Background: Severe aplastic anemia (SAA) is a rare bone marrow failure disorder associated with significant morbidity and mortality. SAA is characterized by severe pancytopenia and a hypocellular (<25%) bone marrow. The standard of care treatment is hemopoietic stem cell transplant or immunosuppressive therapy (IST) for patients (pts) who are ineligible for transplant. IST usually comprises an antithymocyte globulin (ATG) derived from horse or rabbit, and cyclosporine A (CsA). Although IST can be an effective treatment, individual intolerance, insufficient response, relapse, and clonal evolution remain significant limitations. The lack of global availability of the more effective horse ATG also leaves many pts with limited treatment options and poorer outcomes. In addition, pts with SAA often require transfusions which can be burdensome and negatively impact their quality of life. Eltrombopag (ETB) is indicated for use in pts with SAA who have had an insufficient response to IST (FDA PI, 2014) or are refractory to IST (EMA SmPC, 2015). More recently in the USA, ETB may also be used in combination with IST as first-line (1L) treatment (FDA PI, 2018). Aims: To assess the efficacy and safety of ETB + CsA (without ATG) as 1L therapy in adult pts with SAA. Methods: SOAR (NCT02998645) is a Phase 2, single-arm, multicenter, open-label study. Treatment-naive pts with SAA received ETB + CsA for 6 months; responders continued CsA therapy for an additional 24 months (later reduced to 18 months). The primary efficacy endpoint was overall response rate (ORR) by 6 months. ORR was defined as the proportion of pts with complete response ([CR] = absolute neutrophil count [ANC] ≥1000/μL AND platelet count ≥100,000/μL AND hemoglobin ≥10 g/dL) plus the proportion of pts with partial response ([PR] = any 2 of the following counts: ANC ≥500/μL; platelet count ≥20,000/μL; automated reticulocyte count ≥60,000/μL, but not sufficient for a CR). CR and PR were confirmed by 2 assessments ≥7 days apart; transfusion restrictions were also applied. For the primary endpoint to be considered ‘clinically meaningful’ at least 17/54 pts treated were required to have a response. Other endpoints included ORR by 3 months, ORR at 6 months (ie, confirmed response at the 6-month visit), and transfusion independence, which was defined as transfusion not being required in a period of ≥28 days for platelet transfusions and ≥56 days for red blood cell (RBC) transfusions. Results: Pts (N=54) had a median (interquartile range [IQR]) age of 55.0 (40.0-67.0) years and 63.0% were male. The majority of pts were White (40.7%) or Asian (40.7%). The median (IQR) duration of exposure to ETB and CsA was 5.7 (2.5-5.8) months and 5.7 (2.4-8.1) months, respectively, and the median (IQR) daily ETB dose was 150.0 (100.0-150.0) mg/day. In the full analysis set, the primary endpoint was met, with 25/54 pts having a CR or PR by 6 months (ORR 46.3%; 95% confidence interval [CI], 32.6-60.4%). Of the 25 responders, 2 (3.7%) achieved a CR by 6 months. ORR by 3 months was 40.7% (95% CI, 27.6-55.0%; n=22/54), and ORR at 6 months was 37.0% (95% CI, 24.3-51.3%; n=20/54). 70.4% of all pts qualified for ≥1 period of RBC and/or platelet transfusion independence by 6 months, including all 25 (100%) responders and 13/29 (44.8%) non-responders (Fig. 1). 40.7% of all pts (responders: 68.0%; non-responders: 17.2%) qualified for ≥1 period of RBC transfusion independence (corresponding percentages for platelet transfusion independence were the same as for the combined RBC and/or platelet endpoint). Adverse events (AEs) occurred in 52/54 (96.3%) pts; 45 (83.3%) pts experienced treatment-related AEs (TAEs), 23 (42.6%) of whom had a grade ≥3 TAE. The most common all-grade AEs were increased blood bilirubin (40.7%), nausea (29.6%), increased alanine aminotransferase (22.2%), and diarrhea (22.2%). Seven (13.0%) pts discontinued treatment due to grade ≥3 AEs. There were 8 on-treatment deaths (aplastic anemia [n=3]; COVID-19, hemorrhage, multi-organ dysfunction syndrome, pyrexia, and thrombosis [all n=1]); no deaths were considered treatment-related. Conclusion: Data from the SOAR study indicate that ETB + CsA may be beneficial for pts with SAA ineligible for transplant who cannot access or tolerate ATG. All responders and almost half of non-responders qualified for ≥1 period of transfusion independence by 6 months, suggestive of a decreased transfusion burden. No new safety signals were identified. [Formula presented] Disclosures: Vallejo: Novartis: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Finelli: Takeda: Consultancy; Celgene

