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Phase II study and tissue correlative studies of AZD6244 (ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma (IRPTC) and papillary thyroid carcinoma (PTC) with follicular elements.
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2010
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Peripheral EdemaFollicular ElementsMedicineMitogen-activated Protein KinasePapillary Thyroid CarcinomaPharmacologyThyroid DiseasePathologyCancer TreatmentTissue Correlative StudiesThyroid HormoneOncologyCancer ResearchNuclear MedicineMolecular OncologyRadiologyBraf Mutation Status
5536 Background: There is no standard treatment for IRPTC. AZD6244 is an oral, small molecule inhibitor of the mitogen-activated protein kinase, MEK-1/2. Thyroid cancers appear to be dependent on RAF/MEK/ERK (MAPK) signaling. A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of AZD6244 in IRPTC. Correlative studies were performed to include the tumor genotype for BRAF a potent activator of the MAP kinase pathway. Methods: Patients with objective evidence of disease progression within the last 12 months were eligible. AZD6244 was administered as a free base suspension at a dose of 100 mg twice daily for 28-day cycles. The primary end point was objective response rate. The secondary end points were safety, overall survival, and time to progression. 32 evaluable patients were required. Radiologic response was assessed every 8 weeks and determined using RECIST. Correlative studies were performed to include the tumor genotype for BRAF. Results: 39 subjects were enrolled. The median age was 59 years. The population was predominantly men (75%) and Caucasian (88%). Only 19% of subjects had received prior systemic therapy. The most common drug-related adverse events included rash (69%), fatigue (49%), diarrhea (49%), and peripheral edema (36%). Grade 3-4 toxicities included rash (18%), fatigue (8%), diarrhea (5%), and peripheral edema (5%). Best response in 32 evaluable patients who completed at least two cycles was 1 partial response (3%), 21 with stable disease (66%), and 10 with progressive disease (31%). The mean progression free survival (PFS) was 53.6 weeks with a 95% confidence interval of 37.8–69.5 weeks. The median PFS was 32 weeks. Seven patients remain on study with PFS up to 53 weeks. Data on BRAF mutation status will be presented. Conclusions: In the treatment of IRPTC, AZD6244 is well-tolerated. One partial response was reported, along with PFS greater than 1 year in a patient population with previously documented progressive disease and few therapeutic options. These observations suggest that AZD6244 offers benefit in some patients with IRPTC. No significant financial relationships to disclose.