Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia

Novartis Pharmaceuticals54 enrolled

Overview

The purpose of this study was to evaluate the efficacy and safety of eltrombopag in combination with cyclosporine alone as first-line therapy on overall hematologic response

This was an interventional phase II, single-arm, multicenter, open-label, study to investigate the efficacy and safety of the combination of eltrombopag and cyclosporine in treatment-naive, adult subjects with severe aplastic anemia (SAA) as first line therapy. Eligible subjects received eltrombopag and cyclosporine for up to 6 months. Participants who achieved hematologic response any time on or before 6 months were considered as responders; else they were considered as non-responders. Responders at Month 6 discontinued eltrombopag and started to taper cyclosporine until relapse or Month 24, whichever was early. Responders who relapsed prior to 6 months and non-responders discontinued the treatment at 6 months and were followed-up for 30 days. Responders who started to taper cyclosporine and relapsed prior to 24 months discontinued cyclosporine and were followed-up for 30 days.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Severe Aplastic Anemia

Interventions

eltrombopagDRUG

Film-coated tablets (12.5 mg, 25 mg, 50 mg and 75 mg) administered orally, once daily for up to 6 months. East and Southeast Asian participants were treated with 100 mg once daily, to adjust for the lower apparent clearance of eltrombopag. All other participants were treated with 150 mg once daily.

CyclosporineDRUG

Supplied as oral soft gel capsules. The starting dose was based on body weight at 10.0 mg/kg/day (acceptable rounding range was from 9.5 to 10.5 mg/kg/day) in divided doses every 12 hours. After Day 1, dosing was titrated individually according to therapeutic trough level between 200 and 400 μg/L for 6 months. After 6 months (only for responders at Month 6), tapering of cyclosporine was done as follows: * 6-9 months: at the 6 months visit, the dose was reduced by 25% for 3 months * 9-12 months: at the 9 months visit, the dose was further reduced by 25% for another 3 months * 12-24 months: dose was maintained

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patient had signed the Informed Consent (ICF) prior to any screening procedures 2. Patient was male/female ≥18 years old at the time of informed consent and able to swallow a tablet. 3. Patient had SAA characterized by: 1. Bone marrow cellularity \<30% (excluding lymphocytes) and 2. At least two of the following (peripheral blood): * Absolute neutrophil count \<500/µL * Platelet count \<20,000/µL * Absolute reticulocyte count \<60,000/µL 4. Normal ECG defined as the following as determined via the mean of a triplicate ECG * Resting heart rate: 50-90 bpm * QTcF at screening \<450 msec (for male patients), ≤460 msec (for female patients) Exclusion Criteria: 1. Diagnosis of Fanconi anemia. 2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central review 3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG and thrombopoietin receptor (TPO-R) agonists. 4. Hypersensitivity to eltrombopag or cyclosporine or their components. 5. AST or ALT \>3 x ULN. 6. Serum creatinine, total bilirubin, or alkaline phosphatase \>1.5 x ULN. 7. Patient with liver cirrhosis. 8. Patients who were human immune deficiency virus (HIV), hepatitis C virus or hepatitis B surface antigen (HBsAg) positive. HCV-RNA negative patients were allowed to be enrolled. 9. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to consent, be compliant with study procedures, tolerate protocol therapy, or that death within 30 days is likely. 10. Patients with cancer who were not considered cure, were on active chemotherapeutic treatment or who took drugs with hematological effects. 11. Administration of an investigational drug within 30 days or 5 half-lives, whichever was longer, preceding the first dose of study treatment. 12. Pregnancy statements and contraception requirements: Pregnancy or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant (or female partners of male patients), unless they were using highly effective methods of contraception during dosing and for 3 months after stopping medication. 13. Not able to understand the investigation nature of the study or to give informed consent. 14. Clinically significant ECG abnormality including cardiac arrhythmias (e. g. ventricular tachycardia) complete left bundle branch block, high grade atrioventricular block, or inability to determine the QTcF interval on the ECG. 15. Presence of cardiac disease, or family history of idiopathic sudden death or congenital long QT syndrome. 16. Risk factors for Torsades de Pointe including uncorrected hypokalemia or hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong the QT interval that could not be discontinued or replaced by safe alternative medication per www.qtdrugs.org. 17. ECOG performance status of ≥2. 18. Patients under the age of 40 must be referred for consideration of allogeneic bone marrow transplantation (HSCT) if (human leukocyte antigen) HLA matching had been done and a suitable matched sibling donor was available and the patient was willing to undergo transplantation (i.e. patients who did not have a HLA match or were not medically fit, not willing or unable to undergo transplantation were considered for enrollment).

Locations (20)

Novartis Investigative Site

Ribeirão Preto, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Outcomes

Primary Outcomes

Overall Hematologic Response Rate by 6 Months

Overall hematologic response rate by 6 months was defined as the percentage of participants with complete response (CR) or partial response (PR) any time on or before 6 months. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * Absolute neutrophil count (ANC) \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L

Time frame: Up to 6 months

Secondary Outcomes

Overall Hematologic Response Rate by 3 Months

Overall hematologic response rate by 3 months was defined as the percentage of participants with CR or PR any time on or before 3 months. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L

Time frame: Up to 3 months

Overall Hematologic Response Rate at 12 and 24 Months

Overall hematologic response rate at 12 and 24 months was defined as the percentage of participants with CR or PR at 12 and 24 months respectively. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC\>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L

Data from ClinicalTrials.gov

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Novartis Investigative Site

Hong Kong, Hong Kong

Novartis Investigative Site

Hyderabad, Telangana, India

Novartis Investigative Site

Vellore, India

Novartis Investigative Site

Bologna, BO, Italy

Novartis Investigative Site

Brescia, BR, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Mexico D F, Mexico City, Mexico

Novartis Investigative Site

Monterrey, Nuevo León, Mexico

...and 10 more locations

Time frame: 12 and 24 months

Duration of First Hematologic Response

Duration of first hematologic response is the time from the date of the start of first response to the date of first relapse. Relapse is defined as no longer meeting definition of PR or CR. Kaplan-Meier method was used for the analysis. If no relapse occurred, the participant was censored at the date of last contact. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. PR was defined as any 2 of the following parameters at 2 consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL. CR was defined as all 3 parameters meet the following criteria at 2 consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \>1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L