Late-Stage Ponatinib Study Discontinued

The phase III EPIC trial that was exploring ponatinib (Iclusig) in untreated patients with chronic myeloid leukemia (CML) has been discontinued following a high occurrence of arterial thrombotic events, according to a statement released by Ariad Pharmaceuticals, Inc., the company developing the drug.

The decision to end the EPIC trial follows a partial hold placed on the clinical development of ponatinib by the FDA while it investigates an increasing frequency of serious adverse events associated with the drug. The termination of the trial was agreed upon by Ariad, the FDA, and an independent data monitoring committee (DMC). As a result of the discontinuation, patients selected for treatment with ponatinib in the EPIC trial will no longer receive the drug. Additionally, all other trials exploring the agent remain on hold.

"We believe that given the new context, the overall likely clinical and regulatory value of the EPIC trial was limited," stated Timothy P. Clackson, PhD, the president of research and development and chief scientific officer at Ariad, in a webcast. "Working with the FDA, we mutually concluded that it was in the best interest of patient safety and the overall development of the drug to stop the trial now."

Ponatinib is a potent pan—BCR-ABL tyrosine kinase inhibitor that was granted accelerated approval by the FDA in December 2012 based on results from the phase II PACE trial. In this trial, ponatinib at 45 mg daily was explored in a single-arm investigation for the treatment of patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia following resistance or intolerance to dasatinib or nilotinib, or the presence of a T315I mutation.

Initial reports from this trial indicated a tolerable toxicity profile and substantial antileukemic activity in patients with CML treated with ponatinib. Nevertheless, high rates of arterial thrombosis and hepatotoxicity warranted a Boxed Warning. At an FDA-required follow-up, the rate of serious arterial thrombosis had increased from 8% to 11.8% in patients treated with ponatinib, warranting the pause in clinical development.

In response to questions regarding the increase in adverse events and the discontinuation of the EPIC trial, in a conference call Clackson noted that Ariad was "active in productive discussions with the FDA to finalize a new label.” Furthermore, he added that the company “did not believe that removal from the market was being contemplated."

In the open-label EPIC study, ponatinib at 45 mg once daily was being compared to the frontline standard of care, imatinib, for patients with newly diagnosed chronic phase CML. The study required adequate renal, hepatic, and pancreatic function as part of its eligibility criteria. The investigators estimated that 528 patients would be enrolled into the study. At the time of discontinuation, the final enrollment in the trial was 307 patients.

The primary efficacy endpoint of the trial was major molecular response (MMR) rate at 12 months. The secondary endpoints included MMR rate at 5 years, BCR-ABLIS <10% rate at 3 months, CCyR rate at 12 months, progression-free survival, overall survival, and safety.

In reference to the cessation of the trial, Frank G. Haluska, MD, PhD, the chief medical officer at Ariad, noted in a conference call that the investigation “did not cross any predefined thresholds; the DMC did not stop the trial. It's really our evaluation of the data in the context of what we've learned in the last week or so in terms of the regulatory acceptance of our data in the climate of potential registration."

In June, a phase II trial investigating ponatinib in patients with advanced gastrointestinal stromal tumors (GIST) was initiated. This trial plans to enroll 45 patients. Additionally, once the FDA hold is lifted, ponatinib will continue to be investigated for patients with head and neck cancer, endometrial carcinoma, medullary thyroid cancer, and non-small cell lung cancer.

"Consistent with our continuing interest in better understanding the risk profile of Iclusig, we will focus our current efforts on the use of Iclusig in refractory CML patients," Clackson said. "As we contemplate a narrower US label, we will use that as a platform to explore Iclusig use in additional indications both within and beyond CML."