An Open-Label Phase 2 Study of Ofatumumab (Arzerra) in Combination With Oral GSK2110183 in the Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL)
Condition: Chronic Lymphocytic Leukemia (CLL)
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Ofatumumab with GSK2110183
Intervention description: GSK2110183 125mg OD continuously
Ofatumumab 300mg IV first dose, 2000mg weekly x 7 doses, then 2000mg monthly x 4 doses
Intervention MeSH terms: Ofatumumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a phase 2, open-label, single institution trial of combination of intravenous (IV)
      ofatumumab and oral GSK2110183 in patients with relapsed or refractory Chronic Lymphocytic
      Leukemia (CLL). Patients must have received at least one prior line of therapy containing
      fludarabine (single-agent or combination therapy). During the initial 6 months Treatment
      Phase, ofatumumab will be administered weekly for 8 doses, then once every 4 week cycle for
      an additional 4 doses (dose and schedule identical to the pivotal phase 2 trial) and
      GSK2110183 will be given daily PO (Treatment Phase). There will be an initial 10 day lead-in
      with GSK2110183 alone prior to initiation of ofatumumab to allow for evaluation of changes in
      cell surface expression due to GSK2110183 and for GSK2110183 pharmacokinetic studies (Lead-in
      Phase). The official Cycle 1 Day 1 will start on the date of first dose of ofatumumab. Cycle
      duration = 4 weeks. Patients will be assessed for safety, disease assessment, response, and
      survival on day 1 of each cycle during the Treatment Phase. A formal review of safety data by
      the Data Safety Monitoring Board (DSMB) after the first 6 patients have completed cycle 1 of
      the Treatment Phase will be performed before continuing accrual. All patients achieving SD,
      PR or CR by the end of the Treatment Phase will proceed to the Maintenance Phase. Patients
      with PD at any time, including by the end of Treatment Phase, will be taken off study. During
      the Maintenance Phase, single-agent GSK2110183 will be administered daily for a maximum of 12
      months (12 cycles). Maximum duration on any study drug is 18 months (18 cycles). During the
      Follow-up Phase, patients will be assessed for safety, disease assessment, response, and
      survival every 3 months through month 36 (year 3), or until subsequent CLL therapy or death,
      whichever comes first. Key indications for study withdrawal are progressive disease,
      intolerable toxicity, or completion of therapy
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must fulfill all of the following criteria to be eligible for admission to
             the study:

               -  A confirmed diagnosis of B-cell CLL by IWCLL 2008 criteria (Appendix 1)

               -  Patients must have evidence of disease progression as evidenced by rapid doubling
                  of peripheral lymphocyte count, progressive lymphadenopathy or
                  hepatosplenomegaly, worsening anemia or thrombocytopenia, or progressive
                  constitutional symptoms [including fatigue, weight loss, night sweats, fever
                  (without infection)]

               -  Must be relapsed or refractory to at least one prior fludarabine-containing
                  regimen (no maximum number of prior regimens).

               -  Age > 18 years.

               -  ECOG performance status of 0, 1 or 2 (Appendix 3)

               -  Signed the Informed Consent form

               -  Life expectancy of ≥ 6 months

               -  Able to swallow and retain oral medication

               -  Normal HbA1C ≤ 0.07

               -  Fasting blood sugar < 7mmol/L

        Exclusion Criteria:

          -  Subjects meeting any of the following criteria are excluded from this study:

               -  CLL therapy, including stem cell transplantation, within 4 weeks of study
                  initiation. Corticosteroids alone may be administered up to seven days prior to
                  the first dose of study drug.

               -  Treatment with any known non-marketed drug substance or experimental therapy
                  within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer,
                  or currently participating in any other interventional clinical study

               -  Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 3 months
                  prior to start of therapy

               -  Known hypersensitivity to ofatumumab, GSK2110183, or any components therein.

               -  Anticoagulants are permitted only if the subject meets PTT and INR entry criteria
                  (INR and PTT ≤ 1.5 times upper normal limit). Their use must be monitored in
                  accordance with local institutional practice.

               -  Current use of any anti-platelet agent (e.g. dipyridamole, clopidogrel) other
                  than aspirin (81mg daily).

               -  Current use of a prohibited medication based on potential drug-drug interaction -
                  a complete list is found in Appendix 1

               -  Known CNS involvement with CLL

               -  Transformation to aggressive B-cell malignancy (e.g. large B-cell lymphoma,
                  Richter's syndrome, prolymphocytic leukemia [PLL])

               -  "Active" autoimmune disease - prior history of autoimmune hemolysis (DAT positive
                  or negative) or immune thrombocytopenia without current active autoimmune disease
                  is allowed

               -  Subjects who have current active hepatic or biliary disease (with exception of
                  patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or
                  stable non-hepatitis B or C chronic liver disease per investigator assessment -
                  please see below for Hepatitis B and C criteria)

               -  Previously diagnosed diabetes mellitus (Type 1 or 2)

               -  Other past or current malignancy. Subjects who have been free of malignancy for
                  at least 5 years, or have a history of completely resected non-melanoma skin
                  cancer, or successfully treated in situ carcinoma are eligible.

               -  Chronic or current infectious disease requiring systemic antibiotics, antifungal,
                  or antiviral treatment such as, but not limited to, chronic renal infection,
                  chronic chest infection with bronchiectasis, and tuberculosis.

               -  Any medical condition that would require long-term use (> 1 month) of systemic
                  corticosteroids during study treatment (excludes topical or inhaled
                  corticosteroid use)

               -  History of significant cerebrovascular disease in the past 6 months or ongoing
                  event with active symptoms or sequelae

               -  QTc ≥ 470 msec on screening ECG

               -  Clinically significant cardiac disease including unstable angina, acute
                  myocardial infarction within six months prior to study entry, congestive heart
                  failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the
                  exception of extra systoles or minor conduction abnormalities.

               -  Significant concurrent, uncontrolled medical condition including, but not limited
                  to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological,
                  cerebral or psychiatric disease which in the opinion of the investigator may
                  represent a risk for the patient.

               -  Any major surgery within the prior 4 weeks.

               -  Known HIV positive

               -  Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In
                  addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status),
                  a HB DNA test will be performed and if positive the subject will be excluded.

               -  Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in
                  which case reflexively perform a HC RIBA immunoblot assay on the same sample to
                  confirm the result

               -  Screening laboratory values: platelets ≤ 30 x 109/L,neutrophils ≤ 0.7 x
                  109/L,creatinine ≥ 2.0 times upper normal limit, total bilirubin ≥ 1.5 times
                  upper normal limit (unless due to a known history of Gilbert's disease), ALT ≥
                  2.5 times upper normal limit, alkaline phosphatase ≥ 2.5 times upper normal
                  limit, INR and PTT ≤ 1.5 times upper normal limit

               -  Pregnant or lactating women. Women of childbearing potential must have a negative
                  pregnancy test at screening.

               -  Women of childbearing potential, including women whose last menstrual period was
                  less than one year prior to screening, unable or unwilling to use adequate
                  contraception from study start to one year after the last dose of protocol
                  therapy. Adequate contraception is defined as intrauterine device, double barrier
                  method or total abstinence. Oral contraceptives are not adequate due to potential
                  drug-drug interaction.

               -  Male subjects unable or unwilling to use adequate contraception methods from
                  study start to one year after the last dose of protocol therapy.