B52 Background: This phase I study was conducted to determine the safety profile and recommended dose of IMC-11F8, a recombinant human IgG1 monoclonal antibody that targets the EGFR. Methods: Patients (pts) with advanced solid malignancies who were refractory to or had no available standard therapy received IMC-11F8 intravenously at 100, 200, 400, 600, 800, or 1000 mg either weekly (Arm A) or every other week (Arm B) for 6 weeks (1 cycle). Prior to the initial cycle, pts received one IMC-11F8 infusion at their assigned cohort followed by a 2-week pharmacokinetic (PK) period. Pts with stable disease or response after cycle 1 were eligible to receive additional cycles of IMC-11F8. Results: 60 pts were enrolled in the 100-, 200-, 400-, 600-, 800-, and 1000-mg cohorts. 29 pts (M/F 11/18, median age 60 years) received IMC-11F8 weekly and 31 pts (M/F 14/17, median age 59 years) received IMC-11F8 every other week. Dose limiting toxicities (DLTs) of nausea, vomiting, and headache were observed in the peri-infusional period in 2 patients in the 1000-mg cohort with IMC-11F8 administered every other week. Grade 3-4 adverse events considered at least possibly related to IMC-11F8 include fatigue and acne in the weekly dosing schedule and anemia, diarrhea, nausea, vomiting, fatigue, decreased blood magnesium, hypokalemia, headache, and acne in the every other week dosing schedule. Two pts achieved partial responses including 1 pt with melanoma in the 200-mg cohort after 14 weeks of treatment with IMC-11F8 administered once a week (duration of response=15.6 months) and 1 pt with rectal cancer in the 400-mg cohort after 12 weeks of treatment with IMC-11F8 administered every other week (duration of response=5.6 months). An additional 16 pts (Arm A=8 pts, Arm B=8 pts) in the 200- to 1000-mg cohorts had stable disease and received from 10 to 49 weeks of IMC-11F8 treatment; cancer types include colorectal, renal, prostate, melanoma, ovarian, cholangiocarcinoma, and sinus piriformis. A noncompartmental analysis of 39 pts (Arm A=17, Arm B=22) demonstrated that IMC-11F8 exhibits nonlinear PK. As IMC-11F8 escalated from 100 to 1000 mg, T1/2 increased from 70 to 351 hrs and 30 to 138 hrs, Cmax increased from 40 to 804 µg/mL and 33 to 885 µg/mL, AUCinf increased from 2968 to 304457 hr*µg/mL and 1224 to 147879 hr*µg/mL, and CL decreased from 41.6 to 3.8 mL/hr and 90.2 to 7.1 mL/hr in Arm A and Arm B, respectively. Conclusion: IMC-11F8 is well tolerated and no unanticipated safety signals were observed. The maximum tolerated dose of IMC-11F8 was determined to be 800-mg administered every other week. Antitumor activity included 2 pts with tumor regression and several others with prolonged disease stabilization.
3017 Background: AZD2171 is an oral, highly potent, vascular endothelial growth factor (VEGF) signaling inhibitor. This Phase I trial is evaluating the safety, tolerability, pharmacokinetics (PK) and efficacy of AZD2171, in combination with gefitinib (IRESSA), an inhibitor of EGF receptor tyrosine kinase. Methods: Patients with advanced solid tumors refractory to standard therapies received once-daily, oral AZD2171 (20, 25, 30 or 45 mg) and gefitinib 250 (Part A1) or 500 mg (Part B1) until dose-limiting toxicity was observed. The potential PK interaction of AZD2171 30 mg with gefitinib 250 mg was studied in an expanded cohort (Part A2). Part B2 follows the design of Part A2, with a gefitinib dose of 500 mg. Results: As of September 1, 2005, 70 patients (22–78 years) have received treatment ( Table ). Overall, the most frequently reported adverse events (AEs) were diarrhea, anorexia, fatigue and hypertension (91%, 64%, 51% and 51% of patients; respectively), with evidence of an AZD2171-related dose response for hypertension (reported in 36%, 75%, 47% and 75% of patients at AZD2171 20, 25, 30 and 45 mg; respectively). These were also the most commonly reported CTC grade ≥3 AEs, occurring in <13% of patients, in addition to increases in alanine aminotransferase (7%) and aspartate aminotransferase (4%). The steady-state PK parameters for AZD2171 (30 mg) and gefitinib (250 mg) are comparable with those seen previously with either agent alone. In total, 28 patients had a best RECIST response of stable disease (22 patients were non-evaluable). A patient with mesothelioma (45 mg AZD2171, Part A1) and a patient with renal cancer (20 mg AZD2171, Part B1) had confirmed partial responses. The second patient underwent surgery and is currently disease-free. Conclusions: No unexpected toxicities are associated with AZD2171 (20–45 mg) in combination with gefitinib (250 or 500 mg) and the preliminary response data are encouraging. [Table: see text] [Table: see text]
