Clinical trial NCT03025698: A Phase II Dose-escalation Study Characterizing the PK of Eltrombopag in Pediatric Patients With Previously Untreated or Relapsed Severe Aplastic Anemia or Recurrent Aplastic Anemia
Official title: A Phase II, Open-label, Non-controlled, Intra-patient Dose-escalation Study to Characterize the Pharmacokinetics After Oral Administration of Eltrombopag in Pediatric Patients With Refractory, Relapsed or Treatment Naive Severe Aplastic Anemia or Recurrent Aplastic Anemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aplastic Anemia
Keywords: Eltrombopag
Horse anti-thymocyte globulin
Cyclosporine
previously untreated or relapsed severe aplastic anemia
recurrent aplastic anemia
Severe aplastic anemia
Pharmacokinetics
Immunosuppressive therapy
ETB115
Refractory
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-01-19
Enrollment: 51
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase II, open label, multi-center, intra-patient dose escalation study to characterize the pharmacokinetics (PK) after oral administration of eltrombopag in combination with immunosuppressive therapy in pediatric patients with previously untreated or relapsed/refractory severe aplastic anemia or recurrent aplastic anemia.

Detailed description: All patients were treated with eltrombopag for the 26-week Treatment Period, followed by a 52-week Follow-Up Period. Patients who had been previously untreated with immunosuppressive therapy were treated according to the standard of care, hATG/cyclosporine, in addition to eltrombopag. Patients with relapsed/refractory SAA or recurrent AA were enrolled into one of two treatment options: hATG/cyclosporine plus eltrombopag or cyclosporine plus eltrombopag, depending on prior treatment with immunosuppressive therapy. Patients could receive eltrombopag beyond 26 weeks if the investigator thought that the patient was still receiving clinical benefit from the drug.

After initiating treatment with eltrombopag, patients had their dose assessed and modified as tolerated, until the targeted platelet count or maximum dose was achieved. Pharmacokinetic assessments were performed at time points intended to capture steady state PK of the starting dose and highest dose achieved.

There are four separate periods of this study: Screening (signing of written informed consent through Day -1), Treatment (for 26 weeks), Follow-up (additional 52 weeks), and Long-term Follow-up (for additional 3 years). The first 3 periods were considered the Core phase of the study.

Study completion (Core) will occur when the last patient completes the 26-week treatment and 52-week Follow-up Period \[at Week 78\].

Eligibility criteria: Inclusion Criteria:

For Cohort A patients:

* History of prior diagnosis of SAA,
* Diagnosis of relapsed/refractory SAA or recurrent AA following treatment for SAA, as per Section 5.1. Patients with recurrent AA (e.g., losing their response) are exempt from meeting the diagnostic criteria for SAA relapse at the time of study enrollment, but must have been previously diagnosed with SAA.
* Agree to concurrent eltrombopag treatment with appropriate, investigator-selected Immunosuppressive therapy (IST) with either hATG + CsA or CsA.

For Cohort B patients:

* Diagnosis of SAA at time of enrollment.
* Patients must not have been previously treated with IST, and must meet all criteria as described in Table 5-1.
* Patients must agree to treatment with hATG + CsA concurrent with eltrombopag.

All patients eligible for inclusion in this study must meet all of the following criteria:

* Age 1 to \<18 years.
* Assessments to rule out congenital/inherited bone marrow failure syndromes and other causes of immune-mediated pancytopenia, which may be treated with transplant, must be completed prior to enrollment.
* Hematopoietic stem cell transplantation (HSCT) is not suitable or available as a treatment option or has been refused by the patient. (Candidacy for HSCT will be determined as per local practices or national guidelines.)
* Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag.
* Performance status score: Karnofsky ≥50 for patients 16 years of age and older or Lansky ≥50 for patients below 16 years of age.
* Written informed consent must be signed by a parent or legal guardian prior to initiation of any study specific procedure.
* Normal karyotype within 4 weeks prior to first dose of eltrombopag. If there are insufficient metaphases (\< 10) to determine karyotype, a repeat marrow aspirate is required. If upon repeat bone marrow aspirate, the number of metaphases is insufficient (\< 10), then FISH probes performed in marrow aspirate as per protocol must be normal.

Exclusion Criteria:

* Prior and/or active medical history of:

  * Fanconi anemia (via chromosome breakage test or growth arrest by flow cytometry)
  * Other known underlying inherited marrow failure syndrome (such as but not limited to Dyskeratosis Congenita, Congenital Amegakaryocytic Thrombocytopenia, or Shwachman-Diamond Syndrome).
* Symptomatic Paroxysmal Nocturnal Hemoglobinuria (PNH) and/or PNH clones \>50% of White blood cell (WBC) or Red blood cell (RBC) at time of enrollment.