BMS:

Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Calado: Agios: Membership on an entity's Board of Directors or advisory committees; AA&MDS International Foundation: Research Funding; Alexion Brasil: Consultancy; Instituto Butantan: Consultancy; Novartis Brasil: Honoraria; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees. Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals Inc: Consultancy, Honoraria; Swedish Orphan Biovitrum AB.: Consultancy, Honoraria. Kriemler-Krahn: Novartis: Current Employment. Haenig: Novartis: Current Employment. Maier: Novartis: Current Employment. Scheinberg: Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Consultancy; Roche: Consultancy; Abbvie: Consultancy. OffLabel Disclosure: In the United States, eltrombopag is a thrombopoietin receptor agonist indicated in combination with standard immunosuppressive therapy (ATG + CsA) for the first-line treatment of adult and pediatric patients aged 2 years and older with severe aplastic anemia (SAA). It is also indicated for the treatment of patients with SAA who have had an insufficient response to immunosuppressive therapy. The SOAR trial aims to assess the efficacy and safety of eltrombopag + CsA (without ATG) as first-line therapy in adult patients with SAA.

INTERVENTION:

Trade Name: Revolade Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Trade Name: Revolade Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Trade Name: Revolade Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use

CONDITION:

Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] Thrombocytopenic Subjects with Myelodysplastic Syndromes or Acute Myeloid Leukemia ; MedDRA version: 14.0 Level: LLT Classification code 10028534 Term: Myelodysplastic syndrome NOS System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 14.0 Level: LLT Classification code 10060356 Term: Acute myeloid leukaemia without mention of remission System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps)

SECONDARY OUTCOME:

Secondary end point(s): Part 2 of Study:; Secondary endpoints compare the following in subjects treated with eltrombopag and placebo:; ? Hematologic improvement (platelets, neutrophils and hemoglobin); ? Assessment of platelet counts throughout the study; ? Number of platelet transfusions; ? Duration of platelet transfusion‐independence.; ? The occurrence and severity of bleeding, measured using the WHO Bleeding Scale.; ? Disease response and disease progression; ? Physical exam findings, clinical monitoring, vital signs, clinical laboratory tests, and adverse event reporting (including; hemorrhagic and transfusion‐related adverse events).; ? Medical resource utilization, including specifically due to thrombocytopenia and hemorrhage.; ? FACT‐TH‐18 and the EQ‐5D Timepoint(s) of evaluation of this end point: Screening, Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11, End of Therapy ? Week 12, Early Withdrawal Visit, Follow Up Visits ? Week 1, 2, 3 & 4

PRIMARY OUTCOME:

Main Objective: Part 1 open‐label, 8 week first part of the study are:; ? To evaluate the safety and tolerability of eltrombopag.; ? To determine optimal dose escalation scheme for use in Part 2 of the study by assessing the dose of eltrombopag required to achieve platelet count response.; ? To characterize plasma eltrombopag pharmacokinetics (steady‐state plasma eltrombopag Cmax, tmax, AUC(0‐?), CL/F, and half‐life).; Part 2: ? The primary objective of this study is to determine reduction in the number of clinically relevant thrombocytopenic events; (CRTE) in subjects with MDS or AML who have Grade 4 thrombocytopenia (<25 Gi/L) and are treated with eltrombopag compared to those treated with placebo.; Part 3: The objectives of the study are to evaluate the long‐term durability of clinical benefit and the long‐term safety and tolerability of eltrombopag in subjects with MDS and AML Primary end point(s): Part 2 of Study:; The primary endpoint is clinically relevant thrombocytopenic events (CRTE) during weeks 5‐12 of treatment. CRTE are defined as:; ? platelet counts <10 Gi/L, or; ? platelet transfusions, or; ? ?Grade 3 hemorrhagic adverse events. Secondary Objective: Part 2 of Study:; Secondary objectives compare the following in subjects treated with eltrombopag and placebo:; ? To evaluate hematologic improvement; ? To evaluate the effect of eltrombopag on platelet counts; ? To evaluate the effect of eltrombopag on the need for platelet transfusions.; ? To evaluate the effect of eltrombopag on the duration of platelet transfusion independence.; ? To evaluate the effect of eltrombopag on bleeding symptoms.; ? To evaluate MDS and AML disease outcomes; ? To evaluate the safety and tolerability of eltrombopag.; ? To evaluate effect of eltrombopag on medical resource utilization.; ? To evaluate effect of eltrombopag on healthrelated quality of life. Timepoint(s) of evaluation of this end point: Screening, Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11, ; End of Therapy ? Week 12, ; Early Withdrawal Visit, Follow up Visit ? Week 1, 2, 3 & 4

INCLUSION CRITERIA:

Subjects eligible for enrolment in the study must meet all of the following criteria: 1. Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ?50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded. 2. Subjects must have Grade 4 thrombocytopenia (platelet counts <25 Gi/L) due to bone marrow insufficiency (or platelet count ?25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count <10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible. 3. Subjects must have platelet count, bleedin

Context: Eltrombopag (EPAG), a thrombopoietin receptor agonist (TPO-RA), has shown promising results in severe aplastic anemia (SAA), as a single agent in immunosuppressive therapy (IST)-refractory patients and in treatment-naïve patients when combined with horse antithymocyte globulin (hATG) and cyclosporine (CsA). hATG is unavailable in most parts of the world and is associated with increased toxicity, especially in patients aged >60 years. Moreover, ∼1/3rd of patients after ATG/CsA are considered refractory. Objective: To evaluate the efficacy and safety of EPAG+CsA in outpatient setting for the treatment-naïve patients with SAA mainly in countries where hATG is unavailable. Design: Phase 2, open-label, single-arm, 2-stage study (ClinicalTrials.gov NCT02998645). Eligibility: Patients aged ≥6 years with SAA who had no prior IST treatment with CsA, alemtuzumab, rabbit ATG or hATG, or TPO-RAs. Interventions: EPAG will be administered at 150 mg/day, fixed dosage (and a reduced dosage in patients of Asian ancestry and patients aged 6-11 years), with CsA (administered twice daily) at an initial dose of 10 mg/kg/day to be titrated to obtain a therapeutic trough level of 200–400 μg/L. After 6 months, EPAG treatment will be stopped in all patients and CsA treatment will be continued on a taper regimen in responders. Methods: The primary endpoint is overall hematologic response (complete response [CR]+partial response [PR]) by 6 months (Table 1). The study is planned to enroll ∼50 patients, which will provide>94% probability of a positive signal (≥15 responders) if the true response rate is ≥40%. The key secondary endpoints include safety assessments; overall hematologic response by 3 and 12 months; and overall survival with a follow-up to 5 years (Table 2). Results: Eleven countries (Brazil, France, Hong Kong, Hungary, India, Italy, Korea, Mexico, Netherlands, Spain, Turkey) are involved under European commission/health authority submission process. First patient first visit was on May 11, 2017. Currently, 2 patients were screened and none were enrolled. Recruitment is expected to be completed by August 2018 (from 21 committed sites). Conclusion: This prospective multicenter study will help to determine the role of EPAG+CsA as an outpatient regimen for the first-line treatment in naive patients with SAA. [Formula presented] [Formula presented]

Patients with immune thrombocytopenia (ITP) under eltrombopag therapy are vulnerable to thrombotic disbalance, both due to the disease itself and therapy-related hypercoagulability. Vascular events such as the development of a free-floating carotid thrombus are known rare complications of acute COVID-19 infections due to endothelial inflammation and presumptive underlying hypercoagulable state. In patients at risk, the onset of new focal neurological symptoms should prompt immediate angiographic diagnostics and, if necessary, appropriate treatment. Here, we report a case of a 38-year-old female with a medical history of ITP and the presence of COVID-19 infection presenting an acute sensorimotor hemiparesis of the right side while on eltrombopag therapy. Initial CT angiography revealed a free-floating thrombus in the left common carotid artery. Upon admission, the patient's platelet count was significantly elevated at 896 × 109/l. After systemic lysis therapy, the thrombus was fully dissolved. Follow-up diffusion-weighted imaging revealed multilocular cortical infarction of the left MCA territory. The patient soon recovered and was discharged with residual mild sensorimotor deficits in the right arm. Eltrombopag was paused at admission, and the patient's platelet count was quickly returning to normal. She was discharged with a daily intake of acetylsalicylic acid, a reduced daily dose of eltrombopag, and weekly monitoring of her platelet count for the next three months. This unique case highlights the need for caution in patients at vascular risk who contract COVID-19 and discusses thrombocytic derailment under thrombopoietin receptor agonist therapy in the context of an acute COVID-19 infection.

Introduction: The increased risk of bleeding in myelodysplastic syndromes (MDS) is due to low platelet (PLT) counts and abnormalities of PLT morphology and function. Severe thrombocytopenia occurs in about 10% of low and Int-1 International Prognostic Scoring System (IPSS) risk MDS patients in whom PLT transfusions are indicated mainly in the presence of bleeding. Short therapeutic effect and the development of refractoriness to PLT transfusions motivate research in novel treatments. Eltrombopag is an oral, non peptide, non-competitive agonist of the thrombopoetin-receptor (TPOR) which interacts selectively with the TPOR transmembrane domain to initiate TPO signaling. Eltrombopag is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura. Its potential in increasing PLT count in lower risk MDS has not been evaluated. Study Design and Methods: We present preliminary results of a Phase II, multicentre, prospective, placebo-controlled, single blind study to evaluate the safety and efficacy of eltrombopag in low and intermediate-1 risk adult MDS patients with PLT count <30 Gi/L. Patients are included if: ECOG performance status < 4; ineligible for or relapsed or refractory to other treatments; and naive to TPO-R agonists. Secondary endpoints include differences in: changes in quality of life (QoL) scores by EORTC QLQ-C30 and QOL-E v. 3 questionnaires, frequency of PLT transfusions, incidence and severity of bleeding, and overall and leukemia-free survival. Eltrombopag or placebo (2:1 ratio) is administered to 69 patients at a 50 mg daily initial dose with 50 mg increases every 2 weeks to a target PLT count of 100 Gi/L. Dose interruptions or reductions are required for PLT >200 Gi/L or adverse events. PLT response is defined as Response (R) if: 1) baseline > 20 Gi/L: absence of bleeding and absolute increase in PLT 30 Gi/L/mm3; 2) baseline < 20 Gi/L: PLT <20 Gi/L and increase by at least 100%, not due to PLT transfusion; and Complete Response (CR) if PLT count 100 Gi/L and absence of bleeding. Bone marrow (BM) aspirate smears, cytogenetics and peripheral blood (PB) smears are performed throughout the study and blinded centralized morphology review is performed. Results: Seventeen patients (10 on active drug - Arm A) of mean age 64, SD 12, years are randomized and 2 are in screening at the time of the present report. Baseline mean PLT count was 14, SD 8, Gi/L. Three cases had significant bleeding (2 in Arm A, and 1 in Arm B) and 2 patients in each arm required PLT transfusions during screening. After a mean follow up of 6 months, 5 cases on the eltrombopag arm have obtained a CR (1 at day 8, 3 at day 15 with 50 mg dosing, and 1 at day 54 with 100 mg dosing) and one case is in R at 8 weeks follow-up; amongst non-responders, two have reached a 300 mg dose, the remaining are ongoing at a 100 and 150 mg dose, respectively. In Arm B, there was one case with an unstable R. In Arm A, PLT count increased by mean 68 SD 76 Gi/L (p=0.010) after 4 weeks and 114 SD 110 Gi/L (p=0.021) after 8 weeks, versus no significant change in Arm B. Furthermore, after 2 months, no bleeding occurred in Arm A (N=9) versus 3 cases with bleeding in Arm B (N=6). In fact, no PLT transfusions were required in Arm A, while 3 patients were transfused at 2 months in Arm B. At baseline, patients presented poor QoL scores. Overall, of the 9 patients in arm A reaching a 3-month follow-up, there were significant improvements in functional QoL, from baseline median score 33 (IQR 22-67) to 78 (IQR 31-92, p=0.047) and treatment-related scores from median 51 (IQR 35-66) to 74 (IQR 35-82, p=0.029). Grade III-IV adverse events (worsening of pre-existing arthritis; acute febrile enteritis) occurred in only 2 patients in Arm A, all unrelated to eltrombopag. Progressions have not been observed in Arm A, versus 1 progression in Arm B. No deaths have occurred at the time of the present analysis. Conclusions: Preliminary results suggest safety of eltrombopag in terms of drug-related adverse events and disease progression in MDS patients with low and Intermediate-1 risk IPSS and thrombocytopenia. In such patients, eltrombopag treatment is effective in raising PLT counts and in reducing the risk of bleeding and is associated with significant improvements in QoL.

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

Background: In myelodysplastic syndromes (MDS), thrombocytopenia is associated with mortality and treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, be effective in improving outcomes in lower-risk MDS with severe thrombocytopenia within a multicentre clinical trial (EQoL-MDS). Initial interim results of short-term efficacy and safety have been published (Oliva et al. Lancet Hem 2017) in the first 90 subjects. We present interim results of the second phase for long-term results in the initial 90 of 174 subjects. Methods: In a single-blind, randomised, controlled, phase 2 trial of adult patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS and severe thrombocytopenia. Adult patients with a stable platelet (PLT) count <30 Gi/L are randomized (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression. We report results of the second phase of the trial with primary endpoints duration of PLT response and long-term safety and tolerability. Amongst secondary endpoints, we present changes in quality of life (QoL), overall survival (OS) and leukemia-free survival (LFS). Results: The first 90 subjects were enrolled between 2011 and 2016. Characteristics of patients have been previously published (Lancet Hem 2017). PLT responses occurred in 28 (47.5%) of 59 patients in the eltrombopag group versus 1 (3.2%) of 31 patients in the placebo group (odds ratio 27.1 [95% CI 3.5-211.9], p=0.002) in median time 14 days (95% CI 7-40 days). Severe bleeding (WHO bleeding score ≥2) occurred in 19 patients, with a significantly higher incidence in the placebo (11 [35.3%] of 31 patients) than in the eltrombopag arm (8 [13.6%] of 59 patients; p=0.015). Sixty-eight grade 3-4 adverse events occurred in 30 of 59 (50.8%) eltrombopag patients versus 10 events in 6 of 31 placebo cases (19.4%;χ2=8,4, p=0.004, stopping rule not reached). The outcomes acute myeloid leukemia (AML) evolution, progression and death occurred in 5 (8.5%), 4 (6.8%), and 5 (8.5%), respectively of 59 eltrombopag cases versus 2 (6.5%), 3 (9.7%), 2 (6.5%), respectively of 31 placebo cases (P ranging from 0.69 to 1.00). Median LFS, combined outcome (AML, disease progression and death) and OS were not reached in the whole group. Differences in LFS, combined outcome and OS at 2 and 5 years by study arms were adjusted for baseline bone marrow blasts since the proportion of patients with >2% blasts (i.e. the median value of the whole study cohort) tended to be higher (P=0.06) in Eltrombopag (59.3%) than in placebo treated (38.7%) patients and resulted to be a strong predictor of study outcomes at both 2 and 5 years (P<0.002). The between-arm difference in LFS, combined outcome and OS at 2 and 5 years ranged from 0.33 to 0.99 (Fig.1 A-C). QOL-E and EORTC QLQ-C30 scores at baseline have been previously reported (Lancet Hem 2017). Within-arm longitudinal analyses showed that subjects on placebo experienced a significant worsening in QOL-E sexual domain (P=0.025) whereas subjects in the eltrombopag arm had a significant improvement in QOL-E MDS specific (P<0.001) and total scales (P=0.047) and a trend of improvement in QOL-E physical and social scores (both P=0.054). Between-arm comparison revealed that longitudinal changes in QOL-E MDS specific domain significantly differed between the two study arms in favour of eltrombopag (P=0.005). Finally, QOL-E functional (P=0.026), social (P<0.001), fatigue (P=0.01), MDS specific (P<0.001), general (P=0.001), treatment outcome index (P<0.001) and total scale (P<0.001) significantly improved with increasing PLT counts. Conclusion. Eltrombopag is well-tolerated in patients with lower-risk MDS and severe thrombocytopenia and is clinically effective in raising PLT count and reducing bleeding events. QoL improves with response to treatment. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. [Formula presented] Disclosures: Oliva: Novartis: Consultancy, Speakers Bureau; Apellis: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Alati: Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Santini: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Giai: Pfizer: Honoraria;

