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

Novartis Pharmaceuticals36 enrolled

Overview

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).

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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Severe Aplastic Anemia (SAA)

Interventions

eltrombopagDRUG

Tablet 25mg and 12.5mg

rabbit anti-thymocyte globulin (r-ATG)DRUG

r-ATG 25 mg sterile lyophilized powder in 10 mL vials for IV use

cyclosporine A (CsA)DRUG

CsA 25mg Capsule or CsA 5.0g/50mL solution for oral use

Eligibility

Sex: ALLMin age: 6 YearsMax age: 100 Years

Medical Language ↔ Plain English

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).

Locations (12)

Novartis Investigative Site

Guangzhou, Guangdong, China

Novartis Investigative Site

Zhengzhou, Henan, China

Novartis Investigative Site

Nanchang, Jiangxi, China

Outcomes

Primary Outcomes

Complete Response (CR) Rate at Week 26

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.

Time frame: Week 26 (6 months after starting study treatment)

Secondary Outcomes

Complete Response (CR) Rate

Time frame: Week 13 (3 months), Week 52 (12 months) and yearly after up to 3 years

Overall Response (ORR) Rate

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

Data from ClinicalTrials.gov

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Novartis Investigative Site

Changchun, Jilin, China

Novartis Investigative Site

Tianjin, China

Novartis Investigative Site

Tianjin, China

Novartis Investigative Site

Nagoya, Aichi-ken, Japan

Novartis Investigative Site

Fukuoka, Fukuoka, Japan

Novartis Investigative Site

Chuo Ku, Tokyo, Japan

Novartis Investigative Site

Seoul, South Korea

...and 2 more locations

Time frame: Week 13 (3 months), 26 weeks (6 months), 52 weeks and yearly after up to 3 years

Duration of Complete Response

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.

Time frame: Up to aproximately 3 years

Duration of Overall Response

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.

Time frame: Up to aproximately 3 years

Overall Survival (OS)

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.

Time frame: Up to approximately 3 years

Overall Survival (OS) Rate

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.

Time frame: Week 26, Week 52 and yearly after up to 3 years

Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26

Transfusion-free interval was defined as the time from most recent RBC/platelet transfusion preceding response assessment to the date of response assessment.

Time frame: Week 13, 26

Percentage of Participants Who Become RBC Transfusion Independent

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.

Time frame: From date of first dose to approximately 3 years

Percentage of Participants Who Become Platelet Transfusion Independent

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 frame: From date of first dose to approximately 3 years

Time From the Date of First Dose of Investigational Treatment to the Date of First Occurrence of Any Clonal Evolution Events

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.

Time frame: From date of first dose to approximately 3 years

Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUClast

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.