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

• Percentage of Participants Achieving a Clinical Response by Subpopulation [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
  Subpopulations reflect chronic myeloid leukemia (CML) phases: chronic, accelerated, and blast phase.
• Participants with Adverse Events by Subpopulation [ Time Frame: up to 3 years ] [ Designated as safety issue: Yes ]
  Subpopulations reflect chronic myeloid leukemia (CML) phases: chronic, accelerated, and blast phase.

• Participants' Degree of Suppression of the Philadelphia Chromosome (Ph) [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
• Participants' Degree of Suppression of BCR-ABL transcript levels [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
• Percentage of Participants Who Showed a Hematological Improvement [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
• Percentage of CML Participants with Accelerated or Blast Phase Who Return to Chronic Phase [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
• Percentage of CML Participants with Accelerated or Blast Phase Who Show No Evidence of Leukemia [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
• Percentage of Participants with Extramedullary Disease (EMD) at Baseline Who Achieve a Clinical Response [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
• Percentage of Participants Who Had a Significant Reduction of the Proportion of T315I Mutated BCR-ABL [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
• The Number of Induction Cycles to Achieve a Clinical Response [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
• Time to Response [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
• Duration of Response [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
• Time to disease progression [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
• Overall Survival [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

To evaluate the safety and efficacy of subcutaneous administration of omacetaxine mepesuccinate (HHT) in achieving a clinical response in CML patients in chronic, accelerated, or blast phase who have failed prior imatinib therapy and have the T315I kinase domain 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

• Cephalon
• ChemGenex Pharmaceuticals