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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

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ClinicalTrials.gov Identifier: NCT03025698
Recruitment Status : Recruiting
First Posted : January 19, 2017
Last Update Posted : May 21, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:

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 or disease Intervention/treatment Phase
Aplastic Anemia Drug: Eltrombopag Drug: hATG Drug: CsA Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 11, 2017
Estimated Primary Completion Date : August 3, 2021
Estimated Study Completion Date : April 1, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Eltrombopag

Arm Intervention/treatment
Experimental: Cohort A (Option 1) Drug: Eltrombopag
Tablet for oral use, 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

Experimental: Cohort A (option 2) Drug: Eltrombopag
Tablet for oral use, once daily

Drug: CsA
Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day

Experimental: Cohort B Drug: Eltrombopag
Tablet for oral use, 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




Primary Outcome Measures :
  1. Eltrombopag PK parameter: AUCtau [ Time Frame: 2 weeks and 12 weeks after dose initiation ]
  2. Eltrombopag PK parameter: Cmax [ Time Frame: 2 weeks and 12 weeks after dose initiation ]
  3. Eltrombopag PK parameter: Ctrough [ Time Frame: 2 weeks and 12 weeks after dose initiation ]

Secondary Outcome Measures :
  1. Percentage of participants with an overall response (OR) [ Time Frame: Week 12, Week 26, Week 52, and Week 78. ]
  2. Percentage of participants with a platelet response. [ Time Frame: Week 12, Week 26, Week 52, and Week 78. ]
  3. Incidence of clonal chromosomal population in bone marrow, myelodysplasia by morphology or acute leukemia [ Time Frame: Week 12, Week 26, Week 52 and Week 78. ]


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Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

For Cohort A:

  1. Prior history of diagnosis of SAA
  2. Diagnosis of relapsed/refractory SAA or recurrent AA following IST for SAA at the time of enrollment. Patients with recurrent AA (e.g., losing their response) are exempt from meeting the diagnostic criteria for relapsed SAA at the time of enrollment, but must have been previously diagnosed with SAA.
  3. Agree to concurrent eltrombopag treatment with appropriate, investigator-selected IST with either hATG + CsA or CsA.

    For Cohort B:

  4. Diagnosis of SAA at the time of enrollment
  5. Patients must not have been previously treated for SAA
  6. Patients must agree to treatment with hATG + CsA concurrent with eltrombopag.

    For all patients, regardless of cohort:

  7. Age 1 to <18 years
  8. Where appropriate, 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.
  9. Hematopoietic stem cell transplantation (HSCT) is not available or suitable as a treatment option or has been refused by the patient. (Candidacy for HSCT will be determined as per local practice.)
  10. Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag
  11. Normal karyotype with FISH for chromosomes 7 and 8
  12. Performance status score: Karnofsky ≥50 or Lansky ≥50 (depending on age)
  13. Serum creatinine ≤2.5 × ULN
  14. Total bilirubin ≤1.5 × ULN
  15. Written informed consent signed by a parent or legal guardian prior to initiation of any study specific procedure.

Exclusion Criteria:

  1. Prior and/or active medical history of:

    • Fanconi anemia (via chromosomal breakage test or growth arrest by flow cytometry)
    • Other known underlying congenital/inherited marrow failure syndromes
    • Symptomatic Paroxysmal Nocturnal Hemoglobinuria (PNH) and/or PNH clones >50% of PMN or RBC at time of enrollment
    • Any cytogenetic abnormalities, including but not limited to chromosome 7 or myelodysplasia, in bone marrow within 4 weeks of study enrollment
    • Myelodysplastic syndrome (MDS)
    • Other known or suspected underlying primary immunodeficiency
    • Any malignancy
  2. Active infection not responding to appropriate therapy
  3. Prior eltrombopag or other thrombopoietin receptor (TPO-R) agonist treatment for at least 2 months and a lack of response.
  4. Any out of range lab values Creatinine >2.5 × upper limit of normal (ULN), Total bilirubin >1.5 × ULN Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × ULN

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03025698


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com

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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03025698     History of Changes
Other Study ID Numbers: CETB115E2201
First Posted: January 19, 2017    Key Record Dates
Last Update Posted: May 21, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Eltrombopag
hATG
CsA
previously untreated or relapsed severe aplastic anemia
recurrent aplastic anemia
Severe aplastic anemia
Pharmacokinetics
Immunosuppressive therapy
ETB115

Additional relevant MeSH terms:
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Anemia
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases