abstracts 1

ChemGenex¡¯s Omacetaxine to be Showcased in Three Oral Presentations at EHA

http://www.eventure-online.com/eventure/publicAbstractView.do?id=101706

Background: Omacetaxine (formally homoharringtonine, HHT), a first-in-class cetaxine, shows clinical activity against Ph+ CML with a mechanism independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have no activity against T315I.

Aims: To evaluate the safety and efficacy of omacetaxine in Ph+ CML Pts with chronic (CP), accelerated (AP), or blast phase (BP) disease who have failed imatinib and have the T315I mutation.

Methods: Adult CML Pts who have failed imatinib and harbor the T315I kinase domain mutation are enrolled. All patients receive informed consent and then omacetaxine induction at 1.25 mg/m2 subcutaneous (SC) twice daily (BID) for 14 days every 28 days followed by maintenance at 1.25 mg/m2 SC BID for 7 days every 28 days. Maintenance therapy begins after at least one induction cycle and achievement of initial haematologic response.

Results: 69 Pts (40 CP, 16 AP and 13 BP) have been enrolled. All had failed prior imatinib and 80% failed ¡Ý 2 prior TKIs. Median age is 58 years. Median disease duration is 58 months. Omacetaxine is well tolerated with transient myelosuppression as the primary toxicity. Treatment-related grade 3/4 events occurring in ¡Ý10% of patients are: thrombocytopenia (48%), anaemia (30%), neutropenia (28%), and neutropenic fever (12%). Non-haematologic grade 3/4 events are rare with diarrhea (2%) and fatigue (3%) as the most frequently reported. Injection site reactions are mild with only grade 1/2 events reported and erythema the only event reported in > 10% of Pts (13.1%). Efficacy data are available for 47 Pts (28 CP, 11 AP, and 8 BP). In CP Pts, the median number of cycles is 4 (1-25) with 39% having received ¡Ý 6 cycles of therapy. The overall CP Pt complete haematologic response (CHR) rate is 82% with a median duration of response of 8.7 months (2.1 to 28.7+) and an overall cytogenetic response (CyR) rate of 25% (4 complete, 1 partial, 2 minimal). Six CP patients entered the study in CHR and maintained their response for at least 8 weeks to be considered responders. In AP Pts, the overall haematologic response rate is 45% (2 CHR, 1 haematologic improvement, 1 return to chronic phase [RCP]) with a median duration of response of 9.7 months (8.3-10.9+) and an overall CyR rate of 9% (1 minimal response). In BP Pts, the overall haematologic response rate is 13% (1 RCP) with no cytogenetic responses observed. For progression free survival (PFS), progression is defined as the development of advanced disease or death and in CP Pts, the loss of CHR or major CyR. In CP Pts, PFS is 80% at 1 year and 70% at 2 years; in AP Pts, PFS is 25% at 1 year and 18 months; In BP Pts, PFS is 44% at 6 months. In 64% of Pts, the T315I clone is reduced to below detection limits.

Conclusions: Omacetaxine in CML patients who have the T315I mutation results in de-selection of the T315I clone, induces durable haematologic and cytogenetic responses, and results in meaningful progression free survival.