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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 : September 16, 2021
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 : 51 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 : September 30, 2017
Estimated Primary Completion Date : May 24, 2022
Estimated Study Completion Date : May 26, 2025

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 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

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




Primary Outcome Measures :
  1. Eltrombopag PK parameter: AUCtau [ Time Frame: 2 weeks and 11 weeks after dose initiation ]
  2. Eltrombopag PK parameter: Cmax [ Time Frame: 2 weeks and 11 weeks after dose initiation ]
  3. Eltrombopag PK parameter: Ctrough [ Time Frame: 2 weeks and 11 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. ]


Information from the National Library of Medicine

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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

Inclusion Criteria:

For Cohort A patients:

  1. History of prior diagnosis of SAA,
  2. 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.
  3. Agree to concurrent eltrombopag treatment with appropriate, investigator-selected IST with either hATG + CsA or CsA.

    For Cohort B patients:

  4. Diagnosis of SAA at time of enrollment.
  5. Patients must not have been previously treated with IST, and must meet all criteria as described in Table 5-1.
  6. 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:

  7. Age 1 to <18 years.
  8. 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 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.)
  10. 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.

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

Locations
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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    
Other Study ID Numbers: CETB115E2201
First Posted: January 19, 2017    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: September 2021
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 Failure Disorders
Bone Marrow Diseases