Tap, William D.

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.

11007 Background: Patients (pts) with metastatic sarcoma (SAR) have limited options. Nivolumab(N), a fully human anti-PD-1 mAb and ipilimumab (I), a humanized anti-CTLA-4 mAb, have favorable safety & efficacy in other tumors. Pembrolizumab demonstrated a response rate (RR) of 12% in SAR pts. We evaluated N, independently from N+I, in SAR pts. Methods: This open-label multi-center phase II study enrolled pts failing prior regimens. Randomized (non-comparative) pts received either N3 [N (3 mg/kg q2W)] or N3+I1 [N(3 mg/kg Q3W x4, then Q2W) & [I(1 mg/kg q3W x4)]. Treatment continued beyond progressive disease (PD) in 1st12 weeks. 5 confirmed responses in 38 evaluable pts yielded 90% power (0.05 1-sided alpha) to detect a 20% (vs 5%) confirmed RR. Other endpoints: adverse events (AEs), progression-free, overall survival (PFS, OS), and correlative studies including PD-L1 expression by IHC, mutational burden/neoantigen analysis, TCR clonality and TIL characterization. Results: 85 pts (43 - N3; 42 - N3+I1) were enrolled [mean age 54 yrs (21–81), 52% female). No significant differences in histological subtypes across cohorts: 36% LMS, 4% LPS, 10% UPS/MFH, 6% synovial, 5% bone, 5% Ewing’s, and 34% other. Pts were refractory to 1(20%), 2(22%), and ≥3 (58%) regimens. Grade 3-4 treatment related adverse events (TRAE) occurred in 7% (N3) and 14% (N3+I1) and 0 Gr 5 TRAEs. 8% of pts stopped due to AEs (2% N3, 14% N3+I1). 2/3 confirmed responses on N3, with 2 ongoing (range 1.1-3.2 months). 6/7 confirmed responses (2 complete) on N3+N1, with 5 ongoing (range 6-13 months). Responses occurred in 7 histologies. See Table for pt outcomes. Conclusions: N + I showed acceptable safety and encouraging antitumor activity with most responses ongoing across multiple SAR histologies, passing efficacy criteria. There was minimal activity observed with N alone. Increased TRAEs were observed in N3+I1. Correlative analyses ongoing. NCT02500797. Support: U10CA180821, U10CA180882, Conquer Cancer Foundation, BMS. Clinical trial information: NCT02500797. [Table: see text]