Clinical trial NCT01397149: Eltrombopag in Thrombocytopenic Chronic Lymphocytic Leukemia (CLL) Patients (CLL2S Study of GCLLSG)
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Chronic Lymphocytic Leukemia
Thrombocytopenia
Keywords: Chronic lymphocytic leukemia
Thrombocytopenia
Alkylating agents
Purine derivatives
TPO receptor agonist
Lead sponsor: University of Ulm
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
name: German CLL Study Group
name: WiSP Wissenschaftlicher Service Pharma GmbH
First posted: 2011-07-19
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Change in platelet count
timeFrame: up to 7 months
Secondary outcomes:
measure: Adverse events
timeFrame: up to 8 months
measure: Change in vital signs
timeFrame: up to 7 months
measure: Change in clinical laboratory parameters
timeFrame: up to 7 months
measure: Bleeding events
timeFrame: up to 7 months
measure: Number of required platelet transfusions
timeFrame: up to 7 months
measure: Number of chemotherapy dose delay/dose reduction
timeFrame: up to 7 months
measure: CLL overall response rate
timeFrame: up to 7 months
measure: Time to CLL progression
timeFrame: up to 2 years
measure: Trough-level pharmacokinetics of eltrombopag
timeFrame: up to 6 months
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medizinische Universität Wien, Innere Medizin I, Abt. Hämatologie und Hämastaseologie
city: Cologne
country: Germany
facility: Universitätsklinikum Köln; Klinik I für Innere Medizin
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Med. Klinik und Poliklinik I
city: Erlangen
country: Germany
facility: Gemeinschaftspraxis für Innere Medizin, Hämatologie und Internistische Onkologie
city: Essen
country: Germany
facility: Universitätsklinikum; Klinik für Hämatologie
city: Frankfurt (Oder)
country: Germany
facility: Klinikum Frankfurt (Oder) Medizinische Klinik I
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, II. Medizinische Klinik und Poliklinik im Städtischen Krankenhaus
city: Leer
country: Germany
facility: Onkologische Schwerpunktpraxis Leer-Emden
city: München
country: Germany
facility: Städtisches Klinikum München GmbH, Klinikum Schwabing, Klinik für Hämatologie, Immunologie, Palliativmedizin, Infektiologie und Tropenmedizin
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Medizinische Klinik III
Study officials:
affiliation: Universitätsklinikum Ulm, Medizinische Klinik III
name: Stephan Stilgenbauer, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: