In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On October 26, 2012, the FDA granted accelerated approval to omacetaxine mepesuccinate (Synribo) for the treatment of adult patients with chronic phase or accelerated phase chronic myeloid leukemia (CML) with resistance or intolerance to two or more tyrosine kinase inhibitors.1,2 The decision was based on response rates. As yet, there are no trials verifying an improvement in disease-related symptoms or increased survival with omacetaxine.
Approval was based on findings in a combined cohort of adult patients with CML from two trials.1–3 All patients had received two or more approved tyrosine kinse inhibitors and had evidence of resistance or intolerance to dasatinib (Sprycel) or nilotinib (Tasigna). Patients with New York Heart Association class III or IV heart disease, active ischemia, or other uncontrolled cardiac conditions were excluded from the studies.
Patients received subcutaneous omacetaxine at 1.25 mg/m2 twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients received the same dose for 7 consecutive days every 28 days (maintenance cycle). Patients could receive maintenance treatment for up to 24 months.
Among 76 patients with chronic phase CML, median age was 59 years, 62% were male, 30% were aged ≥ 65 years, and 80% were Caucasian; in 47%, treatment with imatinib (Gleevec), dasatinib, and nilotinib had failed, and most had received prior non–tyrosine kinase inhibitor treatments, most commonly hydroxyurea (54%), interferon (30%), and cytarabine (29%). A major cytogenetic response occurred in 14 patients (18.4%, 95% confidence interval [CI] = 10.5%–29.0%). Among patients with major cytogenetic response, mean time to onset was 3.5 months and median response duration was 12.5 months.
Among 35 patients with accelerated phase CML, median age was 63 years, 57% were male, 46% were aged ≥ 65 years, and 68% were Caucasian (23% African American); 63% had failed treatment with imatinib, dasatinib, and nilotinib and most had received prior non–tyrosine kinase inhibitor treatments, most commonly hydroxyurea (43%), interferon (31%), and cytarabine (29%). Major hematologic response occurred in 5 patients (14.3%, 95% CI = 4.5%–30.3%); none of the patients had a major cytogenetic response. Among patients with major hematologic response, mean time to onset was 2.3 months and median duration of response was 4.7 months.
How It Works
The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated, but it includes inhibition of protein synthesis and activity that is independent of direct Bcr-Abl binding. It binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria.
The agent was found to have activity in CML patients in the pre–tyrosine kinase inhibitor era. In vitro, omacetaxine reduces levels of the Bcr-Abl oncoprotein and Mcl-1, an antiapoptotic Bcl-2 family member, and its activity is not affected by presence of Bcr-Abl mutations. It has exhibited activity in mouse models of wild-type and T315I mutant Bcr-Abl CML and in CML patients with the T315I mutation.
How It Is Given
Omacetaxine is given at an induction dose of 1.25 mg/m2 via subcutaneous injection twice daily for 14 consecutive days of a 28-day cycle; cycles should be repeated every 28 days until patients achieve a hematologic response. The recommended maintenance dose is 1.25 mg/m2 via subcutaneous injection twice daily for 7 consecutive days of a 28-day cycle. Treatment should continue for as long as clinical benefit is observed.
Treatment cycles may be delayed or the number of days of dosing during the cycle reduced for hematologic toxicities (eg, neutropenia, thrombocytopenia). Complete blood counts should be performed weekly during induction and initial maintenance cycles. After initial maintenance cycles, complete blood counts should be monitored every 2 weeks or as clinically indicated. In patients experiencing grade 4 neutropenia or grade 3 thrombocytopenia, the next cycle should be delayed until the absolute neutrophil count is ≥ 1.0 × 109/L and platelet count is ≥ 50 × 109/L, and the number of dosing days in the next cycle should be reduced by 2 (ie, to 12 or 5 days).
Safety data are from 163 patients receiving omacetaxine in clinical trials. Among 108 patients with chronic phase CML, 87% had grade 3 or 4 adverse events, including thrombocytopenia (67%), neutropenia (45%), anemia (36%), bone marrow failure (16%), and febrile neutropenia (10%); the most common grade 3 or 4 nonhematologic adverse events were infections/infestations (11%; bacterial, fungal, viral, nonspecified) and fatigue (5%).
Serious adverse events occurred in 51% of patients with chronic phase CML, with the most common being bone marrow failure (10%), thrombocytopenia (10%), infection (8%), and febrile neutropenia (6%). Discontinuation due to adverse events occurred in 18% of patients, with the most common reasons being pancytopenia, thrombocytopenia, and increased ALT (2% each). Death occurred in five patients (5%), due to cerebral hemorrhage in two, multiorgan failure in one, disease progression in one, and unknown cause in one.
Among 55 patients with accelerated phase CML, 84% had grade 3 or 4 adverse events, including thrombocytopenia (49%), anemia (36%), neutropenia (18%), and febrile neutropenia (16%); the most common grade 3 or 4 nonhematologic adverse events were infections/infestations (20%), fatigue (9%), and diarrhea (7%). Serious adverse events occurred in 60% of these patients, including febrile neutropenia (18%), infection (11%), thrombocytopenia (9%), anemia (7%), diarrhea (6%), and convulsions (6%). Discontinuation due to adverse events occurred in 33% of patients, with the most common causes being leukocytosis (6%) and thrombocytopenia (4%). Death occurred in five patients (9%), due to cerebral hemorrhage in two and disease progression in three.
Omacetaxine carries warnings/precautions for myelosuppression (including fatal thrombocytopenia, neutropenia, and anemia), bleeding (including fatal cerebral hemorrhage and severe gastrointestinal hemorrhage), hyperglycemia, and embryo-fetal toxicity. There are no identified drug interactions with omacetaxine and no recommendations for dose modifications according to renal or hepatic function or with concomitant administration of CYP450 inducers or inhibitors (omacetaxine is not a substrate of CYP450 enzymes). There are no specific contraindications to omacetaxine use. ■
1. U.S. Food and Drug Administration: Omacetaxine mepesuccinate. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm325990.htm. Accessed November 12, 2012.
2. SYNRIBO™ (omacetaxine mepesuccinate) for injection, for subcutaneous use, prescribing information, Teva Pharmaceuticals USA, Inc, October 2012.Available athttp://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203585lbl.pdf. Accessed November 12, 2012.
3. Cortes J, Lipton JH, Rea D, et al: Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 120:2573-2580, 2012.