Omacetaxine May Benefit CML Patients With Resistant Disease

Roxanne Nelson

June 15, 2012

June 15, 2012 (Chicago, Illinois) — Omacetaxine mepesuccinate (Teva Pharmaceuticals), an investigational agent that is a first-in-class cephalotaxine, has shown promise in the treatment of resistant chronic myeloid leukemia (CML).

Three studies of omacetaxine were presented here at the 2012 Annual Meeting of the American Society of Clinical Oncology. Two studies demonstrated that it has activity in patients with chronic-phase and accelerated-phase CML who have become resistant to standard therapy, and a pooled analysis showed that it has an acceptable safety profile in patients in all phases of CML.

A New Drug Application submitted to the US Food and Drug Administration was recently accepted for review.

Omacetaxine is a protein synthesis inhibitor and is not dependent on Bcr-Abl signaling. It has a different mechanism of action from other CML drugs (such as imatinib, nilotinib, and dasatinib), which are tyrosine kinase inhibitors (TKIs), explained Neil Shah, MD, PhD, assistant professor of medicine at the University of California, San Francisco, during a poster discussion.

Omacetaxine is not a TKI, but it looks like it might potentiate TKIs, he said. Although it has some efficacy in the treatment of CML, the activity is "rather modest and not as high as we had hoped," said Dr. Shah.

Clinical activity has been demonstrated in 2 phase 2 open-label multicenter studies of patients with treatment-resistant CML who had failed previous therapy with at least imatinib; many were also resistant to or intolerant of dasatinib and/or nilotinib.

Responses in Chronic-Phase CML

One of the studies presented (abstract 6596), led by Luke Akard, MD, from Indiana Blood and Marrow Transplantation in Indianapolis, used a subset of data from the 2 phase 2 studies. The cohort consisted of 81 patients with chronic-phase CML who were resistant (n = 69) to at least 2 TKIs, intolerant to at least 2 TKIs (n = 7), or resistant to one TKI and intolerant of another TKI (n = 5).

The patients received omacetaxine 1.25 mg/m² subcutaneously twice daily for 14 or fewer consecutive days during a 28-day cycle for induction therapy, and for 7 or fewer days per cycle as maintenance therapy.

A major cytogenetic response was achieved by 13 (19%) patients in the resistant group, 2 (29%) patients in the intolerant group, and 1 (20%) patient in the resistant/intolerant group.

Median overall survival was 33.9 months in the resistant group, 25.0 months in the resistant/intolerant group, and not reached in the intolerant group.

Treatment-related grade 3/4 adverse events were reported by 66 (81%) patients. The most common of these were thrombocytopenia and neutropenia, and 15 patients had events that warranted discontinuation of treatment. There were 9 deaths in the cohort, primarily related to disease progression and sepsis.

Responses in Both Chronic- and Accelerated-Phase CML

Another of the studies presented (abstract 6513) evaluated omacetaxine in heavily pretreated patients with either chronic- or accelerated-phase CML. This study also used a subset of patients from the 2 phase 2 studies, and was led by Franck E. Nicolini, MD, PhD, from the Hôpital Edouard Herriot in Lyon, France.

The study involved 122 patients; 62 were previously treated with 2 TKIs (100% had received imatinib, 76% dasatinib, and 24% nilotinib) and 60 were previously treated with all 3 approved TKIs. In addition, a large percentage of patients were previously treated with non-TKI therapies (e.g., 52% had received hydroxyurea and 34% interferon).

Of the 45 patients with chronic-phase CML previously treated with 2 TKIs, 12 (27%) achieved major cytogenetic response, as did 4 (11%) of the 36 patients previously treated with 3 TKIs.

For the 17 patients with accelerated-phase CML previously treated with 2 TKIs, 6 (35%) had major hematologic response, as did 5 (21%) of the 24 patients previously treated with 3 TKIs.

Grade 3/4 adverse events were observed in 52 (84%) patients previously treated with 2 TKIs and in 42 (70%) previously treated with 3 TKIs. The most common event was thrombocytopenia (71% and 48%, respectively).

Pooled Safety Results

In the third study presented (abstract 6604), Meir Wetzler, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues pooled tolerability data from 2 phase 2 open-label studies and a pilot study. All 207 patients had demonstrated resistance or intolerance to previous therapy with the currently approved TKIs. Median age in the cohort was 57 years, which consisted of 108 patients with chronic-phase CML, 55 with accelerated-phase CML, and 44 with blast-phase CML.

According to the abstract, in the "largest safety analysis to date," treatment with subcutaneous omacetaxine 1.25 mg/m² had an acceptable safety profile in all phases of CML. Patients received a median of 4 cycles of treatment (range, 1 to 41); 80% of patients reported at least 1 hematologic adverse event, 60% reported a serious adverse event, 30% reported a hematologic adverse event, 34% reported an event that required hospitalization, and 15% discontinued treatment because of a serious adverse event.

Overall, there were 49 (24%) deaths (15 in the chronic phase, 11 in the accelerated phase, and 23 in the blast phase). The most common adverse events were thrombocytopenia (60%), anemia (51%), diarrhea (40%), neutropenia (37%), and nausea (30%). Injection-site reactions (e.g., pain, erythema) occurred in 32%, but the majority were low grade. Infections (including pneumonia and bronchitis) occurred in 51%. There were 34 (16%) grade 3/4 infections.

"For patients who have failed previous TKI therapies and currently have limited treatment options beyond the third-line setting, a treatment with a different mechanism of action may be an option," said Jorge Cortes, MD, chair of the CML section in the Department of Leukemia at the M.D. Anderson Cancer Center, in a statement. Dr. Cortes participated in all 3 studies.

The studies were all supported by Teva Pharmaceutical Industries Ltd. A number of the researchers report financial relationships, as indicated in the abstracts.

2012 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract 6513, presented June 1, 2012; Abstracts 6596 and 6604, presented June 4, 2012.

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