Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia

• Status: Active, not recruiting
• Trial end date: 2022-06-22
• Target enrollment: 0
• Participant gender: All

Summary

This interventional Phase II, single-arm, multicenter, open-label study will investigate the efficacy and safety of a combination regimen of 6 months eltrombopag and cyclosporine treatment in adult patients with severe aplastic anemia (SAA) as first line therapy, with an additional 18 months follow-up for cyclosporine tapering and duration of response until relapse or 24 months whichever is earlier (responders only who do not relapse prior to 6 months).

The usage of eltrombopag and cyclosporine combines two therapies with different modes of action. Cyclosporine acts as an immunosuppressant and eltrombopag acts as a stimulator of bone marrow progenitor cells. Given that SAA is currently viewed as having an autoimmune pathogenesis resulting in bone marrow progenitor cell destruction, the combination of eltrombopag and cyclosporine is attractive. Preliminary experience with their combined use appears favorable, with no untoward toxicity observed to date.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Novartis Pharmaceuticals
• Treatments: Cyclosporine; Cyclosporins

Criteria

Inclusion Criteria:

1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed.

2. Patient is male/female ≥18 years old at the time of informed consent and able to swallow a tablet.

3. Patient has SAA characterized by:

1. Bone marrow cellularity <30% (excluding lymphocytes) and

2. At least two of the following (peripheral blood):

• Absolute neutrophil count <500/µL

• Platelet count <20,000/µL

• Absolute reticulocyte count <60,000/µL

4. Normal ECG defined as the following as determined via the mean of a triplicate ECG

• Resting heart rate: 50-90 bpm

• QTcF at screening <450 msec (for male patients), ≤460 msec (for female patients)

Exclusion Criteria:

1. Diagnosis of Fanconi anemia.

2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central review

3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG and thrombopoietin receptor (TPO-R) agonists.

4. a. Hypersensitivity to eltrombopag or cyclosporine or their components. b. Contraindications to cyclospsorine.

5. AST or ALT >3 x ULN.

6. Serum creatinine, total bilirubin, or alkaline phosphatase >1.5 x ULN.

7. Patient with liver cirrhosis.

8. a. Infection not adequately controlled with appropriate therapy. b. Patients who are human immune deficiency virus (HIV), hepatitis C virus or hepatitis B surface antigen (HBsAg) positive. HCV-RNA negative patients are allowed to be enrolled.

9. 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 consent, be compliant with study procedures, tolerate protocol therapy, or that death within 30 days is likely.

10. Patients with cancer who are not considered cure, are on active chemotherapeutic treatment or who take drugs with hematological effects.

11. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

12. Pregnancy statements and contraception requirements:

Pregnancy or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant (or female partners of male patients), unless they are using highly effective methods of contraception during dosing and for 3 months after stopping medication.

13. Not able to understand the investigation nature of the study or to give informed consent.

14. Clinically significant ECG abnormality including cardiac arrhythmias (e. g. ventricular tachycardia) complete left bundle branch block, high grade atrioventricular block, or inability to determine the QTcF interval on the ECG.

15. Presence of cardiac disease, or family history of idiopathic sudden death or congenital long QT syndrome.

16. Risk factors for Torsades de Pointe including uncorrected hypokalemia or hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong the QT interval that cannot be discontinued or replaced by safe alternative medication per www.qtdrugs.org.

17. ECOG performance status of ≥2.

18. Patients under the age of 40 must be referred for consideration of allogeneic bone marrow transplantation (HSCT) if (human leukocyte antigen) HLA matching has been done and a suitable matched sibling donor is available and the patient is willing to undergo transplantation (i.e. patients who do not have a HLA match or are not medically fit, not willing or unable to undergo transplantation will be considered for enrollment).