Study of Efficacy and Safety of Eltrombopag in Patients With Poor Graft Function

The ELTION Study - A Multicenter Open-label Interventional Study of Eltrombopag in Patients With Poor Graft Function After Allogeneic Hematopoietic Stem Cell Transplantation

The purpose of this study was to evaluate the efficacy of eltrombopag for poor graft function (PGF) on overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of eltrombopag in patients with poor graft function after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

This was an open-label, single-arm phase II study, in which participants diagnosed with PGF after allo-HSCT were treated with eltrombopag up to week 36 or until the participant's premature withdrawal.

The study consisted of the following periods:

• Screening Period (baseline): the participant screening criteria was reviewed, and the procedures established in the evaluation schedule were performed.
• Treatment Period: from administration of the first dose of eltrombopag until time when participant permanently stopped taking study treatment for any reason or until 36 weeks had passed. Eltrombopag was initiated on Day 1 at a dose of 150 mg once daily (75 mg daily in Asian ancestry participants). During the Treatment Period, participants were evaluated weekly during the first month, every 2 weeks during the next 2 months and subsequently every 4 weeks until week 24. For the last 3 months, participants were followed every 6 weeks Only participants who had a partial or complete response at Week 16 continued to receive eltrombopag up to Week 36 or until loss of response (defined as a decrease in blood counts to levels that did not continue to meet the criteria for response established in the protocol), unacceptable toxicity, or discontinuation for any other reason.

Participants who discontinued eltrombopag because efficacy, continued in the study and attended the scheduled visits of Treatment Period as per protocol. If loss of response occurred, eltrombopag was reintroduced at the last effective dose.

• Final Visit (or Early Withdrawal): this visit took place 30 days after completion of the Treatment Period, or premature participant withdrawal.
• Follow-up for Survival: all participants who discontinued from the study, regardless the reason of discontinuation, were followed for survival for 24 and 36 weeks, unless they withdrew their consent, died or were lost-to follow-up, in which case study visits were no longer carried out.

Inclusion Criteria:

1. Patient must be able to understand and communicate with the investigator and comply with the requirements of the study and must provide written, signed and dated informed consent form before any study assessment is performed

2. Male of female patients ≥ 18 years of age

3. Patients diagnosed with primary or secondary poor graft function (PGF) defined as two or more cytopenias after day +30 post-transplant (re-tested in a peripheral blood analysis at screening):

   1. Platelet count <20,000/ µL (mandatory)
   2. Absolute neutrophil count (ANC) <1,000/µL
   3. Hemoglobin <100 g/L

4. Presence of donor chimerism >90% in screening visit

5. Karnofsky status ≥90% (Karnofsky assessment must be performed within 7 days prior to Day 1)

Exclusion Criteria:

1. Pregnant or nursing (lactating women).

2. Evidence of active acute or chronic graft versus host disease (GVHD).

3. Evidence of any active malignancy.

4. Subjects who are human immune deficiency virus (HIV), hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg) positive in screening visit.

5. Cytogenetic abnormality in chromosome 7 present before the allo-HSC.

6. Evidence of any clonal abnormality on cytogenetics (in bone marrow analysis).

   • A local post-transplant conventional cytogenetic assessment should be available within 8 weeks before Day 1.
   • If the cytogenetics is not valuable, i.e, it does not show metaphases, a FISH for MDS-related most frequent abnormalities including chromosome 7 is accepted.

   As a consequence, patients with dry tap bone marrow aspiration are NOT eligible.

7. Evidence of bone marrow involvement or progression of the underlying disease assessed by the applicable methods in each case.

8. Evidence of thrombotic microangiopathy.

9. Evidence of possible causes of cytopenia other than PGF (active infections, myelotoxic drugs, hypersplenism…).

10. Prior use of any thrombopoietin receptor (TPO-R) agonists for PGF.

11. AST or ALT levels >3 x ULN.

12. Creatinine level ≥1.5 x ULN.

13. Total bilirubin level ≥1.5 x ULN.

14. Previous thromboembolic event (other than line-related upper extremity thrombosis)

15. Hypersensitivity to eltrombopag or its components.

16. Clinically significant ECG abnormality history or current diagnosis of cardiac disease indicating significant risk of safety for subjects participating in the study such as uncontrolled or significant cardiac disease or impaired cardiac function including any of the following:

    1. . Corrected QTc > 450 msec (male subjects), > 460 msec (female subjects) using Fredericia correction (QTcF) on the screening ECG
    2. . Myocardial infarction
    3. . Uncontrolled congestive heart failure
    4. . Unstable angina
    5. . Congenital long QT syndrome.

17. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

18. Patient with liver cirrhosis.

19. Risk factors for Torsade de Pointes including uncorrected hypokalemia or hypomagnesemia.

20. Subjects with any serious and/ or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with patient´s safety, obtaining informed consent or compliance with the study procedures as per investigator discretion.