E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CLL patients with thrombocytopenia and indication for chemotherapeutic treatment with alkylating agents and/or purine analogues |
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E.1.1.1 | Medical condition in easily understood language |
CLL patients with low platelet counts and indication for chemotherapeutic standard treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008977 |
E.1.2 | Term | Chronic lymphocytic leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068919 |
E.1.2 | Term | B-cell chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase I:
The primary objective is to find the safe and potentially efficacious dose of eltrombopag to achieve a durable increase in platelet count.
Phase II:
The primary objective of phase II is to confirm the effect of the selected dose from Phase I in correcting thrombocytopenia to enable patients to receive alkylating agents and/or purine analogue-based therapy. |
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E.2.2 | Secondary objectives of the trial |
•Safety and tolerability of eltrombopag by evaluating adverse events and changes from baseline in vital signs and clinical laboratory parameters (compared to placebo, phase II)
•To evaluate the incidence and durability of platelet response (compared to placebo, phase II)
•To determine the incidence and severity of bleeding events (WHO bleeding scale, compared to placebo, phase II)
•To analyze the pharmacokinetics and the relationship between pharmacokinetics and pharmacodynamics of eltrombopag and platelet counts (compared to placebo, phase II)
•To determine the effect of eltrombopag on the use of platelet transfusion(s) to treat thrombocytopenia (compared to placebo, phase II)
•To evaluate chemotherapy dose delay/dose reduction in eltrombopag groups compared to placebo (phase II)
•To examine the eltrombopag effect in relation to data on the cause of thrombocytopenia
•CLL overall response rate & time to progression
•To evaluate trough-level pharmacokinetics of eltrombopag |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Confirmed diagnosis of CLL (based on immunophenotyping performed at the central reference laboratory of the GCLLSG in Cologne)
•Platelet count <50 000/µl at time of screening (measured and confirmed once)
•Patient is planned to receive alkylating agents, bendamustine and/or fludarabine-based therapy
•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% |
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E.4 | Principal 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 anti-leukemic therapy , including fludarabine and/or bendamustine. 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I: dose-escalation trial (4 doses of eltrombopag: 75mg, 150mg, 225mg, 300mg) to find an appropriate, feasible dose to achieve an increase in platelet count from <50.000/µ to ≥100.000/µl. An empirical, two-step escalation design with 3 to 6 patients on each dose level is used.
Phase II: the platelet stimulation efficacy of the determined dose level will be estimated. Platelet responders are defined as achieving platelet counts ≥100.000/µl prior to cycle 1 of chemotherapy and platelet counts ≥75.000/µl in the subsequent 3 cycles (or 3 month in case of continuous chemotherapy). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I: for the decision on a definite MTD at least 6 patients have to be treated on the respective dose level for 2 weeks, with a maximum of one case of dose limiting toxicity. In case of toxicity in 2 cases or more, the next lower dose is declared as MTD (or the trial terminated completely if this happens on the first dose level).
Phase II: two stage design: The evaluation after the recruitment of 19 patients has to reveal at least 4 platelet responders to continue the trial with the recruitment of 20 additional patients. If at least 9 responders are among the 39 eltrombopag patients, treatment will be considered promising |
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E.5.2 | Secondary end point(s) |
Comparison of:
•adverse event/toxicity rates
•number of bleeding events according to WHO bleeding scale
•rate of patients with chemotherapy dose delay/reduction
•CLL overall best response rate
•platelets nadir
•durations of thrombocytopenia
•number of platelet transfusions
•progression-free survival of CLL disease
•duration of platelet response
•pharmacokinetical analyses
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End points of trial will be evaluated whenever they occur (adverse events) as well as at patient visits during and after study treatment (follow-up). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Combined Phase I/II study - pharmacology |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
combined Phase I/II study (open/controlled) |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Phase I: the trial terminates completely if a non-acceptable toxicity in 2 cases or more are observed on the first dose level.
Phase II: Within this 2-stage design the trial will be stopped althogether if treatment with eltrombopag shows no promising response after the first stage of recruiting (= first 19 eltrombopag patients). Promising response is specified with at least 4 patients with platelet responses. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |