None listed
Conditions
Brief summary
Severe aplastic anaemia is a rare disease where current standard upfront treatment for patients ineligible for haematopoietic stem cell transplant (HSCT) is immunosuppressive therapy (IST). Although patients with severe AA treated with IST (horse antithymocyte globulin [ATG] and CyA) have overall responses reported in 50-75%, the minority achieve complete responses, approximately 20% are refractory to IST and approximately 30% will relapse by 2 years. Partial or no response to IST leaves patients at ongoing risk of life-threatening complications of AA such as infections, haemorrhage and patients will require ongoing supportive treatments such as antibiotics, red blood cell and platelet transfusions, to combat these complications. Eltrombopag is a thrombopoietin (TPO) mimetic and has shown promising efficacy for severe AA in phase II trials. Avatrombopag is a second generation TPO mimetic which has been studied in immune thrombocytopenia and thrombocytopenia due to chronic liver disease. It has several potential advantages over eltrombopag, including dosing, lack of toxicities, pharmacokinetics and potential increased potency. Avatrombopag has not been tested in AA to date. In this study, avatrombopag will be given in addition to standard IST to treatment naive severe AA patients to determine if the rate of production of platelets, red blood cells and white blood cells is increased.
Interventions
Avatrombopag will be administered by an oral tablet, maximum dose of 60 mg per day for up to 180 days. Dose will be adjusted every 2 weeks guided by reticulocyte count, platelet count/platelet transfusion and neutrophil count. Eligibility for extended therapy is based on hematological response at 6 months (180 days): • Avatrombopag will be continued up to 12 months, at the same dose, in participants achieving partial response (PR) at 6 months; • Avatrombopag will be discontinued in all patients achieving complete response (CR) at 6 months • Avatrombopag will be discontinued in all patients achieving no response (NR) at 6 months The extended duration of avatrombopag will be for a further 6 months. Participants who achieve a CR at the completion of 180 days and subsequently relapse within 6 months of discontinuation (defined as no longer meeting criteria of CR) will be able to request extended duration for a further 6 months. The local PI or delegate will be responsible for identifying qualifying participants Titration of avatrombopag will be based on FBE/reticulocyte counts which will be measured at time point, day 14, month 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5.
Sponsors
Monash University
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Severe or very severe aplastic anaemia characterised by bone marrow cellularity <30% (excluding lymphocytes) and at least two of the following: a. Absolute neutrophil count <0.5 x10^9/L b. Platelet count <20 x 10^9/L c. Absolute reticulocyte count <60 x 10^9/L 2. No prior ATG-based immunosuppressive therapy 3. Age >18 years 4. Negative pregnancy test for women of child bearing potential
Exclusion criteria
1. Planned for a sibling allogeneic stem cell transplant 2. Evidence of a myelodysplastic syndrome, defined according to the World Health Organization 2017 criteria. Patients with AA with cytogenetic abnormalities that are recurrent in MDS, who do not meet the WHO diagnostic criteria for MDS, are also excluded. Patients with del(20q), +8 and –Y are not included in this category and are therefore eligible for this trial. 3. Known diagnosis or clinical suspicion of inherited bone marrow failure syndrome (IBMFS), including but not limited to Fanconi Anaemia, Dyskeratosis Congenita, Shwachman-Diamond Syndrome and Diamond-Blackfan Anaemia 4. Previous history of stem cell transplantation 5. Cancer diagnosis within the last 5 years (except for patients with resected basal cell carcinoma or squamous cell carcinoma of the skin) 6. Previous history of melanoma 7. Pregnant or breast feeding patients2,3 8. Active CMV disease 9. Participants with known hypersensitivity to any of the component medications (avatrombopag, cyclosporine, horse or rabbit ATG) 10. Concurrent hepatic, renal or cardiac disease of such severity that it would in the investigator’s opinion, preclude the patient’s ability to tolerate protocol therapy 11. Death anticipated within 14 days
Outcome results
None listed