Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01397149
Recruitment Status : Terminated (Insufficient recruitment)
First Posted : July 19, 2011
Last Update Posted : May 28, 2015
Sponsor:
Collaborators:
GlaxoSmithKline
German CLL Study Group
WiSP Wissenschaftlicher Service Pharma GmbH
Information provided by (Responsible Party):
Stephan Stilgenbauer, University of Ulm

Tracking Information
First Submitted Date  ICMJE June 30, 2011
First Posted Date  ICMJE July 19, 2011
Last Update Posted Date May 28, 2015
Study Start Date  ICMJE October 2011
Actual Primary Completion Date November 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 18, 2011)
Change in platelet count [ Time Frame: up to 7 months ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2011)
  • Adverse events [ Time Frame: up to 8 months ]
    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.
  • Change in vital signs [ Time Frame: up to 7 months ]
    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.
  • Change in clinical laboratory parameters [ Time Frame: up to 7 months ]
    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.
  • Bleeding events [ Time Frame: up to 7 months ]
    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.
  • Number of required platelet transfusions [ Time Frame: up to 7 months ]
    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.
  • Number of chemotherapy dose delay/dose reduction [ Time Frame: up to 7 months ]
    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.
  • CLL overall response rate [ Time Frame: up to 7 months ]
    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.
  • Time to CLL progression [ Time Frame: up to 2 years ]
    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
  • Trough-level pharmacokinetics of eltrombopag [ Time Frame: up to 6 months ]
    Assessment at day 1 of each week with eltrombopag administration.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Eltrombopag in Thrombocytopenic Chronic Lymphocytic Leukemia (CLL) Patients (CLL2S Study of GCLLSG)
Official Title  ICMJE 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
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Lymphocytic Leukemia
  • Thrombocytopenia
Intervention  ICMJE
  • Drug: Placebo
    Dosage form, frequency and duration exactly as experimental arm.
  • Drug: Eltrombopag

    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.

    Other Names:
    • Revolade
    • Promacta
Study Arms  ICMJE
  • Experimental: Eltrombopag
    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.
    Intervention: Drug: Eltrombopag
  • Placebo Comparator: Film coated tablet
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 27, 2015)
4
Original Estimated Enrollment  ICMJE
 (submitted: July 18, 2011)
82
Actual Study Completion Date  ICMJE November 2014
Actual Primary Completion Date November 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01397149
Other Study ID Numbers  ICMJE CLL2S
2010-023022-20 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Stephan Stilgenbauer, University of Ulm
Study Sponsor  ICMJE University of Ulm
Collaborators  ICMJE
  • GlaxoSmithKline
  • German CLL Study Group
  • WiSP Wissenschaftlicher Service Pharma GmbH
Investigators  ICMJE
Principal Investigator: Stephan Stilgenbauer, Prof. Dr. Universitätsklinikum Ulm, Medizinische Klinik III
PRS Account University of Ulm
Verification Date May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP