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A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.

ABSTRACT: Pazopanib, an inhibitor of kinases including vascular endothelial growth factor receptor, demonstrated impressive activity in progressive metastatic differentiated thyroid cancer, prompting its evaluation in anaplastic thyroid cancer (ATC).Preclinical studies, followed by a multicenter single arm phase 2 trial of continuously administered 800 mg pazopanib daily by mouth (designed to provide 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true response rate is >5%), were undertaken. The primary trial end point was Response Evaluation Criteria in Solid Tumors (RECIST) response.Pazopanib displayed activity in the KTC2 ATC xenograft model, prompting clinical evaluation. Sixteen trial patients were enrolled; 15 were treated: 66.7% were female, median age was 66 yr (range 45-77 yr), and 11 of 15 had progressed through prior systemic therapy. Enrollment was halted, triggered by a stopping rule requiring more than one confirmed RECIST response among the first 14 of 33 potential patients. Four patients required one to two dose reductions; severe toxicities (National Cancer Institute Common Toxicity Criteria-Adverse Events version 3.0 grades >3) were hypertension (13%) and pharyngolaryngeal pain (13%). Treatment was discontinued because of the following: disease progression (12 patients), death due to a possibly treatment-related tumor hemorrhage (one patient), and intolerability (radiation recall tracheitis and uncontrolled hypertension, one patient each). Although transient disease regression was observed in several patients, there were no confirmed RECIST responses. Median time to progression was 62 d; median survival time was 111 d. Two patients are alive with disease 9.9 and 35 months after the registration; 13 died of disease.Despite preclinical in vivo activity in ATC, pazopanib has minimal single-agent clinical activity in advanced ATC.

SUBMITTER: Bible KC

PROVIDER: S-EPMC3431569 | biostudies-other | 2012 Sep

REPOSITORIES: biostudies-other

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A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.

Bible Keith C KC Suman Vera J VJ Menefee Michael E ME Smallridge Robert C RC Molina Julian R JR Maples William J WJ Karlin Nina J NJ Traynor Anne M AM Kumar Priya P Goh Boon Cher BC Lim Wan-Teck WT Bossou Ayoko R AR Isham Crescent R CR Webster Kevin P KP Kukla Andrea K AK Bieber Carolyn C Burton Jill K JK Harris Pamela P Erlichman Charles C

The Journal of clinical endocrinology and metabolism 20120706 9

<h4>Context/objectives</h4>Pazopanib, an inhibitor of kinases including vascular endothelial growth factor receptor, demonstrated impressive activity in progressive metastatic differentiated thyroid cancer, prompting its evaluation in anaplastic thyroid cancer (ATC).<h4>Design/setting/patients/interventions/outcome measures</h4>Preclinical studies, followed by a multicenter single arm phase 2 trial of continuously administered 800 mg pazopanib daily by mouth (designed to provide 90% chance of de ...[more]

PMID: 22774206

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Project description:Background:Major challenges in clinical trials of ultra-orphan oncology diseases include limited patient availability and paucity of reliable prior data for estimating the treatment effect and, therefore, determining optimal sample size. Angiosarcoma (AS), a particularly aggressive form of soft tissue sarcoma with an incidence of about 2000 cases per year in the United States and Europe is poorly addressed by current systemic therapies. Pazopanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) is approved for the treatment of AS, with modest benefit. TRC105 (carotuximab) is a monoclonal antibody to endoglin, an essential angiogenic target highly expressed on proliferating endothelium and both tumor vessels and tumor cells in AS, that has the potential to complement VEGFR tyrosine kinase inhibitors. In a phase I/II study of soft tissue sarcoma, TRC105 combined safely with pazopanib and the combination demonstrated durable complete responses and encouraging progression-free survival (PFS). In addition, there was a suggestion of superior benefit in patients with cutaneous lesions versus those with the non-cutaneous lesions. Patients and methods:This article describes the design of a recently initiated phase III trial of TRC105 And Pazopanib versus Pazopanib alone in patients with advanced AngioSarcoma (TAPPAS trial). Given the ultra-orphan status of the disease and the paucity of reliable prior data on PFS or overall survival (end points required for regulatory approval as a pivotal trial), an adaptive design incorporating population enrichment and sample size re-estimation was implemented. The design incorporated regulatory input from the Food and Drug Administration (FDA) and European Medicines Agency and proceeded following special protocol assessment designation by the FDA. Conclusions:It is shown that the benefit of the adaptive design as compared with a conventional single-look design arises from the learning and subsequent improvements in power that occur after an unblinded analysis of interim data. Registered on Clinicaltrials.gov:NCT02979899.

Dataset Information

A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.

Publications

A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.

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