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

INTERVENTION:

Product Name: Eltrombopag Product Code: SB497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Pharmaceutical form of the placebo: Coated tablet Route of administration of the placebo: Oral use Product Name: Eltrombopag Product Code: SB497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Coated tablet Route of administration of the placebo: Oral use

CONDITION:

CLL patients with thrombocytopenia and indication for chemotherapeutic treatment with alkylating agents and/or purine analogues ; MedDRA version: 15.1 Level: LLT Classification code 10008977 Term: Chronic lymphocytic leukemia recurrent System Organ Class: 100000004864 ; MedDRA version: 15.1 Level: LLT Classification code 10068919 Term: B‐cell chronic lymphocytic leukemia System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Blood and lymphatic diseases [C15]

SECONDARY OUTCOME:

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 ; 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).

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 (

PRIMARY OUTCOME:

Main Objective: 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. 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). Secondary Objective: •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 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