FDA- rules against targeted therapy because 'standarized' mutation test is not available.

2010 Mar 22, K Wachter

GAITHERSBURG, Md. (EGMN) - Cancer therapies targeting specific genetic mutations could be required to have corresponding validated diagnostic tests in order to gain approval in the United States, judging by the 7-1 vote of a Food and Drug Administration advisory committee on March 22.

The Oncologic Drugs Advisory Committee agreed with the agency that a validated test for the Bcr-Abl T3151 mutation is required before omacetaxine mepesuccinate (Omapro) - a drug targeting that mutation - can be considered.

ChemGenex Pharmaceuticals Ltd., a company with offices in Australia and Menlo Park, Calif., is seeking approval of omacetaxine for the treatment of adults with chronic myeloid leukemia (CML) after failure on prior therapy with imatinib (Gleevec) and with the Bcr-Abl T3151 mutation.

The vote is an important one in light of the growing number of therapies targeting specific genetic mutations. ODAC chairperson Dr. S. Gail Eckhardt noted that the indication for this drug is molecularly defined - failure on imatinib and the T3151 mutation - and that the question of related diagnostic tests will come up more frequently. Dr. Eckhardt is head of medical oncology at the University of Colorado in Denver.

The T3151 mutation is a thought to be a marker of tyrosine kinase inhibitor resistance. Patients with the mutation do not respond to any of the three approved therapies for CML and have a poor prognosis. T3151 mutation testing is available at a number of laboratories but is not standardized among facilities.

Omacetaxine, a new molecular entity and first in a class of cephalotaxines, is a synthetic formulation of homoharringtonine, a drug isolated from the evergreen tree Cephalotaxus in China. The compound is thought to be a reversible inhibitor of protein elongation, transient inhibition of peptide synthesis (selectively impacting short-lived proteins), although it does not directly inhibit Bcr-Abl protein or T3151 mutation.

The application to the FDA was based on the response rates in a single-arm trial in 66 patients deemed to have the T3151 mutation. In the open-label phase II dosing study CML-202, patients were given subcutaneous omacetaxine 1.25 mg/m² for 14 days of a 28-day cycle. If there was a hematologic response, patients received subcutaneous omacetaxine 1.25 mg/m² twice daily for 7 days of a 28-day cycle.

Patients in chronic, accelerated, or myeloid blast phases of CML were included in the study. Prior imatinib therapy had to have failed, and the T3151 mutation had to be identified and confirmed prior to study enrollment.

Study end points included major cytogenetic response or complete hematologic response for patients with chronic phase CML and overall hematologic response (complete hematologic response, no evidence of leukemia, return to chronic phase) for patients in the accelerated or blast phases.

The study included 40 patients in the chronic phase, 16 in the accelerated phase, and 10 in the blast phase. While all patients were determined to have the T3151 mutation, only 43 had central laboratory confirmation of T3151 status, meaning that roughly a third of patients failed to meet one of the study criteria. Perhaps more importantly, 10 patients who were initially identified as having the T3151 mutation were later determined by the central laboratories not to have the mutation.

The agency's primary concern was the use of multiple assay methods for the detection of T3151 mutation, without any bridging studies between the tests to assess reliability, reproducibility and concordance of results.

"The lack of having a uniform in vitro diagnostic test creates uncertainty about patient selection both in this trial and, more importantly, in a post-approval setting," the agency wrote in its charge to the committee. The majority of panel members expressed the same concerns.

The agency also expressed concern that the results of a small, single-arm incomplete efficacy trial were insufficient for approval, given uncertainty in response determination and duration, and uncertainty of the clinical meaningfulness of response rates.

Among patients in the chronic phase, 25% had a major cytogenetic response with 6-month duration; 85% had a complete hematologic response with 10-month duration. Among those in the accelerated phase, 37% had overall hematologic response with a 7-month duration. Among those in the blast phase, 30% had overall hematologic response with a 2-month duration. However, several committee members noted that the numbers of patients, particularly in the accelerated and blast groups, were too small for meaningful analysis.

Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting.

Copyright © 2010 International Medical News Group