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

Novartis Pharmaceuticals51 enrolled

Overview

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 (SAA) or recurrent aplastic anemia (AA).

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 plus cyclosporine plus eltrombopag. Patients with relapsed/refractory SAA or recurrent AA were enrolled into one of two treatment options: hATG plus 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 \[at Week 78\].

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Aplastic Anemia

Interventions

EltrombopagDRUG

Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily

hATGDRUG

Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP)

CsADRUG

Cyclosporine (CsA) was supplied as either oral capsules or oral solution, administered twice a day.

Eligibility

Sex: ALLMin age: 1 YearMax age: 18 Years

Medical Language ↔ Plain English

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).

Locations (20)

Phoenix Childrens Hospital

Phoenix, Arizona, United States

Arkansas Childrens Hospital

Little Rock, Arkansas, United States

Outcomes

Primary Outcomes

Eltrombopag PK Parameters: AUCtau, AUClast

AUC tau: Area under the curve calculated to the end of the dosing interval ( tau) (mass\*time/volume) AUC last: Area under the curve calculated to the last quantifiable concentration point (Tlast) (mass\*time/volume)

Time frame: at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

Eltrombopag PK Parameter: Cmax

Cmax is the observed maximum plasma concentration following administration (mass/volume)

Time frame: at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

Eltrombopag PK Parameter: Ctrough at the Highest Dose Level

Ctrough is the pre-dose plasma concentration (mass/volume).

Time frame: at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

Secondary Outcomes

Percentage of Participants With an Overall Response Rate and Percentage of Participants With a Platelet Response Rate Based on Per Pediatric Committee of European Medicines Agency (PDCO)

Overall response rate (ORR) is defined as the percentage of participants who have achieved a complete response (CR) or partial response (PR) or No response (NR) by the Investigator. CR criteria: Platelet (PLT) and red blood cell (RBC) transfusion independence, Normal age-adjusted Hgb, PLT \>100 × 10\^9/L and absolute neutrophil count (ANC) \>1.5 × 10\^9/L. PR: PLT and RBC Transfusion independence and at least 2 of the following criteria: Reticulocytes \>30 × 10\^9/L, PLT \>30 × 10\^9/L, ANC \>1.5 x 10\^9L. PLT transfusion independence is defined as a period for at least 28 days without PLT transfusion. Platelet response rate (PRR): Platelet response rate is comprised of CR + PR based on the following criteria: CR: PLT \>100 × 10\^9/L; PR: PLT \>30 × 10\^9/L; NR: PLT transfusion within 4 weeks or PLT \<= 30 × 10\^9/L.

Time frame: Week 12, Week 26, Week 52, Week 78

Data from ClinicalTrials.gov

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Childrens Hospital Colorado

Aurora, Colorado, United States

Aflac Cancerand Blood Disorders Ctr

Atlanta, Georgia, United States

Ann and Robert H Lurie Childs Hosp

Chicago, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

Childrens Hosp Boston Dept of Heme

Boston, Massachusetts, United States

University of MI Health System

Ann Arbor, Michigan, United States

Hackensack University Medical Center SC-2

Hackensack, New Jersey, United States

Duke University Medical Center

Durham, North Carolina, United States

...and 10 more locations

Hematologic Counts (Platelets (Blood), Neutrophils (Blood))

Individual Platelets (PLT) and neutrophil counts were summarized for all participants.

Time frame: Week 12, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234

Hematologic Counts (Hemoglobin (Blood))

Individual hemoglobin (Hgb) counts were summarized for all participants.

Time frame: Week 12, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234

Number of Red Blood Cells (RBC) Transfusions

Number of transfusions during the treatment period refers to total number of RBC transfusions participants have received while on treatment.