Clinical trial NCT04328727: Combination of Eltrombopag With Immunosuppressive Therapy in East-Asian Patients With Severe Aplastic Anemia
Official title: A Non-randomized, Open Label, Multi-center, Phase II Study to Assess the Safety and Efficacy of Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin (r-ATG) and Cyclosporine A (CsA) in East-Asian Patients With Treatment Naive Severe Aplastic Anemia (REACTS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Severe Aplastic Anemia (SAA)
Keywords: Treatment naïve severe aplastic anemia
SAA
eltrombopag
ETB115
immunosuppressive therapy
rabbit anti-thymocyte globulin
r-ATG
cyclosporine A
CsA
East-Asian patients
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-03-31
Enrollment: 36
Sex: ALL
Minimum age (years): 6
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is 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 SAA.


Eligibility criteria: 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 is 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).

Other protocol-defined Inclusion/Exclusion may apply.

Primary outcomes:
measure: Complete response (CR) rate
timeFrame: Week 26 (6 months after starting study treatment)
measure: PK Outcome: The AUC calculated to the end of a dosing interval (tau) at steady-state (AUCtau)
timeFrame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose
Secondary outcomes:
measure: CR rate
timeFrame: Week 13 (3 months), Week 52 (12 months) and yearly after until end of study up to approx. 3 years
measure: Overall response (ORR) rate
timeFrame: Week 13 (3 months), 26 weeks (6 months), 52 weeks, yearly after until end of study up to approx. 3 years
measure: Time from the date of the start of response to the date of relapse or death, which ever occurs first at any time during the study.
timeFrame: from the date of the start of response to the date of relapse or death, whichever occurs first at any time during the study up to 3 years
measure: Time from the date of first dose of study treatment to the date of death
timeFrame: from date of first dose to date of death up to approx. 3 years
measure: Overall survival (OS) rate
timeFrame: Week 26, Wee 52 & yearly after up to 3 years
measure: Time from the most recent transfusion to week 13 and week 26
timeFrame: week 13, 26
measure: Percentage of participants who become (platelet/RBC) transfusion independent
timeFrame: From date of first dose to approx. 3 years
measure: Time from the date of first dose of investigational treatment to the date of first occurrence of any clonal evolution events
timeFrame: Week 13, Week 26, Week 52 and yearly after, and when clinically indicated till approximately 3 years
measure: Pharmacokinetics (PK) parameters: Area under the concentration-time curve from time zero to the last measurable concentration sampling time (AUClast)
timeFrame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose
measure: Plasma trough concentration of eltrombopag
timeFrame: Baseline to week 26
measure: PK Outcome: Observed maximum plasma concentration following administration (Cmax)
timeFrame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose
measure: PK Outcome: The time to reach peak or maximum concentration (Tmax)
timeFrame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose
measure: PK Outcome:Apparent systemic (or total body) clearance at steady state from plasma (CLss/F)
timeFrame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose
Other outcomes:
Locations:
city: Guangzhou City
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Zhengzhou
country: China
facility: Novartis Investigative Site
state: Henan
city: Nanchang
country: China
facility: Novartis Investigative Site
state: Jiangxi
city: Chang Chun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: