Ariad Pharmaceuticals Inc. : Myeloid Leukemia and Lymphoblastic Leukemia Update

By Andrea: http://nursingoncologyjob.com

Ariad Pharmaceuticals Inc. (ARIA) recently announced the initiation of the pivotal Phase 2 clinical trial of its investigational pan-BCR-ABL inhibitor, ponatinib (previously known as AP24534), in patients with resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL). The PACE (Ponatinib Ph+ ALL and CML Evaluation) trial is designed to provide definitive clinical data for regulatory approval of ponatinib in this setting. Ponatinib has been granted orphan drug status in both the United States and Europe for the treatment of CML and Ph+ ALL.

"The start of the pivotal PACE trial represents an important step in the development of our second molecularly targeted cancer therapy," stated Harvey J. Berger, M.D., chairman and chief executive officer. "With the strong clinical evidence observed to date of hematologic, cytogenetic and molecular anti-leukemia activity of ponatinib in heavily pretreated patients with CML, including those patients with the T315I mutation for whom no current treatments are available, we are highly optimistic about the likelihood of success for ponatinib in this registration trial. We also believe that the time to full patient enrollment in this study and to potential regulatory approval of ponatinib will be swift."

Trial Design

The PACE trial is a global, single-arm clinical study of oral ponatinib in 320 patients with chronic phase, accelerated phase, or blast phase CML, as well as Ph+ ALL. Patients resistant or intolerant to dasatinib (Sprycel(R)) or nilotinib (Tasigna(R)), or with T315I mutation of BCR-ABL, will be enrolled in the trial. Patients will be grouped into one of six separate cohorts based on their phase of CML (i.e., chronic, accelerated or blast) and BCR-ABL mutation status (i.e., with or without the T315I mutation); Ph+ ALL patients will be grouped with blast phase CML. A total of 160 patients with chronic phase CML will be included. The primary endpoints are major cytogenetic response rate for chronic phase patients and major hematologic response rate for accelerated or blast phase CML patients and Ph+ ALL patients. Secondary endpoints in the trial include major molecular response rate, duration of response, progression-free survival, and overall survival.

Patients will receive ponatinib in tablet form once daily at a dose of 45 mg. The PACE trial will be conducted at approximately sixty centers in North America, Europe, Australia and Asia. Full patient enrollment is anticipated by year-end 2011.

"Clinical results from the ongoing Phase 1 trial of ponatinib, taken together with the preclinical data that characterize ponatinib as a potent, pan-BCR-ABL inhibitor, provide a strong rationale for advancing directly to a pivotal trial of ponatinib in a population of patients who have extremely limited, if any, treatment options," stated Jorge Cortes, M.D., professor and deputy chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center and a leading investigator in the PACE trial. "There is great interest in the PACE trial from clinicians and patients, and I look forward to having this investigational option available for patients with this disease."

Regulatory Agency Agreement on Study Design

The PACE trial protocol was developed in consultation with leading CML experts from around the world. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) provided valuable input on the design and analysis of the pivotal trial. Based on these favorable interactions and depending on the actual results of this pivotal trial, ARIAD anticipates that it will be able to submit data from this single-arm trial with six months of follow-up response data.

All patients in the PACE trial will be genotyped in a central laboratory upon enrollment in the study to determine their BCR-ABL mutation status. Direct sequencing for determination of the T315I mutation will be applied rigorously and uniformly throughout the study. In parallel, ARIAD is proceeding with plans to have a companion diagnostic test for the T315I mutation developed and commercialized. The need for a commercialized companion diagnostic test in the United States applies only to the T315I cohorts and not to the larger resistant/intolerant CML patient population.

"We will use the same diagnostic test to determine T315I mutation status in the PACE trial that we used in the Phase 1 clinical trial of ponatinib, performed at a single site and applied uniformly," stated Frank G. Haluska, M.D., Ph.D., vice president and chief medical officer at ARIAD. "We have agreement with the FDA on how to proceed with genotypic evaluation of all patients in the PACE trial and will finalize plans for development and commercialization of the companion diagnostic as the PACE trial moves ahead."