AMN107+Gleevec clinical trial opens
Testing will be on just 35 patients at six sites, two of them in the U.S.
By Jerry Call and Norman Scherzer
A new phase I
trial combining the new Novartis drug
AMN107 and Gleevec is opening at four
European and two United States sites.
This trial is for GIST patients whose
cancer is resistant to Gleevec. Patients
must have spent two weeks on 800mg. of
Gleevec prior to starting the trial.
Currently there are 35 slots allocated
for this trial. Although it is expected
that all six trial sites will have some
slots, it is first-come, first-served.
This
means
that the earliest trial sites may get a
disproportionate number of slots.
In the U.S., the
investigators and sites are:
— George Demetri, Dana-Farber, Boston.
Recruitment has begun.
— Margaret von Mehren, Fox Chase,
Philadelphia. Recruitment is beginning.
European
investigators and sites are listed
below. To the best of our knowledge they
have not yet begun recruiting but this
information changes constantly.
— Peter Reichert, Berlin, Germany
— Paolo Giovanni Casali, Milan, Italy
— Jean-Yves Blay, Lyon, France
— Patrick Schöffski, Leuven, Belgium
This is a dose
escalation trial to determine the
maximum tolerated dose. What follows is
our preliminary understanding of the
intended dose escalation scheme. This is
subject to change/ modification as
information about the combination is
obtained.
— The first six patients will receive
800 mg. of AMN107 (400 mg. twice a day)
without any Gleevec.
— The next group will receive 200 mg. of
AMN107 plus 800 mg. of Gleevec.
— The next group will receive 400 mg. of
AMN107 plus 800 mg. of Gleevec.
— The next group will receive 800 mg. of
AMN107 plus 800 mg. of Gleevec.
AMN107 was developed to overcome some of the mechanisms of resistance to Gleevec in CML patients. It is 10 to 50 times more potent than Gleevec at inhibiting Bcr/Abl-induced proliferation in cells derived from CML patients. It is able to inhibit almost all of the Bcr/Abl secondary mutations that it has been tested against except the highly resistant T315I mutation.
In contrast, much less has been reported about its effects on GIST cells, or KIT/ PDGFRA mutations. In the few KIT/PDGFRA mutation variants that have been reported, AMN107 has about the same potency as Gleevec.
The phase I trials for AMN107 in CML patients have gone remarkably well. They are in many ways reminiscent of the original Gleevec phase I trials, producing response rates of about 90 percent, but this time in Gleevec-resistant CML patients. Such response rates are almost unheard of in phase I trials.
Regardless, it is much too early to draw any conclusions about the efficacy of this drug with GIST patients.
AMN107 inhibits Bcr/Abl, KIT, and PDGFRA. These are the same targets as Gleevec. The combination of AMN107 and Gleevec has proved to be synergistic in Bcr/Abl cell lines. However, the most compelling reason to use two inhibitors with the same target may be that each has a different mutation inhibition profile.
Using two drugs may provide a broader spectrum of inhibition and hopefully delay or prevent the emergence of resistant clones.
