Myelodysplastic syndromes (MDS) prevail in elderly patients and are characterized by inefficient erythropoiesis and peripheral cytopenias. Supportive care still represents the main therapeutic option in most patients. Quality of life is deteriorated mostly by anemia and by limitations due to dependence on transfusions, thrombocytopenia, and neutropenia. The only treatment available for severe thrombocytopenia consists of PLT transfusions, mainly in the presence of bleeding.

In patients with low and intermediate-1 risk MDS with an isolated deletion 5q cytogenetic abnormality, red blood cell (RBC) transfusion-dependence is a prevalent condition. For these latter patients reaching transfusion-dependence, lenalidomide, an immunomodulatory drug, has been approved by FDA and EMA. It has been shown that the drug induces significant erythroid (about 65%) and cytogenetic responses which have been associated with a survival benefit. In patients with MDS with del5q and serum erythropoietin levels \> 500 miU/L, lenalidomide dosing of 10 mg/day for 21 days every 28, rather than 5 mg dosing, induces higher rates of transfusion-independence and cytogenetic responses with a trend to survival advantage. As a consequence, the recommended starting dose of lenalidomide is 10 mg orally once daily on days 1-21 of repeated 28-day cycles. Lenalidomide treatment must not be started if the Absolute Neutrophil Counts (ANC) \< 0.5 Gi/L and/or PLT counts \< 25 Gi/L.

For patients who are dosed initially at 10 mg and who experience thrombocytopenia \< 25 Gi/L (45-75%), it is recommended to interrupt lenalidomide treatment until PLT count returns to ≥ 25 Gi/L on at least 2 occasions for ≥ 7 days or when the PLT count recovers to ≥ 50 Gi/L at any time, to resume lenalidomide at 50% dose reduction.

Eltrombopag is an orally bioavailable agonist of the thrombopoietin receptor. It has been shown that in patients affected by MDS and by acute myeloid leukemia, Eltrombopag neither increases the proliferation, nor the clonogenic growth capacity of bone marrow blasts. Furthermore, Eltrombopag induces an increase in the megakaryocytic differentiation and in the formation of normal megakaryocytic colonies. These results provide the rationale for pursuing further research on Eltrombopag for the treatment of thrombocytopenia in case of MDS.

Preliminary results of an ongoing randomized trial, EQoL-MDS, for the evaluation of efficacy, safety of eltrombopag for thrombocytopenia of low and intermediate-1 IPSS risk MDS has shown that eltrombopag is able to significantly raise PLT counts in about 65% of patients without additional toxicity Furthermore, the combination of lenalidomide and eltrombopag resulted in significant inhibitory effects on the growth of leukemic colonies in the majority of primary MDS and AML samples. Most importantly, eltrombopag was able to reverse the anti-megakaryopoietic effects of lenalidomide in primary MDS patient samples. These results provide a preclinical rationale for the use of this combination in MDS and AML

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BACKGROUND:

</b>Eltrombopag is an oral thrombopoietin receptor agonist that stimulates thrombopoiesis and shows higher exposure in East Asian patients than in non-Asian patients. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with thrombocytopenia associated with chronic liver disease (CLD).<b>

METHODS:

</b>Thirty-eight patients with CLD and thrombocytopenia (platelets <50,000/μL) were enrolled in this phase II, open-label, dose-ranging study that consisted of 2 parts. In the first part, 12 patients received 12.5 mg of eltrombopag once daily for 2 weeks. After the evaluation of safety, 26 patients were randomly assigned to receive either 25 or 37.5 mg of eltrombopag once daily for 2 weeks in the second part.<b>

RESULTS:

</b>Pharmacokinetics showed that the geometric means of the maximum plasma concentration (C(max)) and the area under the curve (AUC) in the 12.5 mg group were 3,413 ng/mL and 65,236 ng h/mL, respectively. At week 2, the mean increases from baseline in platelet counts were 24,800, 54,000, and 60,000/μL in the 12.5, 25, and 37.5 mg groups, respectively. The median platelet counts increased within 2 weeks of the beginning of administration in all groups, and remained at the same level throughout the 2-week post-treatment period in the 12.5 mg group, whereas the platelet counts peaked a week after the last treatment in both the 25 and 37.5 mg groups. Most adverse events reported were grade 1 or 2; 2 patients in the 37.5 mg group had drug-related serious adverse events.<b>

CONCLUSIONS:

</b>Eltrombopag ameliorated thrombocytopenia in Japanese patients with CLD and thrombocytopenia. The recommended dose for these patients is 25 mg daily for 2 weeks.

