Eltrombopag in Thrombocytopenic Chronic Lymphocytic Leukemia (CLL) Patients (CLL2S Study of GCLLSG)
Eltrombopag in Thrombocytopenic Chronic Lymphocytic Leukemia (CLL) Patients (CLL2S Study of GCLLSG)
The aim of this study is to find the appropriate dose of eltrombopag in thrombocytopenic CLL
 patients, that shortens the duration of the thrombocytopenia and achieves platelet count of ≥
 100/nl prior to the start of chemotherapy containing alkylating agents and/or Purine
 Analogues.
The study is divided in a Phase I and a Phase II part. The phase I part uses an open-label,
 dose escalation design in order to find the appropriate, feasible dose of eltrombopag to
 achieve a durable increase in platelet count.

 In phase II, patients will be randomized (2:1 eltrombopag : placebo) to explore the efficacy
 and confirm the safety of the identified eltrombopag dose from Phase I. Eltrombopag/placebo
 will be administered before starting each cycle and will continue during all cycles of
 treatment until subjects finish treatment with chemotherapy. The schedule and days of
 eltrombopag dosing in Phase II will be determined based on data analyzed from Phase I, but
 will not exceed the defined maximum tolerable dose (MTD).

 Severe thrombocytopenia is a frequently associated hematologic condition in patients with
 CLL. In the earlier stages of the disease, mild thrombocytopenia is common in approximately
 25% of CLL patients. Later in the disease, the bone marrow will become more extensively
 infiltrated by the neoplastic cells, which results in more severe thrombocytopenia.
 Thrombocytopenia in patients with CLL could result from the disease, a packed marrow or from
 autoimmunity/ITP. For patients with CLL who develop severe thrombocytopenia, treatment
 options are limited and administration of platelet transfusions is common. Additionally,
 treatment of CLL patients with chemotherapy to treat the disease can be hampered due to
 severe thrombocytopenia. The clinical consequences of severe thrombocytopenia include an
 increased tendency for bleeding, probably due to thrombocytopenia, compromised hemostasis,
 and delayed administration of chemotherapy with the consequence of less optimal disease
 control.

 Eltrombopag is an orally bioavailable small molecule TPO receptor (TPO-R) agonist being
 developed by GlaxoSmithKline (GSK) as a treatment for thrombocytopenia. Eltrombopag has been
 shown to stimulate platelet production and elevates platelet counts in healthy volunteers and
 in patients with chronic ITP, and in patients with thrombocytopenia related to hepatitis C
 virus (HCV) (Jenkins, Blood 2007; Bussel, NEJM 2007; McHutchinson NEJM 2007).

 The optimal dose of eltrombopag for thrombocytopenic patients with CLL is currently unknown.
 As such, one objective of this study is to define a safe and effective dose of eltrombopag
 for thrombocytopenic patients with CLL prior to alkylating agent and/or fludarabine-based
 therapy. The eltrombopag doses proposed for administration in this study are 75 mg up to 300
 mg once daily.

 As a prerequisite for the trial, detailed studies have been performed in laboratory of the
 principal investigator on the in-vitro effects of eltrombopag on CLL cells regarding cell
 survival, differentiation and proliferation. The results suggest that eltrombopag is unlikely
 to act as a growth factor in CLL. Therefore clinical trials investigating its effect on
 platelet counts in CLL are warranted (Zenz T. et al., ASH 2009).
Inclusion Criteria:

 -  Confirmed diagnosis of CLL (based immunophenotyping performed at the central reference
 laboratory of the GCLLSG in Cologne)

 -  Platelet count <50 000/μl at time of screening (measured and confirmed twice)

 -  Patient is planned to receive alkylating agents and/or fludarabine-based therapy as
 2nd or higher-line treatment

 -  ECOG Performance Status of 0-2

 -  Age >= 18 years

 -  Signed written informed consent, according to ICH-GCP, and national/local regulation,
 prior to performing any study-specific procedures

 -  Negative pregnancy test and willingness to use highly effective methods of
 contraception (per institutional standard) during treatment and for 6 months (male or
 female) after the end of treatment (adequate: oral contraceptives, intrauterine device
 or barrier method in conjunction with spermicidal jelly).

 -  Able to understand and comply with protocol requirements and instructions and intend
 to complete the study as planned.

 -  Adequate renal function (creatinine must not exceed the upper limit of normal (ULN)
 reference range by more than 50%) at study entry

 -  Adequate liver function: bilirubin £ 1.5 times the upper limit of normal. ALT or AST
 <= 3 times the upper limit of normal without liver involvement with CLL and <= 5 times
 the upper limit of normal in case of the liver involvement with CLL

 -  Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must be
 within 80 to 120% of the normal range with no history of hypercoagulable state

 -  Total albumin must not be below the lower limit of normal (LLN) by more than 20%.

 Exclusion Criteria:

 -  Thrombocytopenia that is primarily caused by ITP

 -  Refractory CLL: defined as treatment failure (failure to achieve a CR or PR) or
 disease progression within 6 months of last fludarabine and/or bendamustine based
 therapy. NOTE: Subjects refractory to rituximab monotherapy as last therapy are
 permitted

 -  No prior therapy for CLL

 -  Active autoimmune hemolytic anemia (AIHA) requiring corticosteroid therapy >100mg
 equivalent to hydrocortisone, or chemotherapy

 -  Platelet count > 50 000/μl at screening

 -  Richter's transformation

 -  CNS involvement of B-CLL

 -  Active infectious disease requiring systemic antibiotics, antifungal, or antiviral
 treatment

 -  Past or current malignancy other than CLL (with the exception of basal cell carcinoma
 of the skin or in situ carcinoma of the cervix or breast) unless tumor was
 successfully treated with curative intent at least 2 years prior to trial entry

 -  Clinically significant cardiac disease including unstable angina, acute myocardial
 infarction within 6 months, congestive heart failure, etc.

 -  History of significant cerebrovascular disease

 -  Recurring venous thrombosis or pulmonary embolism

 -  Glucocorticoids unless given in doses <= 100 mg/day hydrocortisone (or equivalent dose
 of other glucocorticoids) and for exacerbations other than CLL (e.g. asthma)

 -  Known HIV positivity

 -  Active hepatitis B, C

 -  Treatment with an investigational drug within 30 days or five half-lives (whichever is
 longer) preceding the first dose of eltrombopag.

 -  Subjects known or suspected of not being able to comply with a study protocol

 -  Patients with recent history of arterial or venous thrombosis (stroke, transient
 ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism)
 within the preceding 6 months. Patients with recurrent arterial or venous
 thromboembolic events.