Ted Bosworth New Orleans?In patients with chronic myeloid leukemia (CML) who have stopped responding to tyrosine kinase inhibitors (TKIs), a new drug called omacetaxine (Omapro, ChemGenex) may extend survival.
This news comes from preliminary results from an ongoing Phase II/III trial, CML-202. The drug, a first-in-class cetaxine, may be a breakthrough for CML patients who have run out of other options, but its activity appears to be specific to individuals with a T315I BCR-ABL mutation.
?Omacetaxine appears to be an option for a patient population who currently has no available approved drug therapies,? said Jorge E. Cortes-Franco, MD, deputy chair, Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston. At the most recent annual meeting of the American Society of Hematology (ASH abstract 644), Dr. Cortes-Franco presented evidence of durable responses with this new drug, an agent that patients self-inject. Myelosuppression is the most common toxicity, but the drug is otherwise relatively well tolerated.
On March 22, the FDA?s Oncologic Drugs Advisory Committee voted 7 to 1 that a validated, well-characterized test to identify the T315I mutation should be reviewed by the FDA prior to approval of omacetaxine. Two different in vitro tests were used in trial CML-202 and the comparability of these tests is unknown, said the agency. On April 9, ChemGenex met with the FDA?s Center for Devices and Radiological Health to discuss a path forward to develop a test.
Study Design
The CML-202 study was not controlled, primarily because there is no current alternative therapy for CML patients who have become resistant to TKIs?imatinib (Gleevec, Novartis), dasatinib (Sprycel, Bristol-Myers Squibb) and nilotinib (Tasigna, Novartis). However, response rates and survival rates compared favorably to historical controls. Although survival is short for CML patients who are initiated on therapy in blast phase, 80% of patients in chronic-phase CML were alive at two years, and the median survival has not yet been reached in follow-up that is still ongoing.
The study enrolled patients with CML who were resistant to imatinib and had a T315I mutation. Almost 80% of the patients had failed two or more TKIs. According to Dr. Cortes-Franco, the T315I mutation is found in about 50% of patients who become resistant to imatinib and is a major reason for CML progression after initial response to TKIs. Of the 81 patients who have been evaluated to date, 49 (60%) were in chronic phase, 17 (21%) were in accelerated phase and 15 (19%) were in blast phase. The median duration of the disease was 54 months, with a range of five to 285 months. Baseline clonal evolution was identified in 25% of those in chronic phase, 38% of those in accelerated phase and 70% of those in blast phase.
Patients received an induction of 1.25 mg/m2 omacetaxine in a twice-daily subcutaneous injection for 14 days every 28 days for six cycles. Those with a hematologic response went on to a maintenance dose, which was the same as the induction dose except that it was administered for seven days over each 28-day cycle. Patients were instructed to self-administer the injections.
Patient Response
The degree of response correlated with the activity of the disease. For those in chronic phase, 86% achieved a complete hematologic response, which was observed in only 22% of those in accelerated phase and 20% of those in blast phase (Figure 1). A cytogenetic response was achieved in 41% of those in chronic phase compared with 6% of those in accelerated phase and no patients in the blast phase. A major cytogenetic response was achieved in 26% of patients in chronic phase, including a complete cytogenetic response in 18%. The median time to achieve a complete hematologic response was one month, while the median time to achieve a major cytogenetic response was approximately four months.
Although the median follow-up is only seven months, the responses have been prolonged. Eleven of the 13 patients have sustained their major cytogenetic response to date. The median duration has been five months. Importantly, the benefit appears to be largely confined to patients with chronic disease. Although the median survival in the accelerated- phase patients so far has been close to 19 months, suggesting some activity of the therapy compared with historical controls in this group, the median survival in blast-phase patients has been only 2.4 months. The investigators say, however, that the clinical activity of omacetaxine is supported by clonal monitoring which has demonstrated a reduction in mutation in 50% of treated patients, even though Dr. Cortes-Franco acknowledged that ?only a handful have demonstrated a disappearance of the mutated clone.?
Except for some cases of grade 3 diarrhea, most of the side effects associated with omacetaxine in this study, including diarrhea, nausea, fatigue and fever have been relatively mild. The most common non-hematologic side effect was diarrhea in 43% of patients. Grade 3 and 4 hematologic side effects have been common including thrombocytopenia (71%), anemia (49%) and neutropenia (45%) (Figure 2). However, with dose adjustments, the incidence of these hematologic events fell substantially, and cases of febrile neutropenia were relatively uncommon.
Filling a Niche
From this evidence, the investigators concluded that omacetaxine, which has received orphan drug status approval from the FDA, can extend the lives of CML patients who are no longer responding to TKIs. The efficacy of this drug in patients with the T315I mutation suggests that new strategies to address mutating CML may be a productive approach to advancing care. Researchers not involved with the study agree.
?Omacetaxine appears to represent a potentially viable therapeutic option for CML patients who develop a secondary T315I BCR-ABL mutation, which is highly resistant to the three available tyrosine kinase inhibitors,? said Richard Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, in Boston. ?The drug is myelosuppressive, so one wonders if the hematological responses are nonspecific in nature. Would similar results have been obtained if low-dose Ara-C (and stopping the TKI which reduces the selection pressure for this mutation) was employed? Nonetheless, the fact that there is a high hematological response rate and an impressive cytogenetic response rate is encouraging. While there are more specific inhibitors of T315I BCR-ABL in development, omacetaxine could help at least some patients in the near future who develop this refractory type of CML.?
According to Frank Giles, MD, chief of the Division of Hematology and Medical Oncology, University of Texas Health Science Center, San Antonio, omacetaxine is ?a very important? development for patients with T315I BCR-ABL CML. Although he reported that he is among those now conducting early phase clinical studies with oral kinase inhibitors targeted at this form of CML, he does not anticipate that viable agents will be available for several years. In the meantime, omacetaxine will fill an important void.
?I greatly admire both the investigators and company for developing a compound from a class with a long and erratic development history, in a niche where the need is great and where other companies have not been proactive enough, on occasion because of their unfortunate belief that patients with T315I disease did not constitute a sufficiently large population to meet commercial aims,? Dr. Giles said."
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