Thrombocytopenia occurs frequently in patients with myelodysplastic syndromes (MDS), and the survival of patients after failure of hypomethylating agents (HMAs) is poor. We conducted a trial of eltrombopag in patients with MDS, MDS/myeloproliferative neoplasm (MPN) or acute myeloid leukemia (AML) with 20-30% myeloblasts after HMA failure and mean baseline platelet count ≤ 50 × 109/L. Eltrombopag was escalated from 50 mg daily up to 200 mg daily. The primary objective was to determine the maximally tolerated dose (MTD). 37 patients were enrolled, and MTD was not reached. Responses were observed in 9 patients (24%), 2 achieving marrow CR with hematologic improvement (HI), 1 marrow CR without HI, and 6 HI. Median overall survival was 7.5 months. Eltrombopag was well-tolerated and yielded modest responses in heavily treated, predominantly higher-risk MDS patients after HMA failure. Future studies should focus on determining characteristics that predict response.

Liver cirrhosis is the end stage of chronic liver disease, but no definitive pharmacological treatment is currently available. It has been reported that thrombopoietin (TPO) promotes liver regeneration and improves liver cirrhosis by increasing platelet count. We have shown the direct effect of platelet transfusion on the improvement of liver function in patients with chronic liver disease. However, platelet transfusion often causes adverse events, such as platelet transfusion refractoriness and pruritus. Therefore, we conducted an exploratory clinical trial and administered eltrombopag, an orally bioavailable, small-molecule, non-peptide TPO receptor agonist that has been approved for the treatment of chronic idiopathic thrombocytopenic purpura. The study included five male patients, aged from 49 to 75 years (57.6 ± 10.4 years), with both chronic liver disease and hepatitis C virus infection, who presented with thrombocytopenia but without cancer. Eltrombopag, ranged from 6.25 to 50 mg/day (18.75 ± 18.22 mg/day), was administrated to the five patients during six months. All of the patients maintained platelet counts between 10 and 15 × 10[10]/L during the study. The indicators of liver function in patients were stable throughout the clinical trial, although we had predicted the same degree of the improvement of liver function, compared to platelet transfusion. Importantly, the liver volumes were also stable, and no cancerous lesions were observed. These results indicate the safety of long-term eltrombopag administration for patients with chronic liver disease and hepatitis C virus infection.

The purpose of this study is to evaluate the effect of two different doses of ianalumab added to eltrombopag to prolong Time to Treatment Failure (TTF) in adults with primary ITP who failed previous first-line treatment with steroids.

Background: Myelodysplastic syndromes (MDS) are malignant clinical disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias and a property to transform into acute myeloid leukemia (AML). Standard of care for MDS includes the hypomethylating agents (HMAs) (i.e. azacitidine, decitabine) to improve quality of life, decrease transfusion requirements and improve clinical outcome. However not all patients (pts) respond to HMAs and even in responding pts, cytopenias may persist. HMA-failure MDS has extremely poor prognosis and currently there are no approved therapeutic options for such pts who are often of advanced age with frequent comorbidities. Objectives: The dual primary objectives of this study evaluate the safety and efficacy of the second-generation thrombopoietin-receptor agonist (TPO-RA) eltrombopag (EPAG) for the treatment of MDS pts at the time of HMA-failure. Secondary objectives include incidence of transformation to AML and evaluation of bone marrow fibrosis during therapy. Methods: Eligible pts for this 2-arm phase 2 open-label clinical trial included adults with MDS after completing >4 HMA cycles with failure to achieve at least a partial response, or the presence of ongoing cytopenias per IWG criteria. Arm A includes eltrombopag monotherapy and Arm B includes eltrombopag with continuation of the HMA at the previous dosing schedule. The starting eltrombopag dose is 200mg orally daily, which can be increased to 300mg in the absence of toxicity. First response is assessed after 2 cycles with each cycle lasting 28 days. The primary efficacy endpoint was overall response rate based on the IWG-2006 criteria. Results: To date, 23 pts with a median age of 72 years (range 42-84 years) have been enrolled. Prior to study entry, pts had received a median of 6 (range 4-25) HMA cycles. Cytogenetics were diploid in 12 (53%), intermediate in 7 (30%), and high risk in 4 (17%) pts by IPSS. Median bone marrow blasts at study start was 3% (range 0-15%). Arm A has enrolled 7 pts with a median age of 74 years; Arm B has enrolled 16 pts with median age of 69 years. In Arm B, ongoing HMA therapy includes azacitidine in 7 (44%) and decitabine in 9 (56%). Nine (39%) pts increased to 300mg EPAG after median of 8 weeks on study. Median total cycles received on study is 5 (1-17); median OS has not been reached. Overall, 16 pts are response-evaluable; 7 pts discontinued prior to the first response assessment at 2 months (4 due to AEs including myalgias/fatigue (n=2), hyperbilirubinemia (n=1), and pneumonia (n=1), 2 per pt request and 1 for pt inability to comply with protocol requirements). Of the 16 response-evaluable pts, 3 (19%) in Arm B demonstrated platelet improvement, including one pt necessitating EPAG dose-reduction to 100mg due to platelet count exceeding 450 x109/L with concomitant ANC recovery at 200mg EPAG dose level. An additional 8 (35%) pts have remained on study for a median of 5 cycles (2-17) with stable disease. Two pts discontinued therapy due to disease progression, including 1 (4%) that progressed to AML. The most common non-hematologic AEs regardless of attribution included hyperbilirubinemia (n=14, 61%), fatigue (n=13, 56%) myalgias (n=11, 48%), fever (7, 30%), dyspnea (7, 30%), nausea (6, 26%) and transaminitis (4, 17%). No significant increase in bone marrow fibrosis has been observed. Conclusion: Eltrombopag orally daily appears to be a safe and beneficial supportive adjunct for pts with MDS while receiving HMA-therapy or after HMA-failure due to persistent cytopenias. Treatment on this study continues and larger prospective clinical trials are needed to confirm these preliminary findings.

INTERVENTION:

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

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: range Concentration number: 25‐100

CONDITION:

Patients with lower and intermediate‐1 risk myelodysplastic syndromes. Therapeutic area: Diseases [C] ‐ Blood and lymphatic diseases [C15]

PRIMARY OUTCOME:

Main Objective: Evaluation of the proportion of patients with an increase of the platelet count (eltrombopag effect on platelet count), according to the international criteria.; Measurement of survival, differentiation and maturation characteristics of BMMCs & megakaryotic progenitor cells throughout the study’s duration. Primary end point(s): Evaluation of the platelet count throughout the duration of the study and evaluation of the type of response according to international criteria.; Measurement of platelet response parameters before treatment and at end of month 3, month 12 and month 24. Secondary Objective: 1. Safety and tolerability of eltrombopag.; 2. Change in bone marrow blast counts from baseline and as well as differences in % of bone marrow blasts between the two groups.; 3. Progression of disease. ; 4. Overall survival.; 5. Number of platelet transfusions.; 6. Duration of platelet transfusion‐independence.; 7. Incidence and severity of bleeding.; 8. Changes in hemoglobin levels and neutrophil counts. Timepoint(s) of evaluation of this end point: Throughout the duration of the study.

SECONDARY OUTCOME:

Secondary end point(s): • Clinical examination findings, clinical follow‐up, vital signs, laboratory tests and reported adverse events (including bleeding and transfusion‐related AEs). ; • Percentage of blasts in blood or/and bone marrow. ; • Percentage of neutrophils, platelets, haemoglobin, appearance of chloroma, appearance of B symptoms. ; • Disease response, disease progression, final outcome. ; • Number of platelet transfusions. ; • Duration of platelet transfusion‐independence. ; • Incidence and severity of bleeding (according WHO Bleeding Scale). ; • Improvement in haemoglobin levels, platelets and neutrophil counts. Timepoint(s) of evaluation of this end point: Throughout the duration of the study.

