The FDA has placed a partial hold on the clinical development of the BCR-ABL inhibitor ponatinib (Iclusig) as it investigates the high occurrence of arterial thrombosis in patients treated with the drug. As part of this hold, new patient enrollment into all clinical trials investigating ponatinib has been stopped.
Ponatinib was granted accelerated approval in December 2012 at a 45-mg daily dose for patients with chronic myeloid leukemia (CML) or Philadelphia chromosome—positive acute lymphoblastic leukemia (Ph+ALL). This approval was based on data from the phase II PACE trial that enrolled patients who were resistant or intolerant to dasatinib or nilotinib, or harbored a T315I mutation.A Boxed Warning was included in the approval, based on the development of arterial thrombosis in 8% of patients and hepatotoxicity in the trial. However, at an FDA-required median 24-month planned follow-up, the rate of arterial thrombosis had increased to 11.8% in patients treated with ponatinib, warranting the pause in patient enrollment.
Ariad Pharmaceuticals, Inc, the company developing ponatinib, is seeking the approval of dose modification from the FDA, in order to resume its ongoing clinical development program. Additionally, the company is consulting with the FDA on needed adjustments to the drug’s prescribing information to reflect the newly discovered increase in toxicity. “We believe that the actions we are taking will help us ensure the most appropriate and safe use of Iclusig. With 2 years of follow-up, we have learned a great deal about both the efficacy and safety of Iclusig in patients with Philadelphia-positive leukemias,” stated Harvey J. Berger, MD, chairman and chief executive officer of Ariad.
The PACE trial was a single-arm investigation of 449 patients, of which 444 were eligible for efficacy analysis. The primary end point for patients with chronic-phase (CP)-CML (n = 267) was major cytogenetic response (MCyR). The primary end point was major hematologic response (MaHR) for patients with accelerated-phase (AP)-CML (n = 83), blast-phase (BP)-CML (n = 62), and Ph+ALL (n = 32). Ponatinib was approved based on a 10-month analysis of the PACE trial that found that treatment with ponatinib demonstrated a 54% MCyR rate in patients with CP-CML. Specifically, 70% of the 64 patients with the BCR-ABL T315I mutation achieved MCyR. The MaHR rate was 52% in patients with AP-CML, 31% in patients with BP-CML, and 41% in patients with Ph+ ALL.
At this early follow-up, the median duration of MCyR for patients with CPCML had not yet been reached. The median duration of MaHR was 9.5 months in patients with AP-CML, 4.7 months in patients with BP-CML, and 3.2 months in patients with Ph+ ALL. At the 24-month follow-up, the PACE trial data demonstrated continued efficacy, even following dose reductions.
Overall, 190 patients with CP-CML received a reduced dose of either 30 mg or 15 mg. Despite this reduction, 90% of patients who achieved MCyR maintained this response for a median of 19 months. Furthermore, Ariad noted in a release, for the 35 patients reduced to a 15-mg dose, 94% maintained a MCyR. The most common adverse events were thrombocytopenia, rash, and dry skin. The most common serious adverse event was pancreatitis, which led to 1 patient discontinuing the drug. At 24 months, serious venous occlusion occurred in 2.9% of ponatinib-treated patients, compared with 2.2% when the drug was approved. In total, all types of arterial and venousrelated adverse events occurred in approximately 20% of ponatinib-treated patients.
“We are focused first and foremost on the needs of cancer patients—to have new medicines that provide both safe and effective treatment of their malignancies. Our unwavering commitment to patients has led us to promptly take the steps we have outlined,” Berger said in a statement. To support the accelerated approval of ponatinib, the phase III EPIC trial was initiated to compare 45 mg ponatinib with imatinib for patients with newly diagnosed CML. As a result of the new safety findings, Ariad, in collaboration with a data monitoring committee, is proposing that the daily dose of ponatinib be adjusted to 30 mg daily in this trial. However, if patients have already achieved a major molecular response (MMR), the dose will be further reduced to 15 mg daily.
Additionally, the company announced, the eligibility criteria for all ponatinib clinical trials will be modified to exclude patients with prior arterial thrombosis that has resulted in heart attack or stroke.