Tappas: An adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (AAS).

Abstract

TPS11081 Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.

Antibodies to watch in 2018

“…The initial enrollment is 124 patients, but may expand up to a maximum of 200 patients. 78 The estimated primary completion date of the study is September 2018.…”

Optimal, Two-Stage, Adaptive Enrichment Designs for Randomized Trials, using Sparse Linear Programming

“…Data from an earlier trial provided suggestive evidence that the treatment may have a greater likelihood of benefiting the subpopulation who enter the trial with cutaneous lesions compared with those with non‐cutaneous lesions. The TAPPAS trial design goals included having 80% power to detect a benefit (hazard ratio of 0.55 for progression‐free survival) in the combined population, and also 80% power to detect such a benefit only in the subpopulation with cutaneous lesions (Jones et al ., ). A two‐stage, adaptive enrichment design was implemented.…”

“…As an example, consider the phase 3 randomized trial of a treatment for angiosarcoma called the ‘TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma trial’ (which is known as the ‘TAPPAS’ trial) (Jones et al ., ; Mehta et al ., ). Data from an earlier trial provided suggestive evidence that the treatment may have a greater likelihood of benefiting the subpopulation who enter the trial with cutaneous lesions compared with those with non‐cutaneous lesions.…”

Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs

“…Example TAPPAS [164,165] is a trial of TRC105 (an antibody) and pazopanib versus pazopanib alone in patients with advanced angiosarcoma. The study identified two sub-groups, those with cutaneous advanced angiosarcoma and those with non-cutaneous advanced angiosarcoma.…”