BMS:

Honoraria; Novartis: Honoraria. Balleari: Celgene: Membership on an entity's Board of Directors or advisory committees. Ferrero: Novartis: Honoraria. Germing: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Fenaux: Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Palumbo: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Hospira: Honoraria. Liberati: Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Molteni: Celgene: Membership on an entity's Board of Directors or advisory committees. Buccisano: Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bocchia: Novartis: Honoraria; Incyte: Honoraria;

BMS:

Honoraria. Candoni: Merck SD.: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Martino: Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Latagliata: Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Eltrombopag is indicated for: 1. the treatment of patients aged 1 year and above with primary immunethrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments; 2. in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy; 3. in adult patients with acquired severe aplastic anaemia who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplantation

Background: Patients with myelodysplastic syndrome or acute myeloid leukaemia who are thrombocytopenic and unable to receive disease‐modifying therapy have few treatment options. Platelet transfusions provide transient benefit and are limited by alloimmunisation. Eltrombopag, an oral thrombopoietin receptor agonist, increases platelet counts and has preclinical antileukaemic activity. We aimed to assess the safety and tolerability of eltrombopag for the treatment of thrombocytopenia in adult patients with advanced myelodysplastic syndrome, secondary acute myeloid leukaemia after myelodysplastic syndrome, or de‐novo acute myeloid leukaemia. Methods: We did this multicentre, randomised, placebo‐controlled, double‐blind, phase 1/2 trial at 37 centres in ten countries in Europe, east Asia, and the Americas. Patients aged 18 years or older who had relapsed or refractory disease or were ineligible for standard treatments; had platelet counts of less than 30 x 109 platelets per L; had 10‐50% bone‐marrow blasts; or were platelet transfusion dependent were randomly assigned (2:1), via a telephone‐based interactive voice‐response system (GlaxoSmithKline Registration and Medication Ordering System) with a permuted‐block randomisation schedule (block size of three), to receive once‐daily eltrombopag or matching placebo dose adjusted from 50 mg to a maximum dose of 300 mg. Randomisation was stratified by presence of poor‐prognosis (complex) karyotype (presence of at least three abnormalities, or chromosome 7 abnormalities, vs absence) and bone‐marrow blast count (<20% vs >20%). Patients and study personnel were masked to treatment allocation. The primary endpoint was safety and tolerability, including adverse events, non‐haematological laboratory grade 3‐4 toxic effects, and changes in bone‐marrow blast counts from baseline. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00903422. Findings: Between May 14, 2009, and May 9, 2013, we randomly assigned 98 patients to receive either eltrombopag (n=64) or placebo (n=34). 63 (98%) patients in the eltrombopag group and 32 (94%) patients in the placebo group had adverse events. The most common adverse events were pyrexia (27 [42%] vs 11 [32%]), nausea (20 [31%] vs 7 [21%]), diarrhoea (19 [30%] vs 6 [18%]), fatigue (16 [25%] vs 6 [18%]), decreased appetite (15 [23%] vs 5 [15%]), and pneumonia (14 [22%] vs 8 [24%]). Drug‐related adverse events of grade 3 or higher were reported in six (9%) patients in the eltrombopag group and four (12%) patients in the placebo group. Increases in the proportion of peripheral blasts did not differ significantly between groups. Haemorrhage of grade 3 or higher was reported in ten (16%) patients given eltrombopag and nine (26%) patients given placebo. 21 (33%) patients receiving eltrombopag and 16 (47%) patients receiving placebo died while on treatment. No deaths in patients receiving eltrombopag and two deaths in patients receiving placebo were regarded as treatment related. Post‐baseline bone‐marrow examinations were done in 40 (63%) patients in the eltrombopag group and 17 (50%) patients in the placebo group. The most common reason for no examination was death before the scheduled 3 month assessment. There were no differences between median bone‐marrow blast counts or proportions of peripheral blasts between groups. Interpretation: Eltrombopag doses up to 300 mg daily had an acceptable safety profile in patients with advanced myelodysplastic syndrome or acute myeloid leukaemia. The role of eltrombopag in these patients warrants further investigation. Funding: GlaxoSmithKline.

