As a result of adverse events, all trials of the tyrosine kinase inhibitor ponatinib (Iclusig) have been placed on partial clinical hold.
The US Food and Drug Administration (FDA) has paused new enrollment in the trials.
Patients already enrolled will continue to receive ponatinib, but at reduced doses. If trial enrollment resumes, eligibility criteria will change.
These actions come after ponatinib’s makers, Ariad Pharmaceuticals, reviewed extended follow-up data from the PACE trial and observed an increase in thrombotic events.
This phase 2 trial is testing ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have resisted or cannot tolerate therapy with dasatinib or nilotinib.
At a median follow-up of 24 months, 11.8% of PACE patients developed serious arterial thrombosis, including 6.2% with cardiovascular events, 4% with cerebrovascular events, and 3.6% with peripheral vascular events. (Some patients had more than one type of event.) In comparison, 8% of patients had serious arterial thrombosis at 11 months of follow-up.
The rate of serious venous occlusion also increased with extended follow-up. At 24 months, the event had occurred in 2.9% of patients, compared to 2.2% at 11 months of follow-up.
Ariad noted, however, that the incidence rate of arterial thrombotic events has not increased when it is normalized to the duration of treatment exposure. There were 10 events per 100 patient-years in the original analysis and 9.6 events per 100 patient-years in the current analysis.
Nevertheless, Ariad has announced the following changes to the clinical development program for ponatinib.
First, the FDA has paused patient enrollment in all clinical studies of ponatinib. Subject to agreement with the FDA, enrollment will resume with dose changes and other modifications.
Patients who are currently receiving ponatinib will continue on therapy. However, doses will be reduced, on a trial-by-trial basis, from the current 45-mg-daily dose.
The dose in patients enrolled in the EPIC trial will be reduced to 30 mg daily, unless they have achieved a major molecular response. In these patients, the dose will be reduced to 15 mg daily. EPIC is a phase 3 trial testing ponatinib in patients with newly diagnosed CML.
Once enrollment resumes for ponatinib trials, the eligibility criteria will be modified to exclude patients who have experienced prior arterial thrombosis resulting in heart attack or stroke.
The US prescribing information for ponatinib has not yet changed. The drug is still available in the US to patients with resistant or intolerant CML or Ph+ ALL at the approved, once-daily dose of 45 mg. Ponatinib was approved for this indication in the US in December and in the European Union in July.
Ariad is consulting with the FDA and other health authorities about changes in ponatinib’s product labeling to reflect the updated information.
The company is sending a written communication to healthcare providers outlining this information. Ariad is also informing the European Medicines Agency and other regulatory agencies of the changes.
For more information about the changes in ponatinib trials, visit www.clinicaltrials.gov, email inquiries to medinfo@ariad.com, or call the Ariad US toll-free number: (855) 552-7423, the European Union toll-free number: 800 00027423, or the international number: +1 (617)-503-7423.
