An enriched phase I, pharmacokinetic and pharmacodynamic study of the N-cadherin (NCAD) cyclic competitive binder exherin (ADH-1) in patients with solid tumors

3042 Background: N-cad is a cell adhesion molecule expressed by vascular endothelium and tumor cells of invasive tumors. ADH-1, a cyclic pentapeptide, antagonizes N-cad, causing rapid tumor vascular disruption and apoptosis in preclinical models. We report results from a Phase I study of weekly doses of intravenous ADH-1 given to patients with N-cad+ solid tumors, to evaluate safety, PK, antitumor activity, and effect of ADH-1 on tumor vasculature assessed by DCE-MRI. Methods: ADH-1 starting dose was 150 mg/m2 administered weekly for 3 W in 28 D cycles. DCE-MRI was performed to assess changes in tumor perfusion 90 mins after the first dose of ADH-1, and repeated on D 15 if no changes were noted. Following the 3rd dose level (DL 3, 600 mg/m2 ), the schedule was amended to weekly ADH-1 without interruption, in 21 D cycles. Results: 55 pts with refractory solid tumors were screened, 56% were N-cad+ [screened/N-cad+: GYN 16/21 (Ovarian 13/17), GI 5/14, breast 2/6, renal 5/5, head & neck 2/3, others 2/6]. 13 pts (5 males, median age 53 yrs.) received 20 cycles of ADH-1 by bolus injection at 150, 300 and 600 mg/m2/weekly ×3 W Q21–28 D. No DLTs have occurred to date. No pts have experienced > grade 2 study drug related AEs. One pt, with fallopian tube ca. had a mixed response. There was a 30% reduction in retroperitoneal nodal disease at the end of cycle 3, and a 37% reduction at the end of Cy 4. However, new bone lesions were also noted at the end of cycle 4 assessment. Tumor blood flow reduction of ≥40% was noted in this patient, and she also reported pain in the region of the tumor following multiple doses of ADH-1. PK parameters are available for the first 3 DLs (150, 300, and 600 mg/m2): mean Cmax 22.1, 37.0, and 50.8μg/mL, respectively; AUCinf 24.3, 60.6, and 110.3 h·μg/mL; Vss 12.6, 15.1, and 16.3 L/m2; and T1/2 1.8, 2.7, and 2.4hr. Conclusions: ADH-1 has been well tolerated in 4 dose levels tested to date, dose escalation is proceeding. No DLTs have occurred and the MTD has not been reached. Anti-tumor activity has been noted. Updated clinical, PK and PD results will be presented. [Table: see text]