A phase I study of AVE1642, a humanized monoclonal antibody IGF-1R (insulin like growth factor1 receptor) antagonist, in patients(pts) with advanced solid tumor(ST)

3582 Background: AVE1642, a humanized mAb, binds the human IGF1R specifically and with high affinity (Kd<1nM). It delays growth of cancer cells in vitro and of human tumors xenografted to nude mice. Materiel and Methods: this study aims to select the dose of AVE1642 to be combined with docetaxel 75 mg/m2 (D). AVE1642 was administered as single agent at cycle(cy)1 and then in combination with D from cy2, q3w. Sequential tumor biopsies were performed in a subset of pts. Main eligibility criteria: ≥ 18y.o; measurable or evaluable advanced ST; PS ≤2; HbA1c≤7.5% or FPG≤160mg/dL. PK/PD: blood was collected at d1, d2, d8, d15 and d22 cy1 and cy2 and at d22 of each subsequent cy. Selection of the dose is based on safety (<33% pts with DLT) and on PK, PD parameters. Results: as of 20-Dec-07, 14 pts (4 at 3mg/kg; 4 at 6mg/kg; 4 at 12mg/kg; 2 at 18mg/kg) received 49cy, including 35cy with T. Safety: No DLT/related SAE were reported so far. Gr1/2 related AEs: hyperglycemia(1), hypersensitivity reactions (2), asthenia(2), anemia(1), nail disorder(1), paresthesia(1), pruritus(1). No anti-drug antibodies detected. Activity: 1 pt with breast cancer has had reduction in skin nodules and is on study cy6. In addition, 4 SD confirmed at cy4 are reported (small cell oesophagus, colon, melanoma, epithelioid sarcoma). Preliminary PK/PD data (mean, [CV%], (n)). AVE1642 concentrations increased dose-proportionally. Elimination t½ was ≈ 9 days. No PK interaction was observed. At all dose levels, mean IGF1 levels increased up to 6-fold from baseline, plateauing from 14–21d. Conclusion: AVE1642 is well tolerated as single agent and in combination with D. PK/PD data suggest a substantial and maintained biological effect from dose level 3mg/kg. Dose (mg/kg) AVE1642 IGF1 Cmax (μg/mL) t½(day) CL (L/day) maxEffect (ng/mL) tmax (day) 3 76.4 [12.7] (5) 9.31[17.9] (5) 0.471 [67.9] (5) 558 (3) 63 (3) 6 158 [22.1] (8) 8.60[14] (8) 0.265 [48.4] (8) 589 (3) 63 (3) 12 249 [25.1] (3) 9.01[12.7] (3) 0.281 [23.1] (3) 633 (2) 14 (2) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis