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

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).

Study Overview

• Status: Terminated
• Conditions: Poor Graft Function
• Intervention / Treatment: Drug: Eltrombopag

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
  • Islas Baleares
    • Palma De Mallorca, Islas Baleares, Spain, 07120
      • Novartis Investigative Site
  • Pais Vasco
    • San Sebastian, Pais Vasco, Spain, 20080
      • Novartis Investigative Site
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36212
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eltrombopag; Patients received eltrombopag orally once daily up to 36 weeks.	Drug: Eltrombopag; Eltrombopag was provided as 50 mg or 25 mg film-coated tablets for oral use administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematologic Response Rate by 16 Weeks After the Initiation of Eltrombopag	Hematologic response rate was defined as the percentage of participants who met the criteria of either complete response (CR) or partial response (PR) by Week 16. PR was defined when any of the following: Platelet count ≥ 20000/microliter(μL) (with platelet transfusion independence), absolute neutrophil count (ANC) ≥1000/μL (when pretreatment ANC was <1000/μL) and/or hemoglobin (Hb) ≥100 gram(g)/ liter(L) (when pretreatment Hb was <100g/L) (with red blood cells transfusion independence), confirmed in two blood tests separated a minimum of 7 days. CR was defined when all of the following: platelet count ≥100000/μL, ANC ≥1500/μL (when pretreatment ANC was <1000/μL) and Hb ≥110 g/L (when pretreatment Hb was <100g/L), confirmed in two blood tests separated a minimum of 7 days. Participants who discontinued before Week 16 were considered as responders if, in the last evaluation, they had PR or CR. The 95% Confidence Interval (CI) was the binomial exact CI based on Clopper-Pearson method.	Baseline up to Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Had a Response in the Neutrophil Lineage	Percentage of participants who had a response (partial or complete) in the neutrophil lineage. A partial response in the neutrophil lineage was defined as absolute neutrophil count (ANC) ≥1000/ µL (when pretreatment ANC was <1000/μL) confirmed in two consecutive blood tests separated a minimum of 7 days. A complete response in the neutrophil lineage was defined as ANC ≥ 1500/ µL (when pretreatment ANC was <1000/μL) confirmed in two consecutive blood tests separated a minimum of 7 days. The 95% CI was the binomial exact CI based on Clopper-Pearson method	Week 16, 20, 24, 30 and 36
Percentage of Participants Who Had a Response in the Platelet Lineage	Percentage of participants who had a response (partial or complete) in the platelet lineage. A partial response in the platelet lineage was defined as platelet count ≥20000/µL (with platelet transfusion independence) confirmed in two consecutive blood tests separated a minimum of 7 days. A complete response in the platelet lineage was defined as platelet count ≥ 100000/µL confirmed in two consecutive blood tests separated a minimum of 7 days. The 95% CI was the binomial exact CI based on Clopper-Pearson method.	Week 16, 20, 24, 30 and 36
Percentage of Participants Who Had a Response in the Hemoglobin Lineage	Percentage of participants who had a response (partial or complete) in the hemoglobin (Hb) lineage. A partial response in the Hb lineage was defined as Hb ≥100 g/L (when pretreatment Hb was <100g/L) (with RBC transfusion independence), confirmed in two consecutive blood tests separated a minimum of 7 days. A complete response in the Hb lineage was defined as Hb≥ 110 g/L (when pretreatment Hb was <100g/L) confirmed in two consecutive blood tests separated a minimum of 7 days. The 95% CI was the binomial exact CI based on Clopper-Pearson method.	Week 16, 20, 24, 30 and 36
Hematologic Response Rate at Week 24 and 36	Hematologic response rate was defined as the percentage of participants who met the criteria of either complete response (CR) or partial response (PR) at 24 weeks and 36 weeks after the initiation of eltrombopag. PR was defined when any of the following: Platelet count ≥20000/microliter (μL) (with platelet transfusion independence), absolute neutrophil count (ANC) ≥1000/μL (when pretreatment ANC was <1000/μL) and/or hemoglobin (Hb) ≥100 gram (g)/ liter (L) (when pretreatment Hb was <100g/L) (with red blood cells transfusion independence), confirmed in two blood tests separated a minimum of 7 days. CR was defined when all three of the following: platelet count ≥100000/μL, ANC ≥1500/μL (when pretreatment ANC was <1000/μL) and Hb ≥110 g/L (when pretreatment Hb was <100g/L), confirmed in two blood tests separated a minimum of 7 days. The 95% CI was the binomial exact CI based on Clopper-Pearson method.	Week 24 and 36
Percentage of Participants Who Were Previously Platelet Transfusion-dependent and Did no Longer Require Platelet Transfusions After the Initiation of Eltrombopag	Percentage of participants who received at least one platelet transfusion before starting treatment and who did no longer require platelet transfusion before and after the first 16 weeks of treatment. The 95% CI was the binomial exact CI based on Clopper-Pearson method.	From start of treatment to end of treatment, assessed up to 36 weeks
Percentage of Participants Who Were Previously Red Blood Cells Transfusion-dependent and Did no Longer Require Red Blood Cells Transfusions	Percentage of participants who received at least one red blood cells transfusion before starting treatment and who did no longer require red blood cells transfusion before and after the first 16 weeks of treatment. The 95% CI was the binomial exact CI based on Clopper-Pearson method.	From start of treatment to end of treatment, assessed up to 36 weeks
Duration of Transfusion Independence	Duration of transfusion independence defined as the period of time where participants did not receive any platelet or red blood cells transfusions during the treatment period	From start of treatment to end of treatment, assessed up to 36 weeks
Percentage of Participants Who Discontinued or Reduced the Use of Concomitant Erythropoietin (EPO) Therapy	Percentage of participants who discontinued or reduced by ≥50% from baseline the use of concomitant EPO therapy while receiving eltrombopag. The 95% CI was the binomial exact CI based on Clopper-Pearson method.	From start of treatment to end of treatment, assessed up to Week 36
Percentage of Participants Who Discontinued or Reduced the Use of Concomitant Granulocyte Colony-stimulating Factor (G-CSF) Therapy	Percentage of participants who discontinued or reduced by ≥50% from baseline the use of concomitant G-CSF therapy while receiving eltrombopag. The 95% CI was the binomial exact CI based on Clopper-Pearson method.	From start of treatment to end of treatment, assessed up to Week 36
Overall Survival (OS)	OS defined as the time from the date of inclusion until the date of death due to any cause was calculated using Kaplan-Meier estimated. All patients who discontinued from the study, regardless the reason of discontinuation, were followed for survival, unless they withdrew their consent, died or were lost-to follow-up, in which case were censored at the last contact.	From start of treatment until the date of death, assessed up to 40 weeks
Overall Survival Rate at 24 and 36 Weeks	Overall survival rate defined as the rate estimate of the percentage of participants who were alive at 24 and 36 weeks. All patients who discontinued from the study, regardless the reason of discontinuation, were followed for survival at Week 24 and 36, unless they withdrew their consent, died or were lost-to follow-up, in which case were censored at the last contact.	Week 24 and 36

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Plain Language Trial Summary

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2018
• Primary Completion (Actual): November 3, 2020
• Study Completion (Actual): November 3, 2020

Study Registration Dates

• First Submitted: October 23, 2018
• First Submitted That Met QC Criteria: October 23, 2018
• First Posted (Actual): October 24, 2018

Study Record Updates

• Last Update Posted (Estimated): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Adult; Phase II; Stem cell transplantation; Eltrombopag; Poor graft function; Hematological response; ELTION
• Other Study ID Numbers: CETB115EES03; 2018-001129-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No