PACE Trial: Phase II trial of ponatinib in patients with chronic myeloid leukaemia (CML)

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Published: 17 Dec 2012
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Dr Jorge Cortes - MD Anderson Cancer Center, Houston, TX, USA

Dr Jorge Cortes talks to ecancer at the 2012 ASH meeting in Atlanta, Georgia about the pivotal phase II PACE trial.


Ponatinib is an oral tyrosine kinase inhibitors developed using computational and structure‑based design with optimal binding to the BCR‑ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR‑ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph leukemia were evaluated in a phase 2, international, open-label clinical trial.

ASH 2012

PACE Trial: Phase II trial of ponatinib in patients with chronic myeloid leukaemia (CML)

Dr Jorge Cortes – MD Anderson Cancer Center, Houston, Texas, USA

This study was specifically meant for patients who had failed to respond to therapy with the second generation tyrosine kinase inhibitors, dasatinib or erlotinib, or who had this mutations T315I. Generally speaking, about 60% of patients that you treat with imatinib respond well so about 40% of all patients will not do well with initial therapy with imatinib and, of those, about half, less than half, probably about 40% will do OK with a second generation tyrosine kinase inhibitor. So I think we’re talking about 25% of all patients from the initial diagnosis that are treated with imatinib are not going to do well with at least two drugs treated. Some of them will have the mutation T315I, others will have other mutations or no mutations but still fail to respond to therapy.

What was the design and method of the study?

The design was that patients with CML in any stage of the disease, chronic, accelerated or blast phase, were included; we also included patients with Philadelphia positive ALL which behaves very much like the blast phase. They were included, all of these patients were treated with ponatinib, which is an oral agent, at a dose of 45mg a day and the treatment is given continuously, uninterrupted. We allocated the patients into two cohorts for each stage – whether they had the mutation T315I or did not have the mutation T315I. Then we looked at the results by different cohorts. The main result of interest in the chronic phase was major cytogenetic response and for the more advanced stages of the disease the results of interest were major hematologic response.  We found a very high rate of responses; in the chronic phase two-thirds of the patients had achieved a cytogenetic response. One important thing to keep in mind to put these results in perspective is that two-thirds of the patients had already received three tyrosine kinase inhibitors or more and more than 90% of the patients had received at least two tyrosine kinase inhibitors, so a very heavily treated population. So two-thirds of patients achieving a cytogenetic response is very good and actually about 50% of the patients the response was complete, a complete cytogenetic response. So a very high rate of response, even some molecular responses which we think will continue improving over time, the study is still quite young, although now we are presenting a follow-up of at least twelve months for all patients. So it’s starting to mature a little bit more and the results look very good.

Are there plans to use it in the front line setting?

We are indeed already starting to use that. We’ve initiated at our institution a study for ponatinib as initial therapy. We’ve already treated about 25 patients and there is another larger study that’s a multi-centre study that is a randomised study of ponatinib versus imatinib as initial therapy. So I think these two studies are going to help us define what ponatinib can do as initial therapy. Usually you predict that there is going to be a higher rate of responses when you use it up front. I think ponatinib is a fantastic drug, it may be the most effective tyrosine kinase inhibitor we have and, granted, we have imatinib which is an excellent drug and then dasatinib and erlotinib are even a step above that, but it looks like ponatinib has properties that can make it the best one available – in the laboratory cells do not develop resistance, it blocks all the different mutations that we know and we see these results which are very, very good. So I think it is a very powerful tool that adds to our very good armamentarium for the treatment of CML.

The side effects are very acceptable, like all the tyrosine kinase inhibitors they all have some side effects. Fortunately the great majority are mild side effects – skin toxicities, some rash, some dry skin, that’s some of the things that we see. We also see some occasional headaches, again just manageable with something for the headache. Pancreatitis was the one side effect that we had a little bit more concern at the highest doses in the initial dose finding study; it was the most problematic side effect at the dose of 60mg, which is higher than what we’re using now. So in this study we found that about 60% of patients had a grade 3 pancreatitis. So it is not very high fortunately, this seems to be able to respond if you stop treatment, then you restart it on a lower dose and with that most patients can actually resume therapy. There has only been one patient out of the more than 440 patients included in the study that have had to come off the ponatinib because of pancreatitis. So, for the most part very well tolerated; like all the drugs you have to be following the patients closely.