A Phase I/II, Multi-centre Trial to Assess the Safety, Efficacy, and Pharmacokinetics of Eltrombopag, Administered to Thrombocytopenic Chronic Lymphocytic Leukemia Patients Prior to Alkylating Agents and/or Purine Analogue-based Therapy
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
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).
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Change in platelet count
Time points of assessment: 1 wk before treatment; 2-3 times/wk during treatment; 30d after end of treatment Treatment duration: Phase I: Two weeks Phase II: Eltrombopag is given as concomitant treatment to chemotherapy, with a max. duration of max. 6 cycles of 28 days each. The exact schedule of Eltrombopag administration will be determined after evaluation of Phase I results.
up to 7 months
Stephan Stilgenbauer, Prof. Dr.
Universitätsklinikum Ulm, Medizinische Klinik III
Austria: Federal Office for Safety in Health Care