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INTERVENTION:

Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Eltrombopag Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use

CONDITION:

thrombocytopenic subjects with Chronic Liver Disease Undergoing Elective Invasive Procedures ; MedDRA version: 9.1 Level: HLT Classification code 10043555 Term: Thrombocytopenias ; MedDRA version: 9.1 Level: HLT Classification code 10027681 Term: Hepatic and hepatobiliary disorders

NEC PRIMARY OUTCOME:

Main Objective: · To demonstrate the ability of eltrombopag, compared to placebo to reduce the proportion of subjects with chronic liver disease and thrombocytopenia (platelets <50,000/mL) who receive platelet transfusions administered prior to, during and up to seven days following elective invasive procedures. Primary end point(s): · Proportion of subjects with chronic liver disease and thrombocytopenia (platelets <50,000mL) who do not require a platelet transfusion prior to, during and up to seven days following elective invasive procedures. Secondary Objective: · To evaluate the effect of eltrombopag on the proportion of subjects with bleeding prior to, during and up to seven days following elective invasive procedures.; · To evaluate the safety and tolerability of eltrombopag when administered once daily to thrombocytopenic subjects with chronic liver disease prior to, during and following elective invasive procedures.; · To demonstrate the ability of eltrombopag compared to placebo, to reduce the number of platelet transfusions administered prior to, during and up to 4 weeks (30 days) following elective invasive procedures in subjects with chronic liver disease and a baseline platelet count <50,000/mL.; · To evaluate the effect of eltrombopag on platelet counts in subjects with chronic liver disease and a baseline platelet count <50,000/mL prior to, during and up to 4 weeks (30 days) following elective invasive procedures.; · To describe the pharmacokinetics (PK) of eltrombopag and explore the relationship between the PK and rele

INCLUSION CRITERIA:

1. Male and female subjects, ≥18 years of age with chronic liver disease. 2. Child‐Pugh score of 12 or less (See Appendix 3). 3. Model of End Stage Liver Disease (MELD) score of 24 or less. 4. Subjects who, in the opinion of the investigator, are appropriate candidates to undergo an elective invasive procedure and who require a platelet transfusion to manage the risk of bleeding associated with the procedure. 5. A baseline platelet count <50,000/mL. 6. A baseline serum sodium level >130mEq/L. 7. Haemoglobin concentration >8g/dL stable for at least one month. 9. Subject has no physical limitation to ingest and retain oral medication. 10. Subject is able to understand and comply with protocol requirements and instructions and is likely to complete the study as planned. 11. Subject is able to provide signed and dated written informed consent. 12. In France, a subject will be eligible for inclusion in this study only if either af