Eltrombopag With Standard Immunosuppression for Severe Aplastic Anemia

NCT ID: NCT01623167

Last Updated: 2025-03-11

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 207 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-02
• Study Completion Date: 2029-11-30

Brief Summary

Background:

• Severe aplastic anemia is a rare and serious blood disorder. It happens when the immune system starts to attack the bone marrow cells. This causes the bone marrow to stop making red blood cells, platelets, and white blood cells. Standard treatment for this disease is horse-ATG and cyclosporine, which suppress the immune system and stop it from attacking the bone marrow. However, this treatment does not work in all people. Some people still have poor blood cell counts even after treatment.
• Eltrombopag is a drug designed to mimic a protein in the body called thrombopoietin. It helps the body to make more platelets. It may also cause the body to make more red and white blood cells. Studies have shown that eltrombopag may be useful when added to standard treatment for severe aplastic anemia. It may help improve poor blood cell counts.

Objectives:

• To test the safety and effectiveness of adding eltrombopag to standard immunosuppressive therapy for severe aplastic anemia.

Eligibility:

• Individuals at least 2 years of age who have severe aplastic anemia that has not yet been treated.

Design:

• Participants will be screened with a physical exam, medical history, and blood tests. Blood and urine samples will be collected.
• Participants will start treatment with horse-ATG and cyclosporine. Treatment will be given according to the standard of care for the disease.
• Cohort 1: After 14 days, participants will start taking eltrombopag. They will take eltrombopag for up to 6 months.
• Cohort 2: After 14 days, participants will start taking eltrombopag. They will take eltrombopag for up to 3 months.
• Cohort 3 and Extension Cohort: Participants will start taking eltrombopag on Day 1. They will take eltrombopag for up to 6 months.
• Participants may receive other medications to prevent infections during treatment.
• Treatment will be monitored with frequent blood tests. Participants will also fill out questionnaires about their symptoms and their quality of life.

Detailed Description

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation offers the opportunity for cure in younger patients, but most are not suitable candidates for transplantation due to advanced age or lack of a histocompatible donor. Comparable long-term survival in SAA is attainable with immunosuppressive treatment with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA). However, of those patients treated with h-ATG/CsA, one quarter to one third will not respond, and 30-40% of responders relapse. The majority of the hematologic responses observed following initial h-ATG/CsA are partial, with only a few patients achieving normal blood counts. Furthermore, analysis of our own extensive clinical data suggests that poor blood count responses to a single course of ATG (non-robust responders), even when transfusion-independence is achieved, predicts a worse prognosis than when robust hematologic improvement is achieved (protocol 90-H-0146). The explanation for partial recovery and relapse are not fully understood, but incomplete elimination of auto-reactive T cells and insufficient stem cell reserve are both possible. Furthermore, 10-15% of SAA patients treated with standard immunosuppression will develop an abnormal karyotype in follow-up, with monosomy 7 being most common, which portends progression to myelodysplasia and leukemia. In contrast, malignant clonal evolution is rare in complete responders to immunosuppression. Although horse ATG/CsA represented a major advance in the treatment of SAA, refractoriness, incomplete responses, relapse, and clonal evolution limit the success of this modality. Thus, newer regimens are needed to address these limitations, and provide a better alternative to stem cell transplantation.

One approach to augment the quality of hematologic responses is to improve underlying stem cell function. Previous attempts to improve responses in SAA with hematopoietic cytokines including erythropoietin, G-CSF, and stem cell factor, have failed. Thrombopoietin (TPO) is the principal endogenous regulator of platelet production. In addition, TPO also has stimulatory effects on more primitive multilineage progenitors and stem cells in vitro and in animal models. Eltrombopag (Promacta ), an oral 2nd generation small molecule TPO-agonist, is currently approved for treatment of chronic immune thrombocytopenic purpura (ITP), chronic hepatitis C-associated thrombocytopenia, and severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. Eltrombopag increases platelets in healthy subjects and in thrombocytopenic patients with chronic ITP and hepatitis C virus (HCV) infection. Our Branch recently completed a pilot study of eltrombopag in refractory SAA. We saw encouraging clinical results in a cohort of patients who have failed on average two prior immunosuppressive regimens (Olnes et al. ASH Annual Meeting Abstracts, San Diego, CA, 2011, oral presentation and N Engl J Med 2012;367:11-9.1). Of the twenty-five SAA patients treated with eltrombopag by mouth for three months, eleven (44%) patients met protocol criteria of clinically meaningful hematologic responses, without significant toxicity. Nine patients demonstrated an improvement in thrombocytopenia (>20k/ L increase or transfusion independence), hemoglobin improved in two patients (>1.5g/dL or achieved transfusion independence, and four patients had a significant response in their neutrophil count. When responders continued the drug beyond three months, the hematologic response to eltrombopag increased; a trilineage response was observed in four patients, and a bilineage response occurred in another four, with median follow-up of 13 months. These results suggest that stem cell depletion, a major component of the pathophysiology of SAA, might be directly addressed by eltrombopag administration. The aim of the current study would be to improve the hematologic response rate and its quality, as well as prevent late complications such as relapse and clonal progression, by addition of eltrombopag to standard immunosuppressive therapy.

This trial will evaluate the safety and efficacy of combining eltrombopag with standard hATG/CSA as first line therapy in patients with SAA. The primary endpoint will be the rate of complete hematologic response at six months. Secondary endpoints are relapse, robust hematologic blood count recovery at 3, 6, and 12 months, survival, clonal evolution to myelodysplasia and leukemia, marrow stem cell content and hematological response of relapse patients that re-start treatment.

Conditions

Severe Aplastic Anemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1: hATG, CsA, EPAG Day 14 to Month 6

Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6

Group Type: EXPERIMENTAL

Cohort 1: hATG, CsA, EPAG Day 14 to Month 6

Intervention Type: DRUG

hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 6

Cohort 2: hATG, CsA, EPAG Day 14 to Month 3

Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3

Group Type: EXPERIMENTAL

Cohort 2: hATG, CsA, EPAG Day 14 to Month 3

Intervention Type: DRUG

hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 3

Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6

Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6

Group Type: EXPERIMENTAL

Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6

Intervention Type: DRUG

hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months at higher dose, then reduced dose for 18 months, eltrombopag (experimental) administered Day 1 to month 6

Extrension Cohort

Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6

Group Type: EXPERIMENTAL

Extension Cohort

Intervention Type: DRUG

Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6

Interventions

Cohort 1: hATG, CsA, EPAG Day 14 to Month 6

hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 6

Intervention Type: DRUG

Cohort 2: hATG, CsA, EPAG Day 14 to Month 3

hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 3

Intervention Type: DRUG

Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6

hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months at higher dose, then reduced dose for 18 months, eltrombopag (experimental) administered Day 1 to month 6

Intervention Type: DRUG

Extension Cohort

Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6

Intervention Type: DRUG

Other Intervention Names

Horse Antithymocyte Globulin, Cyclosporine, Promacta, Eltrombopag; Horse Antithymocyte Globulin, Cyclosporine, Promacta, Eltrombopag; Horse Antithymocyte Globulin, Cyclosporine, Promacta, Eltrombopag; Horse Antithymocyte Globulin (hATG), Cyclosporine (CsA), Promacta, Eltrombopag (EPAG)

Eligibility Criteria

Inclusion Criteria

1. Severe aplastic anemia characterized by Bone marrow cellularity less than 30 percent (excluding lymphocytes)

AND

At least two of the following:

• Absolute neutrophil count less than 500/microL
• Platelet count less than 20,000/microL

Absolute reticulocyte count less than 60,000/microL

2. Age greater than or equal to 2 years old

3. Weight greater than 12 kg

Exclusion Criteria

1. Known diagnosis of Fanconi anemia

2. Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study entry. Patients with super severe neutropenia (ANC less than 200 /microL) will not be excluded initially if cytogenetics are not available or pending. If evidence of a clonal disorder consistent with myelodysplasia is later identified, the patient will go off study.

3. Prior immunosuppressive therapy with any ATG, alemtuzumab, or high dose cyclophosphamide

4. SGOT or SGPT >5 times the upper limit of normal

5. Subjects with known liver cirrhosis in severity that would preclude tolerability of cyclosporine and eltrombopag as evidenced by albumin < 35g/L

6. Hypersensitivity to eltrombopag or its components

7. Infection not adequately responding to appropriate therapy

8. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy, or that death within 7-10 days is likely

9. Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible

10. Current pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during the course of this study

11. Inability to understand the investigational nature of the study or to give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 95 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis

INDUSTRY

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Neal S Young, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Heart, Lung, and Blood Institute (NHLBI)

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006 Oct 15;108(8):2509-19. doi: 10.1182/blood-2006-03-010777. Epub 2006 Jun 15.

