk
             CLL/SLL, regardless of the presence or absence of cytogenetic abnormalities.

          2. 2.CLL and SLL patients with 17p deletion or TP53 mutation will not be required to have
             received any prior therapy, given the poor outcome of CLL/SLL patients to standard
             frontline chemo-immunotherapy, such patients will be eligible if they are untreated or
             if they have received up to 3 lines of prior therapy.

          3. Patients must have an indication for treatment by 2008 IWCLL Criteria.

          4. Patients age > 18 years at the time of signing informed consent. Understand and
             voluntarily sign an informed consent. Be able to comply with study procedures and
             follow-up examinations.

          5. Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance
             status of 0-1.

          6. Patients of childbearing potential must be willing to practice highly effective birth
             control (e.g., condoms, implants, injectables, combined oral contraceptives, some
             intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the
             study and for 30 days after the last dose of study drug. Women of childbearing
             potential include any female who has experienced menarche and who has not undergone
             successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
             bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as
             follows: Amenorrhea >/= 12 consecutive months without another cause and a documented
             serum follicle stimulating hormone (FSH) level >35 mIU/mL; a male of childbearing
             potential is any male that has not been surgically sterilized.

          7. Adequate renal and hepatic function as indicated by all of the following: Total
             bilirubin </=1.5 x institutional Upper Limit of Normal (ULN) except for patients with
             bilirubin elevation due to Gilbert's disease who will be allowed to participate; an
             Alanine (ALT) </=2.5 x ULN; and an estimated creatinine clearance (CrCl) of > 30
             mL/min, as calculated by the Cockcroft-Gault equation unless disease related.

          8. Free of prior malignancies for 3 years with exception of currently treated basal cell,
             squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast.

          9. A Urine Pregnancy Test (within 7 days of Day 1) is required for women with
             childbearing potential

        Exclusion Criteria:

          1. Pregnant or breast-feeding females.

          2. Treatment including chemotherapy, chemo-immunotherapy , monoclonal antibody therapy,
             radiotherapy, high-dose corticosteroid therapy (more than 60 mg prednisone or
             equivalent daily), or immunotherapy within 21 days prior to enrollment or concurrent
             with this trial.

          3. Investigational agent received within 30 days prior to the first dose of study drug or
             have previously taken PCI-32765. If received any investigational agent prior to this
             time point, drug-related toxicities must have recovered to Grade 1 or less prior to
             first dose of study drug.

          4. Systemic fungal, bacterial, viral, or other infection not controlled (defined as
             exhibiting ongoing signs/symptoms related to the infection and without improvement,
             despite appropriate antibiotics or other treatment).

          5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune
             thrombocytopenia (ITP).

          6. Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophil
             count of less than 500/micro-L and/or a platelet count of less than 30,000/micro-L at
             time of screening for this protocol.

          7. Any other severe concurrent disease, or have a history of serious organ dysfunction or
             disease involving the heart, kidney, liver or other organ system that may place the
             patient at undue risk to undergo therapy with PCI-32765 and rituximab.

          8. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
             congestive heart failure, or myocardial infarction within 6 months of screening, or
             any Class 3 or 4 cardiac disease as defined by the New York Heart Association
             Functional Classification.

          9. Significant screening ECG abnormalities including left bundle branch block, 2nd degree
             AV block type II, 3rd degree block, bradycardia, and QTc > 470 msec.

         10. Any serious medical condition, laboratory abnormality, or psychiatric illness that
             places the subject at unacceptable risk if he/she were to participate in the study.

         11. History of stroke or cerebral hemorrhage within 6 months.

         12. Evidence of bleeding diathesis or coagulopathy.

         13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1, anticipation of need for major surgical procedure during the course of
             the study.

         14. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days
             prior to Day 1. Bone marrow aspiration and/or biopsy are allowed.

         15. Serious, non-healing wound, ulcer, or bone fracture.

         16. Treatment with Coumadin. Patients who recently received Coumadin must be off Coumadin
             for at least 7 days prior to start of the study.

         17. Any chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or fludarabine),
             immunotherapy (e.g., alemtuzumab, or ofatumumab), bone marrow transplant, experimental
             therapy, or radiotherapy is prohibited during therapy on this study.

         18. Use of medications known to prolong QTc interval or that may be associated with
             Torsades de Pointes (refer to Appendix F) are prohibited within 7 days of starting
             study drug and during study-drug treatment.

         19. Requires treatment with strong CYP3A4/5 and/or CYP2D6 inhibitors.