An Adaptive Population Enrichment Phase 3 Trial of TRC105 and Pazopanib Versus Pazopanib Alone in Patients with Advanced Angiosarcoma (TAPPAS Trial)

Abstract

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 2,000 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 (TKIs). In a phase 1/2 study of soft tissue sarcoma, TRC105 combined safely with pazopanib and the combination demonstrated durable complete responses and encouraging PFS. In addition, there was a suggestion of superior benefit in patients with cutaneous lesions versus those with the non-cutaneous.

Design

This paper describes the design of a recently initiated Phase 3 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 progression free survival or overall survival (endpoints 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 FDA and EMA, and proceeded following special protocol assessment designation by the FDA.

Conclusions

It is shown that the benefit of the adaptive design as compared to 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