Clinical trial NCT02404025: Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A in Naive Aplastic Anemia (AA) Subjects
Official title: A Non-randomized, Phase II Study of Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A (ATG/CsA) in Subjects With Moderate or More Severe Aplastic Anemia Who Have Not Received Prior ATG/Anti-lymphocyte Globulin (ALG)-Based Immunosuppressive Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aplastic Anemia
Keywords: Eltrombopag
rabbit anti-thymocyte globulin
additive effect
cyclosporine A
bone marrow
hematopoietic stem cells
pancytopenia
leukopenia
platelets
throbocytopenia
mature blood cells
bone marrow biopsy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-03-31
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: This was an open label, non-randomized, phase II study of eltrombopag in combination with rabbit ATG/CsA in subjects with moderate or more severe AA who did not received prior ATG/ALG-based immunosuppressive therapy. The objective was to assess additive effects of eltorombopag on overall response rate (ORR) at 6 months (Week 26) of treatment with ATG/CsA. Subjects were assessed at least weekly for safety during the period from the start of ATG/CsA to 4 weeks after the start of administration of eltrombopag. After that, subjects had visits every 2 weeks until Week 26. Subjects in whom the treatment was assessed as effective at Week 26 could continued treatment with eltrombopag after 6 months when clinically indicated at the discretion of the investigator. There were five follow-up visits: at discontinuation of the treatment of eltrombopag, and Weeks 1, 2, 3, 4 and 26 after treatment discontinuation. As this study was the first Japanese phase II study in which this product was administered in combination with ATG/CsA to subjects with naive moderate or more severe AA, the subject number of this study was determined to be 10 based on the feasibility survey.


Eligibility criteria: Inclusion Criteria:

* Japanese subjects aged \>=18 and \<71 years at the time of informed consent. Note: subjects aged \>=71 and \<75 may be eligible when clinically indicated at the discretion of the investigator by mutual agreement with Novartis medical advisor.
* Diagnosed with moderate or more severe AA according to the diagnostic criteria of AA. The severity classification is: Stage I - Mild - Other than the stages below; Stage II - Moderate - At least two of the following conditions are met: Reticulocyte \<60,000/microliter, Neutrophil \<1,000/microliter, Platelet \<50,000/microliter; Stage III - Moderately severe - At least two of the following conditions are met and regular red blood cell transfusion (a need for transfusion of \>=2 units per month) is required: Reticulocyte \<60,000/microliter, Neutrophil \<1,000/microliter, Platelet \<50,000/microliter; Stage IV - Severe - At least two of the following conditions are met: Reticulocyte \<20,000/microliter, Neutrophil \<500/microliter, Platelet \<20,000/microliter; Stage V - Very severe - At least one of the following conditions is met in addition to neutrophil \<200/microliter: Reticulocyte \<20,000/microliter, Platelet \<20,000/microliter.
* Subjects who are considered an indication for the treatment with rabbit ATG and CsA.
* Adequate baseline organ function defined by the following criteria: Alanine aminotransferase (ALT), aspartate aminotransferase (AST)\<=3 × local upper limit of normal (ULN) Creatinine, total bilirubin, and alkaline phosphatase (ALP) \<1.5 × local ULN (total bilirubin \<2.5 × local ULN with Gilbert's Syndrome)
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 or 1
* Subjects with QTcF\<450 millisecond (msec) or QTcF\<480 msec with branch block: QTc is QT interval corrected by Fridericia formula (QTcF), machine ,or manual overread. QTcF is based on single or averaged QTc value of triplicate ECG.
* Subjects are able to understand and comply with protocol requirements and instructions.
* Subjects have signed and dated informed consent.
* Subjects who meet one of the following conditions: Male subjects who have a female partner of childbearing potential must either have a prior vasectomy or agree to use an acceptable method of contraception from time of enrollment in the study until 16 weeks after the last dose of eltrombopag (based upon the lifecycle of sperm). Female subjects of non-childbearing potential (who are physiologically unable to become pregnant) defined as: Premenopausal women with documented bilateral oophorectomy, bilateral tubal ligation, or hysterectomy; or postmenopausal women after at least 12 months of natural amenorrhea \[if uncertain, postmenopausal state should be confirmed by hematology result of follicle stimulating hormone (FSH) \>40 milli-international units (mIU)/milliliter (mL) or estradiol \<40 picogram (pg)/mL (\<140 picomoles (pmol)/L)\]. Female subjects of childbearing potential: Defined as those not meeting the definition of non-childbearing potential. Female subjects of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) or urine pregnancy test within 7 days prior to the first dose of ATG/CsA. It is recommended that the pregnancy test should be performed as close as possible to the first dose of ATG/CsA. Female subjects with a positive pregnancy test must be excluded from the study. Subjects with a negative pregnancy test must use acceptable contraception including abstinence after the pregnancy test. Subjects must agree to use the acceptable contraception including abstinence from 14 days prior to the first dose of ATG/CsA until 28 days after the last dose of eltrombopag.

