Phase I study of the multikinase prodrug SF1126 in solid tumors and B-cell malignancies.

Abstract

3015 Background: SF1126 is a peptidic prodrug that converts to LY294002, a widely studied dual PI3K/mTOR inhibitor that historically suffered from poor solubility. LY294002 is conjugated to an RGD peptide via a cleavable linker to form SF1126, which demonstrates improved solubility and site selectivity. LY294002 also inhibits other cancer target kinases including DNA-PK, PIM1, and PLK1 and induces oxidative stress in cancer cells. Methods: 39 pts with advanced solid tumors were enrolled in sequential cohorts in a standard 3+3 design. SF1126 was administered days 1, 4 weekly by 90 min i.v. infusion in 4 wk cycles. The maximum administered dose (MAD) level cohort (1,110 mg/m2) was expanded to allow pts with B-cell malignancies. Clinical response was evaluated according to standard disease-specific criteria. Primary objectives were to determine safety and a recommended phase 2 (RP2) dose. Results: Part 1 Solid Tumors. Toxicities were generally grade 1/2 with only 1 DLT (transient G3 diarrhea at 180 mg/m2 dose level). Stable disease (SD) was the best response in 19 of 33 (58%) of evaluable pts. Prolonged SD over 1 yr was noted in one GIST pt (18 cycles) and one renal cell carcinoma pt (21 cycles) who had progressed on temsirolimus representing possible evidence of effect of SF1126 on mTORC1 resistance. Part 2 B-Cell Malignancies. Four CLL pts and 1 DLBCL pt have been treated. One CLL pt who had progressed on rituximab achieved SD after two months of SF1126 alone. SF1126 plus rituximab led to a partial response with decreased absolute lymphocyte count, lesion sum products and spleen size. Flow cytometry and Western blotting of CLL cells showed that SF1126 reduced expression of p-AKT over time and increased late apoptosis demonstrating pharmacodynamic inhibition of activated PI3K signaling. Conclusions: SF1126 is well tolerated at doses up to 1,110 mg/m2 given by i.v. infusion twice weekly and showed significant disease stabilization in multiple solid tumor pts. MTD was not reached. The RP2 dose of 1,110 mg/m2 is the MAD and was reached based on the findings of safety, PK, PD, toxicity, and activity profile in solid tumor pts. In B-cell malignancies promising preliminary activity alone and in concert with rituximab was noted.