Reference Type: BACKGROUND

PMID: 16778145 (View on PubMed)

Zoumbos NC, Gascon P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med. 1985 Jan 31;312(5):257-65. doi: 10.1056/NEJM198501313120501.

Reference Type: BACKGROUND

PMID: 2981406 (View on PubMed)

Young NS, Leonard E, Platanias L. Lymphocytes and lymphokines in aplastic anemia: pathogenic role and implications for pathogenesis. Blood Cells. 1987;13(1-2):87-100.

Reference Type: BACKGROUND

PMID: 3311225 (View on PubMed)

Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017 Apr 20;376(16):1540-1550. doi: 10.1056/NEJMoa1613878.

Reference Type: BACKGROUND

PMID: 28423296 (View on PubMed)

Zaimoku Y, Patel BA, Adams SD, Shalhoub R, Groarke EM, Lee AAC, Kajigaya S, Feng X, Rios OJ, Eager H, Alemu L, Quinones Raffo D, Wu CO, Flegel WA, Young NS. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia. Blood. 2021 Dec 30;138(26):2799-2809. doi: 10.1182/blood.2021012895.

Reference Type: DERIVED

PMID: 34724566 (View on PubMed)

Patel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O, Quinones Raffo D, Wu CO, Young NS. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022 Jan 6;139(1):34-43. doi: 10.1182/blood.2021012130.

Reference Type: DERIVED

PMID: 34525188 (View on PubMed)

Zaimoku Y, Patel BA, Shalhoub R, Groarke EM, Feng X, Wu CO, Young NS. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag. Haematologica. 2022 Jan 1;107(1):126-133. doi: 10.3324/haematol.2021.278413.

Reference Type: DERIVED

PMID: 33910334 (View on PubMed)

Groarke EM, Patel BA, Gutierrez-Rodrigues F, Rios O, Lotter J, Baldoni D, St Pierre A, Shalhoub R, Wu CO, Townsley DM, Young NS. Eltrombopag added to immunosuppression for children with treatment-naive severe aplastic anaemia. Br J Haematol. 2021 Feb;192(3):605-614. doi: 10.1111/bjh.17232. Epub 2021 Jan 7.

Reference Type: DERIVED

PMID: 33410523 (View on PubMed)

Giudice V, Wu Z, Kajigaya S, Fernandez Ibanez MDP, Rios O, Cheung F, Ito S, Young NS. Circulating S100A8 and S100A9 protein levels in plasma of patients with acquired aplastic anemia and myelodysplastic syndromes. Cytokine. 2019 Jan;113:462-465. doi: 10.1016/j.cyto.2018.06.025. Epub 2018 Jun 27.

Reference Type: DERIVED

PMID: 29958797 (View on PubMed)

Giudice V, Banaszak LG, Gutierrez-Rodrigues F, Kajigaya S, Panjwani R, Ibanez MDPF, Rios O, Bleck CK, Stempinski ES, Raffo DQ, Townsley DM, Young NS. Circulating exosomal microRNAs in acquired aplastic anemia and myelodysplastic syndromes. Haematologica. 2018 Jul;103(7):1150-1159. doi: 10.3324/haematol.2017.182824. Epub 2018 Apr 19.

Reference Type: DERIVED

PMID: 29674506 (View on PubMed)

Giudice V, Feng X, Lin Z, Hu W, Zhang F, Qiao W, Ibanez MDPF, Rios O, Young NS. Deep sequencing and flow cytometric characterization of expanded effector memory CD8+CD57+ T cells frequently reveals T-cell receptor Vbeta oligoclonality and CDR3 homology in acquired aplastic anemia. Haematologica. 2018 May;103(5):759-769. doi: 10.3324/haematol.2017.176701. Epub 2018 Feb 1.

Reference Type: DERIVED

PMID: 29419434 (View on PubMed)

Hosokawa K, Muranski P, Feng X, Keyvanfar K, Townsley DM, Dumitriu B, Chen J, Kajigaya S, Taylor JG, Hourigan CS, Barrett AJ, Young NS. Identification of novel microRNA signatures linked to acquired aplastic anemia. Haematologica. 2015 Dec;100(12):1534-45. doi: 10.3324/haematol.2015.126128. Epub 2015 Sep 9.

Reference Type: DERIVED

PMID: 26354756 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2012-H-0150.html

NIH Clinical Center Detailed Web Page

Other Identifiers

12-H-0150

Identifier Type: -

Identifier Source: secondary_id

120150

Identifier Type: -

Identifier Source: org_study_id