Evaluation Of Indibulin, A Novel Tubulin Targeting-Agent, In Combination With Capecitabine, With Mathematically Optimized Dose Scheduling

2538 Background: Indibulin (IDB) is a novel, orally available tubulin-targeting molecule that perturbs cancer cell migration and mitosis. It is active against taxane-resistant cell lines and is synergistic with 5-FU in vitro and in vivo. Two translational studies have been conducted: a Phase IB study of IDB in combination with capecitabine (CAP) in patients with advanced solid tumors, and mathematical modeling applying Norton-Simon models to breast carcinoma MX-1 xenografts to further develop Phase II dose. Methods: IDB is administered continuously starting at 400 mg BID. CAP is administered for 2 weeks with 1 week rest, starting at 875 mg/m2 BID. IDB and CAP are escalated to MTD: IDB 600 mg BID & CAP 1000 mg/m2 BID. Efficacy is evaluated every 9 weeks using RECIST. In the xenograft model indibulin is administered at dose levels from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma. Tumor growth is analyzed using a Gompertzian-type growth model to determine via calculus of variations the optimal schedule to maximize the efficacy/toxicity ratio. Results: To date, 7 patients have been treated and are evaluable for safety. Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are evaluable for efficacy and all have stable disease (3 for 6 cycles, 1 for 3 cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting, anorexia, and headache. Neither DLTs nor grade ≥3 AEs have been observed. In MX-1 xenografts, indibulin demonstrates linear dose-efficacy relationship over the range of 12 to 22 mg/kg. At all dose levels the first 5 days of administration are associated with a rapid accumulation of anticancer effect with lesser effects over the next 5 days to a peak of efficacy at day 10 Conclusions: IDB + CAP is well tolerated, without neurotoxicity. There is preliminary evidence of clinical activity even with this sub-optimal, continuous schedule of IDB. Formal analyses suggest that an intermittent schedule could optimize efficacy, minimize acquired resistance and allow for host recovery from drug-induced toxicity. Pre- clinical evaluation in a breast cancer model supports an intermittent dosing schedule to further increase the activity of IDB. [Table: see text]