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Ponatinib (Iclusig)

Ponatinib is an orally administered multi-kinase inhibitor under development by ARIAD Pharmaceuticals.  In June 2013 it entered a Phase II trial for GIST patients (see below).  Ponatinib received FDA approval in December 2012 for patients with resistant or intolerant CML and Ph+ ALL under the FDA's accelerated approval program.

Because ponatinib was designed to bind to receptors even in the presence of gatekeeper mutations, it is hoped that ponatinib will control exon 17 activation loop secondary mutations that do not respond to sunitinib.  See 2013 ASCO abstract 10509 Use of ponatinib to inhibit kinase mutations associated with drug-resistant gastrointestinal stromal tumors (GIST).  Quoting the abstract, "Using GIST cell lines, Ponatinib inhibited the viability of those harboring primary KIT exon 11 and secondary resistance mutations more effectively than imatinib, sunitinib, and regorafenib."

 

NCI Drug Dictionary definition

ponatinib hydrochloride:   An orally bioavailable multitargeted receptor tyrosine kinase (RTK) inhibitor with potential antiangiogenic and antineoplastic activities. Ponatinib hydrochloride inhibits unmutated and all mutated forms of Bcr-Abl, including T315I, the highly drug therapy-resistant missense mutation of Bcr-Abl. This agent also inhibits other tyrosine kinases including those associated with vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs); in addition, it inhibits the tyrosine kinase receptor TIE2 and FMS-related tyrosine kinase receptor-3 (Flt3). RTK inhibition by ponatinib hydrochloride may result in the inhibition of cellular proliferation and angiogenesis and may induce cell death. Bcr-Abl is a fusion tyrosine kinase encoded by the Philadelphia chromosome.


Information at manufacturer website

http://www.iclusig.com/
http://www.ariad.com/ponatinib

"In addition to its primary target, BCL-ABL, ponatinib also has been shown to selectively inhibit certain other tyrosine kinases in preclinical studies, including FLT3, RET, KIT and the members of the FGFR, PDGFR and VEGFR families of kinases."

 

Phase II trial for GIST

A Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (NCT01874665)

Patients enrolling in this trial must have failed at least one prior TKI therapy. The primary outcome will be clinical benefit (stable disease or partial response or complete response) measured 16 weeks after first dose using RECIST 1.1 critria.  Secondary outcome measures will include progression-free survival, objective response rate, and overall survival.

For a press release from ARIAD about this trial link here.

 

FDA Halts Ponatinib Trials Due to Safety Concerns

The FDA issued a safety alert for ponatinib in October 2013 due to concern about serious blood clots.  See this link:

Clinical trials of ponatinib have been ordered to stop enrollment until further notice.  See this link:

You can read a press release from ARIAD about the trial halt here. 

Patients already enrolled may continue under supervision by the treating physician.

 



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