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

Phase 2

Completed

Conditions: Severe Aplastic Anemia

Interventions: Drug: eltrombopag
Drug: Cyclosporine

Registration Number: NCT02998645

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

Inclusion Criteria

Patient had signed the Informed Consent (ICF) prior to any screening procedures
Patient was male/female ≥18 years old at the time of informed consent and able to swallow a tablet.
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
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

Diagnosis of Fanconi anemia.
Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central review
Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG and thrombopoietin receptor (TPO-R) agonists.
Hypersensitivity to eltrombopag or cyclosporine or their components.
AST or ALT >3 x ULN.
Serum creatinine, total bilirubin, or alkaline phosphatase >1.5 x ULN.
Patient with liver cirrhosis.
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.
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.
Patients with cancer who were not considered cure, were on active chemotherapeutic treatment or who took drugs with hematological effects.
Administration of an investigational drug within 30 days or 5 half-lives, whichever was longer, preceding the first dose of study treatment.
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.
Not able to understand the investigation nature of the study or to give informed consent.
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.
Presence of cardiac disease, or family history of idiopathic sudden death or congenital long QT syndrome.
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.
ECOG performance status of ≥2.
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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Eltrombopag + cyclosporine	eltrombopag	Participants received eltrombopag (orally, 150 mg once daily for non-Asian participants / 100 mg once daily for participants of Asian ancestry) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, responders at Month 6 were treated with cyclosporine until Month 24
Eltrombopag + cyclosporine	Cyclosporine	Participants received eltrombopag (orally, 150 mg once daily for non-Asian participants / 100 mg once daily for participants of Asian ancestry) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, responders at Month 6 were treated with cyclosporine until Month 24

Primary Outcome Measures

Name	Time	Method
Overall Hematologic Response Rate by 6 Months	Up to 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

Secondary Outcome Measures

Name	Time	Method
Overall Hematologic Response Rate by 3 Months	Up to 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
Overall Hematologic Response Rate at 12 and 24 Months	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
Duration of First Hematologic Response	Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)	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
Relapse Rate by 6 and 24 Months	Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)	Relapse was defined as no longer meeting the definition of PR (and not CR). Relapse rate by 6 months and 24 was defined as the percentage of responders by 6 months who relapsed prior to 6 months or prior to 24 months respectively. Responders by 6 months were participants who achieved CR or PR any time on or before 6 months. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. PR: 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: 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
Percentage of Participants With Evolution to Myelodysplasia, Paroxysmal Nocturnal Hemoglobinuria (PNH) and Leukemia	Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)	The percentage of participants with evolution to myelodysplasia, PNH and acute leukemia occurring at any time during the study. Clonal evolution to myelodysplasia was defined as a new marrow cytogenic abnormality with or without characteristic dysplastic marrow findings. Clonal evolution to leukemia was defined as greater than 20% peripheral blood and/or marrow blasts. Clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH) was defined as a clone at baseline \< 10% that rose to greater than 50% on study. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24
Percentage of Participants Who Were Red Blood Cells (RBC) Transfusion Independent	Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)	Percentage of participants who were RBC transfusion independent at least once by 6 months and by 24 months (responders only). Independence was defined as no RBC transfusion for at least 56 days. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Percentage of Participants Who Were Platelet Transfusion Independent	Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)	Percentage of participants who were platelet transfusion independent at least once by 6 months and by 24 months (responders only). Independence was defined as no platelet transfusion for at least 28 days. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Longest Duration of Transfusion Independence (Platelet or RBC)	Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)	Longest duration of transfusion independence (platelet or RBC) by 6 months and by 24 months (responders only). Transfusion independence was defined as no transfusions required in at least a 28-day period for platelet transfusion and at least 56-day period for RBC transfusion. The duration of the longest interval with transfusion independence was summarized using Kaplan-Meier analysis. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24
Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome	Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)	The FACT-G consists of 27-items divided into 4 domains (physical well-being, social well-being, emotional and functional well-being). All items of the FACT-G use a 5 point scale ranging from 0 to 4 with a 0 rating being "not at all" and a 4 rating being "very much". Total FACT-G score is the sum of physical well-being score, social well-being score, emotional well-being score and functional well-being score. Score ranges from 0 to 108, with higher scores indicating better quality of life (QoL). A positive change from baseline indicates improvement in the QoL. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome	Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)	The FACT-TH18 is comprised of FACT-G and a thrombocytopenia specific questionnaire. FACT-G consists of 27-items divided into 4 domains (physical, social, emotional and functional well-being). FACT-TH18 has 18 additional items which asks the patient to rate degree of thrombocytopenia. All items of the FACT-TH18 use a 5 point scale ranging from 0 to 4, with 0 = "not at all" and 4 = "very much". Total FACT-TH18 score is the sum of physical, social, emotional and functional well-being scores, and thrombocytopenia subscale. Score ranges from 0 to 180, with higher scores indicating better QoL. A positive change from baseline indicates improvement in the QoL. Results are presented for responders and non-responders. If any participant achieved hematologic response (CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome	Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)	The FACIT- Fatigue is a 13-item fatigue subscale that asks the patient to rate their degree of tiredness, weakness and fatigue. All items of the FACIT-Fatigue use a 5-point scale ranging from 0 to 4 with a 0 rating being "not at all" and a 4 rating being "very much". Total score ranges from 0 to 52. Negatively worded items were reverse scored before summing so that higher total scores indicate less fatigue. A positive change from baseline indicates improvement. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Pharmacokinetic Parameter- Cmax of Eltrombopag When Combined With Cyclosporine	Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose.	Cmax is the observed maximum plasma concentration following administration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 microgram/milliliter (ug/mL). Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Pharmacokinetic Parameter-AUClast of Eltrombopag When Combined With Cyclosporine	Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose	AUClast is the area under the curve calculated to the last quantifiable concentration point (Tlast). The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Pharmacokinetic Parameter- AUCtau of Eltrombopag When Combined With Cyclosporine	Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose	AUCtau is the area under the curve calculated to the end of the dosing interval (tau). The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Pharmacokinetic Parameter- Ctrough of Eltrombopag When Combined With Cyclosporine	Week 2 at pre-dose	Ctrough is the pre-dose plasma concentration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Pharmacokinetic Parameter- Tmax of Eltrombopag When Combined With Cyclosporine	Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose	Tmax is the time to reach peak or maximum concentration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Pharmacokinetic Parameter- CLss/F of Eltrombopag When Combined With Cyclosporine	Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose	CLss/F is the apparent systemic (or total body) clearance at steady state from plasma. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.