Phase 1 Trial of Ponatinib Shows Early Success in CML

Although early, a small phase 1 study shows that the experimental drug ponatinib acts against a mutation found in a small percentage of chronic myeloid leukemia (CML) cases that is resistant to other forms of therapy. Patients with a T315I gene mutation do not respond to Gleevec (imatinib), Sprycel (dasatinib) or Tasigna (nilotinib), drugs approved for Philadelphia chromosome-positive CML. While the trial was designed to uncover the best dose to administer the drug, it also showed the drug has activity against the mutation-associated CML and others.

In the study, researchers treated 74 patients who have various types of leukemia or other blood cancers; 64 patients were included in the data, with the highest percentage of patients having Philadelphia chromosome-positive CML with the T315I mutation (18 patients). The remaining patients had acute lymphoblastic leukemia, acute myeloid leukemia, myeloma, myelodysplastic syndromes and mycosis fungoides. All patients had progressed on at least two, if not three, of the approved CML drugs.

In addition to determining the maximum tolerated dose of ponatinib—45 mg per day, efficacy of the drug was also established. Most patients with the T315I mutation responded to the drug. Of the 11 chronic phase CML patients with the T315I mutation, eight had complete cytogenetic response, which means there is no sign of the CML-causing Philadelphia chromosome. Twenty chronic phase CML patients, with or without the mutation, had a major cytogenetic response, including 12 complete responses. Eighteen of the 20 patients have not progressed while on treatment. Even in patients with resistant disease with no mutations or non-T315I mutations, ponatinib seemed to initiate a response. Side effects of the drug were few and mild, including low platelet count, headache and nausea.

A phase 2 trial called PACE (Ponatinib Ph+ ALL and CML Evaluation), is currently under way at multiple sites in the United States and recruiting patients. (For more information on the trial, go to www.clinicaltrials.gov [link: http://clinicaltrials.gov/ct2/show/NCT01207440?term=ponatinib&rank=1].)

Another T315I-targeted drug in clinical trials, omacetaxine, also appears to also have activity against the mutation and was recently reviewed by the Food and Drug Administration. The agency stopped short of approving the drug stating omacetaxine will not be approved until a standardized test to identify the mutation is developed. This likely applies to an approval for ponatinib, as well.