Phase I Evaluation Of Sf1126, A Vascular Targeted Pi3k Inhibitor, Administered Twice Weekly Iv In Patients With Refractory Solid Tumors

2558 Background: SF1126 is composed of the pan PI3K inhibitor LY294002 conjugated to an RGD targeting peptide. It is designed to increased solubility and binding to integrins expressed on tumor vasculature. This targeted prodrug enhances tumor delivery of the active inhibitor, improving antitumor efficacy and tolerability in xenograft models. LY294002 inhibits other kinases including mTOR, DNA-PK, PIM1, PLK1, and CK2, and induces oxidative stress in cancer cells independent of its PI3K inhibition. Methods: Pts with advanced solid tumors are enrolled in sequential cohorts in standard 3+3 design. SF1126 is administered days 1, 4 weekly by 90 minute IV infusion in cycles of 4 weeks. Pharmacodynamic (PD) evaluations of PI3K pathways are being measured in PBMC, skin/hair and tumor samples as well as by 18FDG PET scans. Primary objectives are safety, establish MTD and recommended phase 2 dose. Results: 28 pts have been treated with SF1126126 across 7 dose levels of 90, 140, 180, 240, 320, 430, and 630 mg/m2. One dose limiting toxicity (DLT) was seen at the 180 mg/m2 dose, consisting of transient G3 diarrhea. No other grade 3/4 drug related toxicities have been reported. No consistent effects on blood glucose levels noted. Eleven pts showed stable disease for ≥ 8 wks, including durations of 20 wks for one GIST, 1 endometrial, and 1 prostate; 15 wks for 1 pancreatic; 11 wks for 2 GIST, 2 ovarian, and 1 CRC pt. PK: SF1126 is rapidly cleared after infusion termination. PK of active hydrolysis product (LY294002) shows t1/2 ∼1.6–2 hrs; dose proportional Cmax, achieving ∼ 21uM at 630 mg/m2; and AUC(0-t) nearly dose proportional. Mean AUC values at doses ≥ 140 mg/m2 exceed those found effective in mouse xenograft studies. PD: Compared to baseline biopsy, we observed significant inhibition of pS6 by IHC in a tumor biopsy 20 hours after the 8th dose in a pancreatic cancer pt at 240 mg/m2. Conclusions: SF1126 is well tolerated at doses up to 630 mg/m2 given twice weekly. MTD has not been reached; dose escalation continues. Clinical activity includes disease stabilization in multiple pts with refractory tumors. There is early evidence of target pathway inhibition. [Table: see text]