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

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

ClinicalTrials.gov Identifier: NCT03025698

Novartis Reference Number: CETB115E2201

Last Update: Dec 11, 2020

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study Description

This is a phase II, open label, multi-center, intra-patient dose escalation study to characterize the pharmacokinetics 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.

All patients will be treated with eltrombopag for the 26-week Treatment Period, followed by a 52-week Follow-Up Period. Patients who have been previously untreated with immunosuppressive therapy will be treated according to the standard of care, hATG/cyclosporine, in addition to eltrombopag. Patients with relapsed/refractory SAA or recurrent AA will be enrolled into one of two treatment options: hATG/cyclosporine plus eltrombopag or cyclosporine plus eltrombopag, depending on prior treatment with immunosuppressive therapy.

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

Upon completion of the Treatment and Follow-Up Periods, all patients will be offered the opportunity to enroll in an additional 3 year Long Term Follow-Up Period.

Condition 
Aplastic Anemia
Phase 
Phase 2
Overall status 
Recruiting
Enrollment count 
60 participants
Start date 
Sep 30, 2017
Completion date 
Aug 31, 2027
Gender 
All
Age(s)
1 Years - 18 Years (Child, Adult)

Interventions

Drug
Eltrombopag
Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily
Drug
hATG
Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP)
Drug
CsA
Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day

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 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.

12. Performance status score: Karnofsky ≥50 for patients 16 years of age and older or Lansky ≥50 for patients below 16 years of age.

15. Written informed consent must be signed by a parent or legal guardian prior to initiation of any study specific procedure.

16. 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:

2. 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 WBC or RBC at time of enrollment.
Any cytogenetic abnormalities by karyotyping or FISH.
Myelodysplastic syndrome (MDS)
Other known or suspected underlying primary immunodeficiency

Any malignancy 3. Active infection not responding to appropriate therapy. 4. Prior eltrombopag or other thrombopoietin receptor (TPO-R) agonist treatment for at least 2 months and a lack of response.

5. 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. 6. 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.

Study Locations

United States
Phoenix Children's Hospital SC
Recruiting
Phoenix, 85016
Arizona
United States
Arkansas Childrens Hospital SC
Recruiting
Little Rock, 72202
Arkansas
United States
University of California-UCSF SC
Recruiting
San Francisco, 94143-0780
California
United States
Childrens Hospital Colorado
Recruiting
Aurora, 80045
Colorado
United States
University of Florida Shands SC
Recruiting
Gainesville, 32610-0486
Florida
United States
Aflac Cancer and Blood Disorders Center
Recruiting
Atlanta, 30342
Georgia
United States
Ann and Robert H Lurie Childrens Hospital of Chicago SC
Recruiting
Chicago, 60611
Illinois
United States
Indiana University SC Riley Children's Hospital
Completed
Indianapolis, 46202-5225
Indiana
United States
Childrens Hospital of Boston SC
Active, not recruiting
Boston, 02115
Massachusetts
United States
University of Michigan Health System SC
Completed
Ann Arbor, 48109
Michigan
United States
Hackensack University Medical Center SC-2
Completed
Hackensack, 07601
New Jersey
United States
Levine Childrens Hospital
Recruiting
Charlotte, 28203
North Carolina
United States
Duke University Medical Center SC
Recruiting
Durham, 27710
North Carolina
United States
Cleveland Clinic Cleveland Clinic (5)
Completed
Cleveland, 44195
Ohio
United States
Nationwide Childrens Hospital SC
Recruiting
Columbus, 43205
Ohio
United States
Childrens Hospital of Philadelphia SC-2
Recruiting
Philadelphia, 19104 4399
Pennsylvania
United States
University of Pittsburg School of Medicines
Recruiting
Pittsburgh, 15213
Pennsylvania
United States
Prisma Health Childrens Hospital
Recruiting
Greenville, 29605
South Carolina
United States
University of Texas Southwestern Medical Center SC
Recruiting
Dallas, 75390
Texas
United States
Texas Children's Cancer and Hematology Center SC
Recruiting
Houston, 77030
Texas
United States
Seattle Childrens Hospital
Withdrawn
Seattle, 98105
Washington
United States
University of Wisconsin Hospital SC
Recruiting
Madison, 53792
Wisconsin
United States
Hong Kong
Novartis Investigative Site
Recruiting
Shatin,
-
Hong Kong
Netherlands
Novartis Investigative Site
Recruiting
Utrecht, 3584
CS
Netherlands
Portugal
Novartis Investigative Site
Recruiting
Lisboa, 1649-035
-
Portugal
Novartis Investigative Site
Recruiting
Porto, 4099-001
-
Portugal
Novartis Investigative Site
Recruiting
Porto, 4200 319
-
Portugal
Russian Federation
Novartis Investigative Site
Withdrawn
Chelyabinsk, 454076
-
Russian Federation
Novartis Investigative Site
Active, not recruiting
Moscow, 117198
-
Russian Federation
Novartis Investigative Site
Active, not recruiting
Sain Petersburg, 197022
-
Russian Federation
Thailand
Novartis Investigative Site
Recruiting
Bangkok noi, 10700
Bangkok
Thailand
Novartis Investigative Site
Recruiting
Khon Kaen, 40002
THA
Thailand
Novartis Investigative Site
Recruiting
Bangkok, 10400
-
Thailand
United Kingdom
Novartis Investigative Site
Recruiting
London, WC1N 3JH
-
United Kingdom
Novartis Investigative Site
Recruiting
Manchester, M13 9WL
-
United Kingdom

Contacts

Name: 
Novartis Pharmaceuticals
Phone: 
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Novartis Pharmaceuticals
Phone: 

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