No antiCAMG 102 antibodies were detected. Table?4. Patient Incidence of Treatment-Related Adverse Methoxatin disodium salt Eventsa = 40= 20= 60(%)23 (58)8 (40)31 (52)Patients with grade 3 AEs,b(%)4 (10)1 (5)5 (8)AEs occurring in 2 patients, (%)Any GradeGrade 3/4Any GradeGrade 3/4Any GradeGrade 3/4?Fatigue9 (23)1 (3)6 (30)1 (5)15 (25)2 (3)?Nausea5 (13)0 (0)1 (5)0 (0)6 (10)0 (0)?Peripheral edemac4 (10)1 (3)1 (5)0 (0)5 (8)1 (2)?Diarrhea4 (10)0 (0)0 (0)0 (0)4 (7)0 (0)?Dry skin4 (10)0 (0)0 (0)0 (0)4 (7)0 (0)?Arthralgia3 (8)0 (0)0 (0)0 (0)3 (5)0 (0)?Hypophosphatemia3 (8)3 (8)0 (0)0 (0)3 (5)3 (5)?Dysgeusia2 (5)0 (0)0 (0)0 (0)2 (3)0 (0)?Hypoasthesia2 (5)0 (0)0 (0)0 (0)2 (3)0 (0)?Edemab2 (5)1 (3)0 (0)0 F-TCF (0)2 (3)1 (2)?Asthenia1 (3)0 (0)1 (5)1 (5)2 (3)1 (2)Patients with any serious AE, (%)1 (3)1 (3)0 (0)0 (0)1 (2)1 (2)?Edema (grade 3)1 (3)1 (3)0 (0)0 (0)1 (2)1 (2) Open in a separate window AE, adverse event. aAEs are reported for patients who received 1 dose of AMG 102 and include all AEs for ongoing patients and AEs with onset from the first dose of AMG 102 until 30 days after the last dose of AMG 102 for patients who discontinued treatment. 12.05- and 1.12-fold, respectively, from baseline during AMG 102 treatment. AMG 102 monotherapy at doses up to 20 mg/kg was not associated with significant antitumor activity in heavily pretreated patients with recurrent GBM. RNA was determined by quantitative reverse transcription (qRT) PCR analysis.24 Changes in Methoxatin disodium salt log total HGF/SF and soluble c-Met changes over time were analyzed using repeated-measures analysis of variance (ANOVA); their relationships with PFS and best ORR were assessed using proportional hazards and nominal logistics models and 2-way ANOVA. For c-Met immunohistochemistry, associations between categorical variables were assessed with a logistic model using a likelihood ratio test; a log-rank test was used to assess differences in PFS among categorical groups. Relationships between mutations and PFS were assessed by log-rank and Wilcoxon tests. Statistical Analysis The study design had a power of 0.90 for a given cohort to distinguish between an active drug with a 20% true response rate and a drug with a response rate of 5% with an alpha level of 0.05. The best ORR (complete response and partial response) was summarized by dose by calculating the response rate with an exact 2-sided 95% confidence interval (CI) as described previously.25 For PFS and OS, KaplanCMeier estimates and 2-sided 95% CIs for rates at 8-week intervals and for quartiles were calculated, and group differences were evaluated with the log-rank test. PFS was calculated as the time in weeks from the first dose of AMG 102 to disease progression (per Macdonald criteria) or death from any cause. The primary and secondary endpoint and safety analyses were conducted for all patients who received 1 dose of AMG 102 in each cohort. SAS software (version 9.1; SAS Institute, Cary, NC) was used for statistical analyses. Results Patients Between January 12, 2007, and February 20, 2008, 61 patients were enrolled in this study (10-mg/kg cohort, = 41; 20-mg/kg cohort, = 20) and received AMG?102, except for 1 patient (10-mg/kg cohort) who was not treated (Table?1). Approximately one half (= 29, 48%) of patients had previously received bevacizumab (10-mg/kg cohort, = 19 [48%]; 20-mg/kg cohort, = 10 [50%]). Some patients Methoxatin disodium salt received agents with potential anti-angiogenic activity, including vascular endothelial growth factor (VEGF) receptor 2 tyrosine kinase Methoxatin disodium salt inhibitors (= 5), aflibercept (= 4), cilengitide (= 2), thalidomide or lenalidomide (= 2), and/or other nonCanti-angiogenic targeted therapies (= 15). Fifty-nine patients (98%) received prior radiotherapy (10-mg/kg cohort, = 39 [98%]; 20-mg/kg cohort, = 20 [100%]), including 6 (all in the 10-mg/kg cohort) who received treatment within 12 weeks of enrollment and thus may have exhibited pseudoprogression.26 The median (range) duration of treatment with AMG 102 was 4.1 weeks (2.1C167.7) and 4.1 weeks (1.9C25.0) in the 10- and 20-mg/kg cohorts, respectively. The median (range) follow-up times were 27.6 weeks (3.0C106.1) and 23.4 weeks (3.1C56.7) in the 10- and 20-mg/kg dose cohorts, respectively. The reasons for discontinuing the study were disease progression (= 52 [87%]), consent withdrawn (= 3 [5%]), AEs (= 2 [3%]), protocol deviation (= 1 [2%]), and death (= 1 [2%]). As of May 2010, a 51-year-old white male patient (10-mg/kg cohort) diagnosed with stage IV GBM and 90% KPS was still receiving AMG 102 after 167.7 weeks. Table?1. Demographics and Key Baseline Characteristics = 40= 20= 60a(%)?Women15 (38)7 (35)22 (37)?Men25 (63)13 (65)38 (63)Race, (%)?White36 (90)18 (90)54 (90)?Black3 (8)0 (0)3 (5)?Hispanic1 (3)1 (5)2 (3)?Asian0 (0)1 (5)1 (2)Age, median (range)54 (19C71)54 (26C71)54 (19C71)Karnofsky performance status, (%)?1001 (3)1 (5)2 (3)?9018 (45)7 (35)25 (42)?8014 (35)7 (35)21 (35)?704 (10)3 (15)7 (12)?603 (8)2 (10)5 (8)Histologic type for primary tumor, (%)?Glioblastoma multiforme38 (95)20 (100)58 (97)?Low-grade gliomab1 (3)0 (0)1 (2)?Other1 (3)0 (0)1 (2)Months since initial diagnosis,c?median (range)16 (3.9C78)14 (1C40)16 (1C78)Prior therapies,d(%)?00 (0)0 (0)0 (0)?111 (28)3 (15)14 (23)?213 (33)9 (45)22 (37)?316 (40)8 (40)24 (40)Prior radiotherapy, (%)?01 (3)0 (0)1 (2)?133 (85)19 (95)52 (87)?25 (13)1 (5)6 (10)?31 (3)0 (0)1 (2)Prior VEGF pathway inhibitors, (%)?Bevacizumab19 (48)10 (50)29 (48)?Aflibercept3 (8)1 (5)4 (7)?Sorafenib0 (0)2 (10)2 (3)?Pazopanib1 (3)0 (0)1 (2)?Vandetanib1 (3)0 (0)1 (2)?Vatalanib1 (3)0 (0)1 (2)Prior surgery,e(%)40 (100)20 (100)60 (100) Open in a separate window aPatients who received 1 dose of AMG 102. bEnrollment of the.