  * Any cytogenetic abnormalities by karyotyping or FISH.
  * Myelodysplastic syndrome (MDS)
  * Other known or suspected underlying primary immunodeficiency
  * Any malignancy
* Active infection not responding to appropriate therapy.
* Prior eltrombopag or other thrombopoietin receptor (TPO-R) agonist treatment for at least 2 months and a lack of response.
* Have any of the following out-of-range laboratory values:

  * Serum Creatinine \>2.5 × upper limit of normal (ULN),
  * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 × ULN.
* Concurrent participation in an investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer. Note: a parallel enrollment in a registry for patients with SAA or AA is acceptable.

Pregnant or nursing (lactating) women.

* Female patients of childbearing potential (e.g., are menstruating or could reach menarche during the study, this usually includes girls 9 years and older) who do not agree to abstinence or, if sexually active, do not agree to the use of contraception as defined in Section 7.2.1.2.6 (pregnancy section) of the protocol. If local regulations are more stringent than the contraception methods listed in this protocol to prevent pregnancy, local regulations apply and will be described in the ICF.
* Male patients who are sexually active and do not agree to abstinence or to use a condom during intercourse while taking eltrombopag, and for 13 weeks after stopping treatment.
* Patients, who in the investigators' opinion may be unwilling, are unable or unlikely to comply with the requirements of the study protocol.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or its excipient, CSA, or hATG that contraindicates patient participation.
* History of major surgery, serious illness, or traumatic injury within 4 weeks of first dose of study treatment.
* Patients with known history of HIV positivity.
* Patients with known history of hepatitis B or C positivity.
* Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol, such as:

  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome),Active skin, mucosa, ocular or GI disorders of Grade \> 1.
* Impaired cardiac function, such as:

  * Patients with a history of congenital long QT syndrome or known family history of long QTc syndrome,
  * Corrected QTc \>450 msec using Fridericia correction (QTcF) on the screening ECG (using triplicate ECGs),
  * Ventricular arrhythmias and or other cardiac arrhythmia not controlled with medication,
  * Other clinically significant cardio-vascular disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension),
  * History of known structural abnormalities (e.g., cardiomyopathy).

Primary outcomes:
measure: Eltrombopag PK parameter: AUCtau
timeFrame: at the highest dose level, i.e. 11 weeks after dose initiation
measure: Eltrombopag PK parameter: Cmax
timeFrame: at the highest dose level, i.e. 11 weeks after dose initiation
measure: Eltrombopag PK parameter: Ctrough
timeFrame: at the highest dose level, i.e. 11 weeks after dose initiation
Secondary outcomes:
measure: Percentage of participants who have achieved a complete (CR) or partial response (PR)
timeFrame: Week 12, Week 26, Week 52, and Week 78.
measure: Percentage of participants with a platelet response
timeFrame: Week 12, Week 26, Week 52, and Week 78.
measure: Hematologic counts
timeFrame: Week 12, Week 26, Week 52, Week 78, and then annually up to 3 years
measure: Red Blood Cell (RBC) transfusion independence
timeFrame: From date of first dose to approx. 3 years
measure: Platelet transfusion independence
timeFrame: From date of first dose to approx. 3 years
measure: Bone marrow cellularity
timeFrame: Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years
measure: Bone marrow morphology
timeFrame: Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years
measure: Bone marrow cytogenetics
timeFrame: Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years
measure: Acceptability and palatability for both tablets and powder for oral suspension
timeFrame: Week 1, Week 2, Week 3, Week 4, Week, 12, Week 26, Week 78
measure: Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)
timeFrame: Baseline, Week 12, 26, 52, 78 and annually for up to 3 years to at time of disease progression.
measure: Exposure-response relationship of eltrombopag and overall response and platelet response
timeFrame: Week 12 or up to Week 26 when the PK highest dose has been achieved
measure: Alternate Overall response (aOR)
timeFrame: Week 12, Week 26, Week 52, and Week 78.
measure: PK of eltrombopag at the starting dose (AUCtau)
timeFrame: Week 3 Day 1
measure: PK of eltrombopag at the starting dose (Cmax)
timeFrame: Week 3 Day 1
measure: PK of eltrombopag at the starting dose (Ctrough)
timeFrame: Week 3 Day 1
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children s Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Childrens Hospital
state: Arkansas
city: Aurora
country: United States
facility: Childrens Hospital Colorado
state: Colorado
city: Atlanta
country: United States
facility: Aflac Cancerand Blood Disorders Ctr
state: Georgia
city: Chicago
country: United States
facility: Ann and Robert H Lurie Childrens Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Boston
country: United States
facility: Childrens Hosp Boston Dept of Hematology
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of MI Health System
state: Michigan
city: Hackensack
country: United States
facility: Hackensack University Medical Center SC-2
state: New Jersey
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Houston
country: United States
facility: Texas Children's Cancer and Hematology Center
state: Texas
city: Shatin
country: Hong Kong
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: