ARIAD Pharmaceuticals, Inc., an integrated global oncology company focused on transforming the lives of cancer patients with breakthrough medicines, has enrolled of 50 per cent of the patients planned in its randomized phase III trial of Iclusig (ponatinib) in adult patients with newly diagnosed chronic myeloid leukaemia (CML). The trial, formally known as EPIC (Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukaemia), is designed to provide definitive clinical data to support regulatory approval of ponatinib in treatment-naïve CML patients.
An interim analysis of efficacy -- focused on the primary endpoint of major molecular response rate (MMR) at twelve months -- will be performed in the third quarter of 2014 based on the patients enrolled to date. Approximately 264 patients have been enrolled in the EPIC trial, and full patient enrollment of approximately 500 patients in the trial is anticipated by the end of 2013.
"The EPIC trial is a very important study in the ongoing global development of Iclusig and will inform our clinical understanding of Iclusig in patients with newly diagnosed CML," said Harvey J Berger, MD, chairman and chief executive officer of ARIAD. "Depending on the outcome of the interim analysis, we may be able to file for regulatory approval of Iclusig in this front-line setting approximately six months earlier than currently planned."
The EPIC trial is a randomized, two-arm, multi-centre trial that compares the efficacy of ponatinib with that of imatinib in adult patients with newly diagnosed CML in the chronic phase. The trial is currently being conducted at approximately 150 investigational sites in more than 20 countries. Patients in the trial must be at least 18 years of age and diagnosed with CML within six months prior to enrollment. Approximately 500 patients are randomized 1:1 to the standard dose of ponatinib (45 mg given orally once daily) or imatinib (400 mg given orally once daily). Increasing the imatinib dose to 600 mg or 800 mg per day is permitted.
As a primary endpoint, the trial is designed to measure the MMR of patients at 12 months of treatment. This endpoint was chosen to support accelerated approval for front-line treatment in the United States. ARIAD also expects results from the EPIC trial to support regulatory approval in the European Union and Japan. All patients are evaluated for molecular response (MR) using quantitative reverse transcriptase polymerase chain reaction (qRT PCR) at a single central laboratory (Molecular MD, Portland, OR). To achieve MMR, the ratio of BCR-ABL protein transcripts to ABL transcripts in a patients' blood must be 0.1 per cent or less, using the International Scale in peripheral blood.
The EPIC trial is designed to have a 90 per cent power to detect a 15 per cent absolute improvement in 12-month MMR rate by ponatinib compared to imatinib. This was based, in part, on the results of the nilotinib (ENESTnd) and dasatinib (DASISION) phase III trials. The 12-month MMR rates for the imatinib arms in these two trials were 22 per cent and 28 per cent, respectively. Using the more conservative estimate of the 12-month MMR rate for imatinib, the upper bound of the 95th percentile confidence interval for the higher of these two estimates is 34 per cent. The ENESTnd trial was designed to demonstrate a 15 per cent absolute improvement in 12-month MMR rate comparing nilotinib to imatinib. Thus, the EPIC trial is 90 per cent powered to detect a 15 per cent absolute improvement in 12-month MMR rate by ponatinib compared to imatinib (i.e., 49 per cent vs. 34 per cent).
CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to the more aggressive phases referred to as accelerated phase or blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors. The BCR-ABL protein is expressed in both of these diseases.
Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD's computational and structure-based drug design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, a common mutation which has been associated with resistance to other approved TKIs.