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Alkylating Agents

In phase II, patients will be randomized (2:1 eltrombopag : placebo) to receive either eltrombopag or placebo to explore the efficacy and confirm the safety of the identified eltrombopag dose from Phase I.

Dosage form, frequency and duration exactly as experimental arm.

Placebo

Phase I:

Single arm dose-escalation trial part, to test 4 doses of eltrombopag (75mg, 150mg, 225mg, 300mg) to find the appropriate, feasible dose to achieve a durable increase in platelet count (≥100,000/µl). Eltrombopag will be administered once daily at the respective dose level for 2 weeks (unless platelet counts rise to \> 400,000/µl).

Phase II:

Patients will be randomized (2:1 eltrombopag : placebo) to explore the efficacy and confirm the safety of the identified dose level from Phase I. Eltrombopag/placebo will be administered before starting each cycle (and possibly following chemotherapy treatment depending on data from phase I), and will continue during all cycles of treatment until subjects finish chemotherapy (alkylating agents and/or purine analogue-based therapy). The schedule and days of eltrombopag dosing in Phase II will be determined based on data analyzed from Phase I.

Eltrombopag

Stephan Stilgenbauer, Prof. Dr.

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).

Eltrombopag in Thrombocytopenic Chronic Lymphocytic Leukemia (CLL) Patients (CLL2S Study of GCLLSG)

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

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.

Time points of assessment: 1 wk before and continously during treatment up to day 60 after last eltrombopag/placebo administration.

Treatment duration: see primary outcome measure.

Time points of assessment: 1 wk before treatment; at start of each chemotherapy cycle (Phase II); up to day 30 after last eltrombopag/placebo administration. Treatment duration: see primary outcome measure.

Time points of assessment: 1 wk before treatment; at start of each chemotherapy cycle (Phase II); up to day 30 after last eltrombopag/placebo administration.

Assessed by WHO bleeding scale. Treatment duration: see primary outcome measure.

Time points of assessment: 1 wk before treatment; at start of each chemotherapy cycle (Phase II); up to day 30 after last eltrombopag/placebo administration Treatment duration: see primary outcome measure.

Time points of assessment: 1 wk before treatment; at start of each chemotherapy cycle (Phase II); up to day 30 after last eltrombopag/placebo administration. In phase II only.

Time points of assessment: at start of each chemotherapy cycle (Phase II); up to day 30 after last eltrombopag/placebo administration. In phase II only.

In phase II only.

Pre-defined subgroups based on the following stratification factors:

* prior lines of treatment (1 vs. 2 vs. 3)
* platelet count at baseline ≤ 30,000/µL vs \> 30,000

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Eltrombopag in Thrombocytopenic Chronic Lymphocytic Leukemia (CLL) Patients (CLL2S Study of GCLLSG)	NCT01397149	Chronic Lymphoc... Thrombocytopeni...	Placebo Eltrombopag	18 Years -	University of Ulm
Eltrombopag in Thrombocytopenic Chronic Lymphocytic Leukemia (CLL) Patients (CLL2S Study of GCLLSG)	NCT01397149	Chronic Lymphoc... Thrombocytopeni...	Placebo Eltrombopag	18 Years -	University of Ulm

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