Clinical trial NCT00375219
Conditions: Chronic Myeloid Leukemia
Keywords: Chronic Myeloid Leukemia CML HHT Homoharringtonine Omacetaxine T315i ChemGenex ChemGenex Pharmaceuticals
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2006-09-20; Completion date: 2013-06-28
Enrollment: 103 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Treatment was the same for all cohorts: induction therapy was subcutaneous (SC) administration of omacetaxine at 1.25 mg/m\^2 twice a day (BID), administered for 14 consecutive days every 28 (±3) days for up to 6 cycles. Maintenance therapy was subcutaneous (SC) administration of omacetaxine at 1.25 mg/m\^2 twice a day (BID), administered for 7 consecutive days every 28 (±3) days for up to 3 years.
Interventions: intervention 1: Omacetaxine mepesuccinate
Intervention descriptions: intervention 1: Induction:

1.25 mg/m\^2 subcutaneously, twice daily for 14 consecutive days every 28 days until response. Patients not demonstrating evidence of clinical response after 6 induction cycles will be considered for removal from the study.

Maintenance:

1.25 mg/m\^2 subcutaneously, twice daily for 7 consecutive days in a 28-day cycle, for up to 3 years.

Protocol documents: