Combination of Eltrombopag With Immunosuppressive Therapy in East-Asian Patients With Severe Aplastic Anemia

Phase 2

Completed

Conditions: Severe Aplastic Anemia (SAA)

Interventions: Drug: eltrombopag
Drug: rabbit anti-thymocyte globulin (r-ATG)
Drug: cyclosporine A (CsA)

Registration Number: NCT04328727

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This study was designed to evaluate the efficacy and safety of eltrombopag when added to r-ATG and CsA in treatment naive East-Asian adult and pediatric patients with severe aplastic anemia (SAA).

Detailed Description: This was a non-randomized, open label, single arm, multi-center, Phase II study to evaluate the efficacy and safety of eltrombopag in combination with immunosuppressive therapy (IST) regimen of r-ATG + CsA in East-Asian patients with severe aplatsic anemia who had not received prior IST.

Eligible participants were enrolled into the study and received eltrombopag (from Day 1 to Week 26) concomitantly with r-ATG (on Days 1-5) and CsA (from Day 1 to Week 26) in the core treatment part.

Participants who were assessed as responders (meeting complete (CR) or partial (PR) response criteria) at Week 26 were eligible for the extension part of the study and continued treatment with eltrombopag and CsA after Week 26 up to Week 52. During the extension part, eltrombopag treatment was provided up to Week 52. CsA was maintained or tapered at the investigator's discretion according to local practice, with a total duration of at least 2 years (18 months after Week 26). There was a 30 days after end of treatment safety follow-up at the end of the extension part.

All participants were offered to enter the long term follow-up after the discontinuation of eltrombopag, with yearly efficacy and clonal evolution assessments up to Year 3 (Week 156).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

Inclusion Criteria

Written study informed consent and (where applicable) assent from the subject, parent, or guardian must be obtained prior to participation in the study.
Subjects of East Asian ethnicity aged ≥ 6 years old at the time of written informed consent and assent form (if applicable).
SAA characterized by:
Bone marrow cellularity < 25%, or 25-50% with < 30% residual hematopoietic cells and pancytopenia, with at least two of the following parameters in peripheral blood:
Absolute neutrophil count < 0.5×109/L
Platelet count < 20×109/L
Absolute reticulocyte count < 20×109/L
HSCT not suitable or available as a treatment option (determined as per local practices or national guidelines), or has been refused by subject.

Exclusion Criteria

Prior IST with any ATG/ALG , alemtuzumab, high dose cyclophosphamide (≥ 45 mg/kg/day), CsA within 6 months, or prior thrombopoietin receptor agonists.
Eastern Cooperative Oncology Group (ECOG) performance status (age ≥ 16 years) >2, or Lansky performance status (age < 16 years) <50.
Prior and/or active medical history of:
Known underlying congenital/inherited bone marrow failure or aplastic anemia (e.g.,such as but not limited to Fanconi anemia, congenital dyskeratosis, congenital amegakaryocytic thrombocytopenia, or Shwachman-Diamond Syndrome)
Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) and/or PNH clones >50% of polymorphonuclear neutrophil (PMN) or RBC at time of enrollment
Myelodysplastic syndrome (MDS)
Any cytogenetic abnormalities on karyotyping or FISH within 30 days of study enrollment (an evaluable karyotyping with at least 10 metaphases is mandatory for eligibility)
Other known or suspected underlying primary immunodeficiency
Any concomitant malignancies that have not fully recovered from treatment or have not been disease-free for 5 years
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN).
Creatinine ≥ 2.5×local ULN
Past medical history of thromboembolism within 6 months, and/or prior or current antiphospholipid antibody syndrome (APS).
Presence of clinically active uncontrolled significant (of such severity that it would preclude the subject's ability to consent, be compliant with study procedures, tolerate protocol therapy) infection, including bacterial, fungal, mycobacterial, parasitic or viral infection, or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the subject or compliance with the protocol
Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol, such as:
Known hepatocellular disease (e.g. active hepatitis or cirrhosis)
Impairment of gastrointestinal (GI) function or gastrointestinal disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
Active skin, mucosa, ocular or GI disorders of Grade > 1
Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening. A positive serology for Hepatitis B (HB) is considered as a positive test for HBsAg. In addition, if serology is negative for HBsAg but hepatitis B core antibody (HBcAb) is positive (regardless of hepatitis B surface antibody (HBsAb) status), a hepatitis B virus (HBV) DNA test will be performed and if positive the patient will be excluded.
Cardiac disorder (subjects with congestive heart disease of New York Heart Association (NYHA) functional classification Grade II/III/IV (for pediatric subjects, refer to the Grade II/III/IV of Modified ross heart failure classification for Children) should not be enrolled; subjects with NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA Grade II due to aplastic anemia (AA) may be enrolled.), arrhythmia with a risk of thrombosis (e.g. atrial fibrillation), pulmonary hypertension, or uncontrolled hypertension (>180/100 mmHg).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
eltrombopag	eltrombopag	Participants received eltrombopag in combination with r-ATG and CsA. * Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and \< 12 years. Doses could be adjusted based on platelet count * r-ATG was administered intravenously at a dose of 2.5 to 3.5 mg/kg/day on Days 1-5 * CsA was administered orally every 12 h at a starting dose of 3-6 mg/kg/day
eltrombopag	rabbit anti-thymocyte globulin (r-ATG)	Participants received eltrombopag in combination with r-ATG and CsA. * Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and \< 12 years. Doses could be adjusted based on platelet count * r-ATG was administered intravenously at a dose of 2.5 to 3.5 mg/kg/day on Days 1-5 * CsA was administered orally every 12 h at a starting dose of 3-6 mg/kg/day
eltrombopag	cyclosporine A (CsA)	Participants received eltrombopag in combination with r-ATG and CsA. * Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and \< 12 years. Doses could be adjusted based on platelet count * r-ATG was administered intravenously at a dose of 2.5 to 3.5 mg/kg/day on Days 1-5 * CsA was administered orally every 12 h at a starting dose of 3-6 mg/kg/day

Primary Outcome Measures

Name	Time	Method
Complete Response (CR) Rate at Week 26	Week 26 (6 months after starting study treatment)	Complete response rate was defined as percentage of patients achieving complete response (CR). Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders.

Secondary Outcome Measures

Name	Time	Method
Complete Response (CR) Rate	Week 13 (3 months), Week 52 (12 months) and yearly after up to 3 years	Complete response rate was defined as percentage of patients achieving complete response (CR). Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders.
Overall Response (ORR) Rate	Week 13 (3 months), 26 weeks (6 months), 52 weeks and yearly after up to 3 years	Overall response rate was defined as percentage of patients achieving complete response (CR) or partial response (PR). Partial response (PR) was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in SAA, equivalent to at least 2 of the 3 criteria below, but not sufficient for a CR: * Absolute neutrophil count ≥ 0.5 × 10\^9/L * Platelet count ≥ 20 × 10\^9/L * Reticulocyte count ≥ 20 × 10\^9/L Complete response (CR) was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L
Duration of Complete Response	Up to aproximately 3 years	Duration of response was derived as the time from first documented and confirmed complete response (CR) until the time of relapse or death, whichever occurred first. Duration of response was estimated using Kaplan-Meier method. Clinical relapse was considered as the occurrence of any of the following events in a participant who had achieved a hematological response (CR) but had subsequently lost response (not explained by any other independent concomitant medical conditions) in one blood count measurements: * Meeting again the criteria for SAA * Requirement for transfusion again for subjects who had been transfusion independent * Decrease in any of the peripheral blood counts to absolute neutrophil count \< 0.5 x10\^9/L or platelets \< 20 x10\^9/L.
Duration of Overall Response	Up to aproximately 3 years	Duration of response was derived as the time from first documented and confirmed response (either CR or PR) until the time of relapse or death, whichever occurred first. Duration of response was estimated using Kaplan-Meier method. Clinical relapse was considered as the occurrence of any of the following events in a participant who had achieved a hematological response (CR or PR) but had subsequently lost response (not explained by any other independent concomitant medical conditions) in one blood count measurements: * Meeting again the criteria for SAA * Requirement for transfusion again for subjects who had been transfusion independent * Decrease in any of the peripheral blood counts to absolute neutrophil count \< 0.5 x10\^9/L or platelets \< 20 x10\^9/L.
Overall Survival (OS)	Up to approximately 3 years	OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. If a subject was not known to have died, survival was censored at the date of last contact. The distribution function of OS was estimated using the Kaplan- Meier method.
Overall Survival (OS) Rate	Week 26, Week 52 and yearly after up to 3 years	OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. The OS rate is the estimated probability that a patient will remain event-free up to the specified time point and was obtained from the Kaplan-Meier survival estimates. If a subject was not known to have died, survival was censored at the date of last contact.
Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26	Week 13, 26	Transfusion-free interval was defined as the time from most recent RBC/platelet transfusion preceding response assessment to the date of response assessment.
Percentage of Participants Who Become RBC Transfusion Independent	From date of first dose to approximately 3 years	Transfusion independent participants were defined as those participants who were transfusion dependent at baseline but became transfusion free for a period of ≥ 8 weeks post-baseline for RBCs.
Percentage of Participants Who Become Platelet Transfusion Independent	From date of first dose to approximately 3 years	Transfusion independent participants were defined as those participants who were transfusion dependent at baseline but became transfusion free for a period of ≥ 4 weeks post-baseline for platelets.
Time From the Date of First Dose of Investigational Treatment to the Date of First Occurrence of Any Clonal Evolution Events	From date of first dose to approximately 3 years	Clonal evolution events were assessed by karyotyping (G-banding) and FISH (Fluorescence in situ hybridization) targeting abnormalities including, but not restricted to chromosome 3q del,5q del, monosomy 7, trisomy 8 and those associated with SAA (Severe aplastic anemia), MDS (Myelodysplastic syndrome), AML (Acute myeloid leukemia). Time to clonal evolution was to be estimated using the Kaplan-Meier method.
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUClast	Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose	AUClast is the area under the curve from time zero to the last measurable concentration sampling time. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUCtau	Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose	AUCtau is area under the curve calculated to the end of a dosing interval (tau) at steady-state Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Ctrough	Pre-dose on day 15 after initation of eltrombopag and and pre-dose on the 15th day after each new dose up to week 26	Cthrough is the pre-dose concentration at the end of dose interval. Blood samples were collected to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach. Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and \< 12 years. Doses could be adjusted based on platelet count every 2 weeks by decreasing it by 25 mg/day (12.5 mg/day, for participants below 12 years old) if the platelet count was above 200×10\^9/L. or interrupted if platelet count rose above 400×10\^9/L. In partial response participants dose could be restarted or increased to that before the decrease if platelet counts \< 30 x10\^9/L, Hb\< 90 g/L, ANC\< 0.5 x 10\^9/L or participant needed transfusion. In complete response participants dose could be restarted or increased to that before decrease if blood counts dropped to not meet CR criteria.
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Cmax	Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose	Cmax is the The maximum (peak) observed plasma drug concentration after dose administration. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: CLss/F	Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose	CLss/F is Apparent systemic (or total body) clearance at steady state from plasma. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Tmax	Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose	Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.