A Three-part Study of Eltrombopag in Thrombocytopenic Subjects with Myelodysplastic Syndromes or Acute Myeloid Leukemia (Part 1: open-label, Part 2: randomized, double-blind, Part 3: extension).;ASPIRE: A Study of EltromboPag In Myelodysplastic SyndRomes and AcutE Myeloid Leukemia

The standard therapy for thrombocytopenia in patients with malignancies is
dependent upon the degree of thrombocytopenia, the cause and whether or not
bleeding is present. Guidelines recommend platelet transfusions if platelet
counts are <10Gi/L, or if an acute thrombocytopenic hemorrhage requires
immediate elevation in platelet counts. Patients with less severe
thrombocytopenia or without bleeding may be followed closely with a watch and
wait approach. If thrombocytopenia is due to acute chemotherapy, the next cycle
of chemotherapy may either be dose reduced or delayed until megakaryopoiesis
has recovered.
General limitations and risks associated with platelet transfusions include a
short-lived therapeutic effect (1-5 days) and mild to severe transfusion
reactions or the development of refractoriness to platelet transfusions.
Therefore, platelet transfusions are not a viable option to maintain platelet
counts sufficient to reduce hemorrhagic risk over time or to enable patients to
receive chemotherapy.
Eltrombopag olamine is an orally bioavailable, small molecule thrombopoietin
receptor agonist that is being studied in patients with medical disorders
associated with thrombocytopenia. It has been approved for the treatment of
chronic idiopathic thrombocytopenic purpura (ITP) in adults (after splenectomy
or if refractory for other treatments). In myelodysplastic syndrome (MDS) and
acute myeloid leukemia (AML), megakaryopoiesis can be impaired in both a
quantitative (lack of megakaryocytes), and qualitative way (increased apoptosis
in megakaryocytes from patients with MDS). Interestingly, increased apoptosis
of megakaryocytes has also been observed in ITP. Based on the pathophysiology
of thrombocytopenia in MDS and AML and based on eltrombopag*s known mechanism
of action, it is very likely that eltrombopag will be able to increase platelet
counts and reduce thrombocytopenic sequelae (platelet transfusions and
haemorrhages) in patients with MDS and AML.

Part 1 (open-label, 8 week): safety and tolerability of eltrombopag, optimal
dose escalation scheme for use in Part 2, PK.
Part 2:
Primary: the reduction in the number of clinically relevant thrombocytopenic
events (*Grade 3 hemorrhagic adverse events, or platelet counts <10 Gi/L, or
platelet transfusions).
Secondary: need for platelet transfusions, effects on hematologic improvement,
platelet counts, bleeding symptoms, disease progression, overall survival.
Safety and tolerability. Medical resource utilization. quality of life.
Population PK.
Part 3: Long-term durability of clinical benefit, safety and tolerability.
Overall survival.

Phase II study in 3 sequential parts. Subjects who complete the treatment
period for Part 1 or Part 2
may enter Part 3.

Part 1 (open-label): 6-10 patients, 8 weeks treatment with eltrombopag 100
mg/day. Dose escalation up to 300 mg/day allowed. Supportive care allowed, no
disease modifying treatment or chemotherapy.

Part 2 (randomized, double-blind): 140 patients, 12 weeks supportive care
randomisation (2:1) to eltrombopag or placebo. Start dose eltrombopag 100
mg/day. Dose escalation up to 300 mg/day allowed. No disease modifying
treatment or chemotherapy.

Part 3 (open-label extension study): All subjects will receive eltrombopag.
Supportive care allowed (incl. azacitidine, decitabine, lenalidomide and
chemotherapy).

Maximal duration approx. 1 year in total.

Note: Subjects who do not enter Part 3 will undergo weekly follow-up
assessments for 4 weeks following the last dose of study medication and monthly
assessments for survival for 1 year.

Treatment with eltrombopag (part 1 and 3) or eltrombopag or placebo (part 2).

Risk: Adverse effects of study medication. Supportive treatment accepted.
Burden: Part 1 and 2 weekly visits during 8 or 12 weeks resp.. Part 3: visits
every 1-2 weeks during rest of the year.
Every visit: pulse, BP and blood tests (10-30 ml/visit).
Physical examination and ECG: 2x during part 1 or 2 and end of study.
Pregnancy test (if relevant): 2x.
Bone marrow sample: if needed at baseline (if no recent sample available) and
every 3 months during part 3.
Questionnaires: quality of life: part 1 2x, part 2 every visit and during part
3 every 4 weeks.
Optional: pharmacogenetic research (1x 10 ml blood).