Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation

Point mutations within the ABL kinase domain of the BCR-ABL gene are emerging as the most
frequent mechanism for resistance to imatinib and resultant reactivation of kinase activity.
The risk of mutation development is particularly high in patients who are beyond chronic
phase, as well as those with a long duration of disease prior to imatinib therapy.

The T315I kinase domain (KD) point mutation has merited particular attention, as T315I
expressing CML cells are markedly resistant to imatinib. CML patients with the T315I KD
mutation, therefore, do not respond to continued treatment with imatinib, and preliminary
clinical data indicate that neither of two newer tyrosine kinase inhibitors will have
activity in patients with T315I KD mutation either.

Omacetaxine mepesuccinate (HHT) is a potent inducer of apoptosis (programmed cell death) in
myeloid cells and inhibits angiogenesis (blood vessel formation). In Phase 2 studies, HHT has
demonstrated clinical activity in patients with CML, both as a single agent and
in-combination with other chemotherapeutic drugs. HHT works via a different mechanism than
imatinib or other tyrosine kinase inhibitors (TKI's), and HHT has been shown to inhibit in
vitro CML cell lines which harbor the T315I KD mutation and are highly resistant to imatinib.
Therefore, CML patients who have the T315I KD mutation may still respond to treatment with
HHT. HHT may therefore be an attractive therapeutic option for patients with the T315I KD
mutation.

On this basis, a multicenter clinical trial is being conducted of HHT therapy for CML
patients who have failed prior imatinib therapy and have the T315I KD mutation.

Patients will be treated with an induction course consisting of subcutaneous (SC) HHT twice
daily for 14 consecutive days every 28 days. Patients who demonstrate a response, may receive
maintenance therapy for up to 24 months, consisting of subcutaneous (SC) HHT twice daily for
7 days every 28 days.

Inclusion Criteria:

- Male or female patients, age 18 years or older

- Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic,
accelerated, or blast phase

- The patient will have the T315I BCR-ABL gene mutation

- Patients will have failed prior imatinib therapy

- ECOG performance status 0-2

Exclusion Criteria:

- NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac
condition such as angina pectoris, clinically significant cardiac arrhythmia and
requiring therapy, uncontrolled hypertension or congestive heart failure

- Myocardial infarction in the previous 12 weeks

- Lymphoid Ph+ blast crisis