ActivePhase 2ACTRN12619001043123

Avatrombopag in Relapsed or Refractory Severe Aplastic Anaemia – a Bayesian Optimal Phase II study

Avatrombopag iN Relapsed or Refractory severe Aplastic Anaemia as EXtra Therapy – a Bayesian Optimal Phase II study

Sponsor

Monash University

Enrollment

55 participants

Start Date

Oct 22, 2019

Study Type

Interventional

Conditions

Refractory/relapsed severe aplastic anaemia

Summary

Severe aplastic anaemia is a rare disease where current standard upfront treatment is immunosuppressive therapy (IST) in those ineligible for haematopoietic stem cell transplant (HSCT). Approximately 20% of patients with severe AA are refractory to IST and another third of patients will relapse within two 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 to severe AA patients relapsed or refractory to IST to determine if the rate of production of platelets, red blood cells and white blood cells is increased.

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria13

Refractory severe aplastic anaemia with an incomplete response following at least one course of horse or rabbit ATG given greater than 6 months ago. Incomplete response defined as any one of the following:
o Absolute neutrophil count <0.5 x10^9/L
o Platelet count <20 x 10^9/L
o Absolute reticulocyte count <60 x 10^9/L or ongoing requirement for red cell transfusion support (if not due to independent medical condition)
OR
Relapsed severe aplastic anaemia, defined as the occurrence of any of the following, after a haematological response to a prior course of horse or rabbit ATG given greater than 6 months ago:
meeting again the criteria for SAA
requirement for transfusion support (if not due to independent medical conditions)
decrease in any of the peripheral blood counts as follows
absolute neutrophils < 0.5 x 10^9/L
platelets <20 x 10^9/L
Age >18
Negative pregnancy test for women of child bearing potential

Exclusion Criteria9

Evidence of a myelodysplastic syndrome, defined according to the World Health Organization 2017 criteria. Patients with AA with cytogenetic abnormalities, which 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.
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
Cancer diagnosis within the last 5 years (except for patients with resected basal cell carcinoma or squamous cell carcinoma of the skin)
Previous history of melanoma
Pregnant or breast feeding patients2
Participants with known hypersensitivity to avatrombopag
Severe renal impairment (defined as creatinine clearance =30m/min)
Treatment with horse or rabbit ATG within 6 months of trial entry. Concurrent treatment with Cyclosporine A is permitted.
Death anticipated within 14 days

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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.