A phase I study of pazopanib in combination with escalating doses of 131I in patients with well-differentiated thyroid carcinoma borderline refractory to radioiodine

Abstract

Objective: This trial was conducted to evaluate the ability of pazopanib to overcome therapeutic 131I resistance.

Materials, methods and patients: This phase 1 trial assesses the combination of pazopanib and escalating doses of radioiodine (131I) in patients with recurrent or metastatic thyroid cancer that are borderline or relatively iodine refractory. Radioiodine uptake scans were assessed post therapy and compared to historical pre-treatment scans. Patients underwent FDG PET/CT before and after the initial pazopanib treatment to identify the impact of pazopanib on the cancer prior to 131I therapy.

Results: A dose limiting toxicity (cardiac arrhythmia and grade 3 fatigue) in the first patient in the first cohort prompted expansion to a total of 6 patients. Additional grade 3-4 hematologic toxicity and low accrual in the expanded cohort led to the decision not to pursue further study of the regimen. In patients with measurable disease 4/5 (80%) achieved stable disease. Median progression free survival was 6.7 months. At 3 years of follow up, one patient died due to progressive disease, two are being treated with systemic therapy and 3 continue without requiring subsequent therapy at 15, 27 and 35 months from the last dose of pazopanib. There was no convincing impact of pazopanib on iodine uptake in scans performed pre- and post-therapy compared to scans from historical 131I treatments without pazopanib.

Conclusion: Despite a suggestion of therapeutic efficacy, combined pazopanib and 131I resulted in increased toxicity. There was no convincing evidence that the administration of pazopanib improved iodine uptake or retention.

Trial registration: ClinicalTrials.gov NCT01413113.

Conflict of interest statement

Competing Interests: This clinical trial was funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by the Novartis Pharmaceuticals Corporation (formerly GlaxoSmithKline, LLC). The funding agency did not play any role in the analysis of the results or the writing of this manuscript. The authors have declared that no other competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Consort flow diagram.

Fig 2

Fusion PET/CT image at baseline (A.Pre) and after 4 weeks of therapy with pazopanib (B.Post) in a patient with well-differentiated thyroid cancer. Post-pazopanib scan demonstrate some improvement in FDG-avid disease, although overall this patient had stable disease (Patient 6). FDG, 18F-fluorodeoxyglucose; PET, positron-emission tomography.

Fig 3

Fusion PET/CT scans at baseline (A.Pre) and after 4 weeks of therapy with pazopanib in a patient with well-differentiated thyroid. Post-pazopanib scan (B.Post) demonstrates new disease along superomedial margin of RFA site (Patient 2). RFA, Radiofrequency ablation; PET, positron-emission tomography.

Fig 4. Historical (left) and post-pazopanib (right) post-131Iodine therapy images demonstrate multiple metastatic lesions, without increase in iodine-avidity post pazopanib.