Date: 2013-01-07
Type of information: Initiation of the trial
phase: 3
Announcement: agreement
Company: Ariad Pharmaceuticals (USA - MA) Newcastle University (UK)
Product: ponatinib (Iclusig®)
Action
mechanism: Ponatinib (Iclusig®) is a multitargeted oral tyrosine kinase inhibitor. Its primary target is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia -chromosome positive acute lymphoblastic leukemia (Ph+ ALL). It 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, which is the most common mutation among resistant patients.
Iclusig® is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior TKI therapy. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig. The recommended dose of Iclusig is a 45 mg tablet taken once-daily with or without food.
Disease: chronic myeloid leukemia
Therapeutic area: Cancer - Oncology
Country: UK
Trial
details: The SPIRIT 3 trial is a randomized, two-arm, multicenter trial that compares major molecular response (MMR) at three years in newly diagnosed patients treated with imatinib to those treated with nilotinib, when patients are \"rescued\" with ponatinib upon suboptimal response at three or 12 months or treatment failure. It will enroll adult patients with chronic-phase CML diagnosed within three months and previously untreated for CML with any TKI therapy. Approximately 1,000 patients will be randomized 1:1 to standard doses of imatinib (400 mg orally once daily) or nilotinib (300 mg orally twice daily). Patients will be switched to ponatinib (45 mg orally once daily) based on defined criteria of suboptimal response, treatment failure, or intolerance to first-line therapy. The primary endpoint of the study is the proportion of patients who have achieved MMR at three years on their initially allocated first line of therapy, regardless of switch to ponatinib. MMR is defined as a less than or equal to 0.1% ratio of BCR-ABL to ABL transcripts on the International Scale measured in peripheral blood by PCR testing. The sample size of 500 patients per arm in the SPIRIT 3 protocol provides over 90 percent power to show noninferiority in three-year MMR rates between patients starting on imatinib, allowing switch to ponatinib, and patients starting on nilotinib, allowing switch to ponatinib. These sample size calculations use a noninferiority margin of a 10 percent absolute difference and assume a 73 percent MMR rate at three years in each arm.
Secondary endpoints include the proportion of patients who have achieved therapy cessation three years from having achieved stable MMR, cost of therapy (measured as incremental cost per quality adjusted life year gained), overall survival, progression-free survival, event-free survival, and treatment failure rates at five years, as well as safety and tolerability of the TKIs. Each patient will be followed for a minimum of five years from the time the last patient in the trial is randomized to either treatment arm.
A key feature of the trial is that patients achieving stable MMR will be offered the opportunity to reduce the dose of their TKI therapy or stop treatment altogether. These patients will be monitored more closely with monthly PCR testing and will be reverted back to full-dose TKI therapy for loss of MMR at any time or rising BCR-ABL transcript ratio on two consecutive tests.
Latest
news: * On January 7, 2013, ARIAD Pharmaceuticals and Newcastle University, on behalf of the U.K. National Cancer Research Institute (NCRI) CML Working Group, have announced an agreement to collaborate on a multicenter, randomized Phase 3 trial, named SPIRIT 3, to assess the impact of switching patients with chronic myeloid leukemia (CML) being treated with a first-line tyrosine kinase inhibitor, upon suboptimal response or treatment failure, to ponatinib. The NCRI expects to begin enrollment in the trial of 1,000 patients at approximately 172 clinical research sites in the U.K. in the second quarter of 2013.