INCLUSION CRITERIA:

1. Adult subjects (= 18 years old) with low and intermediate‐1 MDS type according to the WHO classification and IPSS. 2. Mean baseline platelet count <30x Gi/L or <50 Gi/L with bleeding manifestations. 3. Patients with data on platelet count, bleeding and platelet transfusions covering a period of at least 4 weeks before enrolment. 4. Bone marrow examination 4 weeks before randomization. 5. Supportive/palliative therapies such as cytokines (except for IL‐11; oprelvekin), valproic acid and all‐trans retinoic acid are allowed, provided those therapies have been at a stable dose for 4 weeks or were completed 4 weeks prior to enrolment into this study. 6. ECOG Status 0‐2. 7. Adequate baseline liver and renal function defined by the criteria below: • total bilirubin (except for Gilbert’s Syndrome) = 1.5xULN • ALT and AST = 3xULN • serum creatinine = 1.5mg/dl or calculated creatinine clearance = 40ml/min (calculated buy the Cock

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Purpose: Prolonged intervals of thrombocytopenia are common after hematopoietic stem cell transplantation (HSCT), and platelet transfusions are the only effective therapy. Risk of thrombocytopenia is greater in patients (pts) receiving total body irradiation (TBI) in their conditioning regimen. Eltrombopag (ePag) is a small-molecule, nonpeptide oral agent that functions as an agonist of the thrombopoietin receptor. It is approved by FDA for the treatment of chronic ITP and is being developed as a treatment for thrombocytopenia of other various etiologies. We report results of an ongoing Phase I clinical trial assessing the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of once daily oral ePag in pts undergoing HSCT with a conditioning regimen containing TBI ≥ 400 cGy. Methods: A Phase I dose-escalation clinical trial was conducted to evaluate the safety and PK of ePag at 4 different dose levels: 75, 150, 225, and 300 mg, once daily for 27 days, starting 24-48 hours post HSCT to eligible pts ≥18 yrs old. Pts with various indications for stem cell transplantation, KPS ≥70%, and TBI ≥ 400 cGy were eligible. Pts receiving either an autologous (Auto) or allogeneic (Allo) HSCT from a sibling, related donor, or matched unrelated donor (MUD) were eligible. Stem cells from peripheral blood (PBSC) or bone marrow were permitted; however, cord blood transplant was not permitted. Pts at risk of thromboembolism, or with a history of thromboembolic disease in the preceding 6 months, were excluded. PK sampling was obtained over a 24 h period after the first dose of ePag, as well as during the second week of treatment (steady-state). Results: As of July 1 2011, a total of 10 subjects (4 AML, 2 lymphoma, 1 CML, 1 MDS, 1 myelofibrosis, and 1 CLL/SLL) were enrolled, and 9 completed protocol treatments. All 9 were PBSC transplants with 6 MUD, 2 Allo and 1 Auto. Three subjects were completed at each dose level up to 225 mg. Enrollment is continuing at the 300 mg dose level. To date, 6/9 are alive while 3/9 died of non-relapse related causes (CMV pneumonitis and respiratory failure in 1, and steroid refractory GI GvHD in 2, f/u interval: 4.4 - 6.9 mo). No dose limiting toxicities (DLTs) have been observed. Most common adverse events up to 225 mg dose level were related to standard stem cell transplantation, which included low blood counts, fatigue, headache, diarrhea, nausea, peripheral edema, hypoalbuminemia, hyperglycemia, hypocalcemia, and hypomagnesemia. There were 9 SAEs observed in 5 pts, which included infection (3/9), pulmonary embolism (PE) (1/9), acute renal failure (2/9), gastrointestinal (2/9), and ARDS (1/9). Most SAEs were considered unrelated or unlikely related to ePag treatment except for the PE, which was considered possibly related to ePag but not considered a DLT. This subject had other risk factors for PE and the PE occurred 9 days after ePag had stopped at a platelet count of 252K. Time to platelet engraftment and number of platelet transfusions were documented for each enrolled pt. PK sampling demonstrated a dose dependent increase in plasma concentration of ePag (Figure 1). PK parameters for the 75, 150, and 225 mg dose levels are summarized in Table 1. [Image Presented] [Table Presented] Conclusions: 27-day once daily dosing of ePag to enhance platelet recovery for post-transplant thrombocytopenia is well tolerated, with no DLTs observed up to the 225 mg dose level to date. Most AEs were transplant related. PK and the plasma exposure of ePag appears dose proportional over the studied dose range after single-dose and steady-state administration. Once-daily administration of up to 225 mg ePag for the transplant population receiving TBI ≥ 400 cGy as part of the conditioning regimen appears to be safe and well tolerated. Acknowledgement: The study is supported by Biomedical Advanced Research and Development Agency (BARDA), and by GlaxoSmithKline who also provided the study drug.

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