Measurement of interstitial fluid pressure (IFP) and circulating biomarkers in soft tissue sarcoma (STS): An exploratory phase II clinical and correlative study of sorafenib (SOR) in patients with refractory STS (NCI Protocol 6948).

Abstract

10091 Background: Interstitial hypertension may contribute to chemo-resistance in STS. Sorafenib is a small molecule tyrosine kinase inhibitor with potent activity against c-RAF/B-RAF, VEGFR-2, and PDGFR-β. By affecting vascular permeability, SOR may potentially reduce IFP. We assessed anti-tumor activity and measured the IFP and circulating biomarkers in patients with superficial refractory STS treated with SOR. Methods: Eligibility criteria included advanced/metastatic STS with no known curative therapy, measurable disease with at least one superficial lesion (>1cm) amenable to biopsy, age ≥18, ECOG performance status ≤2, and no prior SOR therapy. SOR was administered at 400mg BID. IFP measurements were performed intraoperatively as described (Boucher et al 1991); plasma biomarkers were collected pre- and on Day 28 post-SOR. Results: Fifteen patients (median age 59, range 30-84) were enrolled, 14 of whom had prior chemotherapy and/or radiation. Median tumor size was 6.6cm (range 1.3-10.7cm). Common sarcoma sub-types included leiomyosarcoma (27%), myxofibrosarcoma (13%) and synovial sarcoma (13%). Of these, 11 had superficial tumor amenable to biopsy. In this group, median TTP was 28 days (range 10-81). In four pts lacking palpable superficial tumor, mean TTP was 173 days (range 28-227). Best response was stable disease in 10 of 15 pts, maintained for a median 57 days (range 20-168 days). IFP measurements were obtained in 6 pts at baseline and showed a direct correlation with tumor size (Kendall's tau=0.87, p=0.017). Two pts with SD had corresponding post-SOR IFP evaluation and demonstrated a decline in IFP. SOR significantly increased plasma VEGF, PlGF and SDF-1a and decreased sVEGFR2 (p<0.05 for all). Conclusions: SOR has modest benefits in this population, most of whom had advanced refractory disease. IFP appears to decrease when response is maintained. Biomarker changes were consistent with inhibition of angiogenesis by SOR. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, ARIAD, ArQule, AstraZeneca, Bayer, Daiichi Sankyo, Dyax, Genentech, Infinity, Johnson & Johnson, Millennium, Novartis, Pfizer, PharmaMar, Regeneron, Roche, SynDevRx, ZIOPHARM Oncology SynDevRx Novartis, Pfizer, PharmaMar Amgen, ARIAD, ArQule, Daiichi Sankyo, Genentech, Infinity, Johnson & Johnson, Novartis, Pfizer, PharmaMar, Roche, ZIOPHARM Oncology ARIAD, ArQule, Daiichi Sankyo, Infinity, Johnson & Johnson, PharmaMar