Exclusion Criteria:

* Diagnosis of congenital AA (e.g. Fanconi anemia or Dyskeratosis congenital).
* Subjects who have a sibling donor with matched human leukocyte antigen (HLA) or who underwent hematopoietic stem cell transplantation (HSCT) previously. However, such subjects may be enrolled if HSCT is not indicated, or the subject does not want to undergo HSCT.
* Subjects with abnormal chromosome (monosomy 7 detected by fluorescence in situ hybridization (FISH), or other aberrations detected by G-band staining). Note: Subjects with abnormal chromosome which is not adopted into the clone definition of An International System for Human Cytogenetic Nomenclature (ISCN) may be enrolled after consulting with medical monitor.
* Previous ATG/ALG-based immunosuppressive therapy or steroid pulse therapy for AA.
* Treatment with CsA within 6 months before administration of ATG.
* Subjects with a paroxysmal nocturnal hemoglobinuria (PNH) clone size in granulocytes of \>50% by flow cytometric analysis.
* Pre-existing cardiac disease (congestive heart failure New York Heart Association (NYHA) Grade II/III/IV), or arrhythmias known to involve the risk of thromboembolic events (e.g. atrial fibrillation)
* Past history of thromboembolic event (including anti-phospholipid antibody syndrome) and current use of anticoagulants.
* Subjects with past or current malignancy. Note : Subjects who have a history of completely resected malignant tumor and have been disease-free for 5 years are eligible.
* Subjects who test positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody at screening.
* Infection not adequately responding to appropriate therapy.
* Subject with liver cirrhosis
* Subjects with any clinically significant severe cardiac, renal, or hepatic medical condition.
* Pregnant women (a positive serum or urine pregnancy test within 7 days prior to the first dose of ATG/CsA or lactating women) Note: Female subjects who are lactating are eligible to participate if they discontinue nursing prior to the first dose of ATG/CsA and refrain from nursing until 5 days after the completion of treatment with eltrombopag.
* Known hypersensitivity, intolerance or allergy to rabbit ATG, cyclosporine A, eltrombopag or any of their excipients.
* Current alcohol or drug abuse.
* Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) proceeding the first dose of ATG/CsA.
* Subjects who is not candidates for ATG.
* Subjects who is not candidates for CsA.
* History of treatment with eltrombopag, romiplostim or other thrombopoietin-receptor (TPO-R) agonists.

Primary outcomes:
measure: ORR at 6 Months: Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26
timeFrame: Week 26
Secondary outcomes:
measure: ORR at 3 Months
timeFrame: Week 14
measure: Complete Response (CR), and Partial Response (PR) Rate at 3 Months
timeFrame: Week 14
measure: CR Rate Based on the Criteria Used in NIH 12-H-0150 Study at 6 Months
timeFrame: Week 26
measure: Changes in Hematology Parameters (Haemoglobin) in the Absence of Platelet Transfusion
timeFrame: Week 26 and week 104
measure: Changes in Hematology Parameters in the Absence of Platelet Transfusion
timeFrame: Week 26 and week 104
measure: Frequency of Platelet and Red Blood Cells (RBC) Transfusions
timeFrame: Baseline, Week 26
measure: Volume of Platelet and RBC Transfusions
timeFrame: Baseline, Week 26
measure: The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent
timeFrame: Week 26
measure: Duration of Hospitalization
timeFrame: Week 26
measure: Time to Onset of CR and PR
timeFrame: Week 26
measure: Duration of CR or PR
timeFrame: Week 104
measure: Degree of Exposure to Eltrombopag : Average Daily Dose
timeFrame: Week 104
measure: Degree of Exposure to Eltrombopag : Cumulative Dose
timeFrame: Week 104
measure: Degree of Exposure to Eltrombopag : Days on Study
timeFrame: Week 104
measure: Number of Participants With Adverse Events
timeFrame: though study completion , approximately 2 years
measure: Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability
timeFrame: baseline and Week 26
measure: 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability
timeFrame: Baseline, Week 26
measure: The Trough Concentrations of Eltrombopag Following Repeat Doses of at 75 mg, 50 mg and 25 mg
timeFrame: day 15
measure: The Concentration After 4 Hours of Dose of Eltrombopag 75 mg
timeFrame: day 15
measure: Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin).
timeFrame: Baseline, Week 26
measure: Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils).
timeFrame: Baseline, Week 26
measure: Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) .
timeFrame: Baseline, Week 26
measure: Composite of Laboratory Parameters Assessment as a Safety Measure.
timeFrame: Baseline, Week 26
measure: Vital Signs (Temperature) as a Measure of Safety and Tolerability
timeFrame: baseline and Week 26
measure: Vital Signs (Pulse Rate) as a Measure of Safety and Tolerability
timeFrame: baseline and Week 26
Other outcomes:
Locations:
city: Aichi
country: Japan
facility: Novartis Investigative Site
city: Aichi
country: Japan
facility: Novartis Investigative Site
city: Ibaraki
country: Japan
facility: Novartis Investigative Site
city: Ishikawa
country: Japan
facility: Novartis Investigative Site
city: Miyagi
country: Japan
facility: Novartis Investigative Site
city: Okayama
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Tochigi
country: Japan
facility: Novartis Investigative Site
city: Tokyo
country: Japan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: