Undevia, Samir D.

10003 Background: Preclinical studies demonstrate synergistic anti-tumor activity by inhibiting mTOR and IGF-1R. This study evaluated the safety and efficacy of A12 and TEM in 3 chemo-refractory cohorts: IGF-1R (+) STS (Arm A), IGF-1R (+) bone (Arm B), and IGF-1R (-) bone and STS (Arm C). Methods: An optimal Simon 2 stage design was used for each arm. The primary end-point was progression free survival (PFS) at 12 weeks. Based on historical data, a 40% PFS rate was considered promising and a 20% PFS non-promising (type I/ II error, 0.05/0.10). ≥5 PFSs at 12 weeks were required in the first 19 and ≥16 PFSs were required in a total of 54 pts to consider each arm positive. Key eligibility: measurable disease (RECIST 1.1), age ≥18, 1- 4 priors, ECOG status 0-1. A12 (6 mg/kg) and TEM (25 mg) were administered IV weekly. Pre and post treatment tumor biopsies and plasma for IGF-1 and IGFBP3 were obtained. 20 Sarcoma Centers participated. Results: Starting in 02/2010, 383 pts were tested for IGF-1R by immunohistochemistry (IHC; 54% +) and 171 were treated: mean age 47 (range: 18-80), mean # priors 2.2 (range: 1-4). Grade 3/4 toxicities ≥10%: lymphopenia (12%), mucositis (10%). By intent to treat (ITT) analysis, each arm of the study achieved its primary 12 week PFS end-point (≥16 PFSs): Arm A: 18/56 (32%), Arm B: 19/50 (38%) (4 too early), Arm C: 27/63 (43%). The one-sided 95% CI for 12-week PFS is (0.22, 1), (0.27, 1), and (0.32, 1), respectively. By ITT the median PFS (95% CI) in weeks for each arm is 6.3 (5.9, 12.0), 11.0 (8.0, 18.0) and 11.6 (9.0, 17.9), respectively, and for chondro (n=18), Ewing’s (n=24), and osteo (n=23) only it is 22.6 (5.7, 40.9), 10.4 (5.7, 17.9) and 6.0 (6.0, 18.0), respectively. Westerns on 32 matched pair tumor biopsies indicate inhibition of IGF-1R, pAKT and pS6. Of biopsies on 7 IGF-1R (-) IHC pts (Arm C), 5 were IGF-1R (+) by western. Plasma biomarkers did not correlate with PFS. Conclusions: A12 and TEM met its primary end-point of improved PFS in pts with metastatic sarcoma. This effect was independent of IGF-1R status by IHC. These results support further clinical development of this combination in bone and STS.

Background This single‐arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. Methods Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28‐day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). Results Forty‐seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%‐58%), which was superior to the null hypothesis rate of 30%, but the 2‐sided P value (exact test) was .09 (1‐sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3‐35.0 months), and the median progression‐free survival was 7.9 months (95% CI, 3.7‐12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. Conclusions This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.