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ESMO 2012 Ficlatuzumab PKPD Poster 443PD Pharmacodynamic–pharmacokinetic study of fi clatuzumab, a monoclonal antibody directed to the hepatocyte growth factor (HGF), in patients with advanced solid tumors who have liver metastases E. Elez1, J. Tabernero1, L. Prudkin1, S. Agarwal2, M. Han2, M. Credi2, W. Yin2, N. Kuriyama2, J. Baselga3 1Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain; 2AVEO Oncology, Cambridge, Massachusetts, United States; 3Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States • PK profi les for fi clatuzumab are depicted in Figure 2 and showed a clear relationship in Figure 1. Ficlatuzumab’s Mechanism of Action1-5 Table 2. TEAEs Occurring in ≥3 Pts drug levels versus dose Figure 5. Correlations Between Percent Changes in p-Met Versus p-S6K and p-ERK Abstract 2 mg/kg 10 mg/kg 20 mg/kg Total (%) • The PK of fi clatuzumab was characterized by low clearance (CL) ranging from 0.178 to 0.261 HGF p-Met versus p-S6K FICLATUZUMAB 200 n=6 n=7 n=6 n=19 mL/hr/kg, a long half-life (t1/2) ranging from 7.4 to 10 days, and Vd ranging from 61 to 75 mL/kg n=18 2 mg/kg 150 r=0.479 10 mg/kg • There were no statistically signifi cant changes in CL or t with dose. C and area P=0.044 20 mg/kg Background: Ficlatuzumab is a humanized IgG1 mAb directed to HGF that Asthenia 2 3 1 6 (32) 1/2 max 100 under the curve (AUC) increased in an approximately dose-proportional manner inhibits activation of the c-Met receptor and has potential anti-tumor activity. Hepatic pain 2 3 1 6 (32) 50 This study defi ned the optimal dose using pharmacodynamic and pharmacokinetic • There was evidence of accumulation between Cycle 1 and 2 p-S6K H-score 0 Three pts experienced decreases in Peripheral edema 1 3 2 6 (32) -50 (PK) assessments. change from baseline (%) p-S6K and had the strongest decrease -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 in p-Met. Pts with p-Met decreases Cough 1 2 2 5 (26) p-Met change from baseline (%) Methods: Patients (pts) with solid tumors and liver metastases and with phospho c-MET Table 6. PK Parameters of Ficlatuzumab by Treatment Group in Cycle 1 appeared to have less of an increase (p)-Met expression were sequentially enrolled to receive 2, 10, or 20 mg/kg (RP2D, p-Met versus p-ERK in p-S6K. Correlation between p-Met Abdominal distension 1214 (21) C t AUC CL t V 100 to p-S6K and p-ERK suggests that Parameter max max 0-∞ 1/2 d n=18 2 mg/kg defi ned in a previous study) of intravenous (IV) fi clatuzumab every 2 weeks (wks) (μg/mL) (h)a (mg•h/mL)b (mL/h/kg)b (h)b (mL/kg)b r=0.456 10 mg/kg these downstream signaling changes Abdominal pain 1 2 1 4 (21) P 20 mg/kg and were evaluated every 8 wks for response using Response Evaluation Criteria 50 =0.057 may result from changes in p-Met. 2 mg/kg In Solid Tumors (RECIST) 1.1. Target pathway modulation was assessed by Increased blood bilirubin 3 1 0 4 (21) 0 n 6 6 4 4 4 4 p-ERK H-score measuring the following pharmacodynamic markers by immunohistochemistry (IHC) P P Constipation 0213 (16) -50 in biopsies of liver metastases: p-Met, p-Akt, p-ERK, p-S6K, HGF, c-Met, Ki67, change from baseline (%) Scattering Decreased appetite 1 2 0 3 (16) Mean 39.1 1.5 8.38 0.245 178 61.3 -90 -80 -70 -60 -50 -40 -30 -20 -10 01020304050607080 cleaved caspase-3, and CD31. Pharmacodynamic-evaluable pts had measurable PI(3)K P Rac (SD) (14.0) (0.58-3.5) (1.59) (0.0484) (32.7) (4.16) p-Met change from baseline (%) P Anoikis Dyspnea 0 2 1 3 (16) p-Met at Cycle 1, Day 1 pre-dose, and at least one post-dose time point. Serum was Akt (apoptosis) protection %CV 36 NA 19 20 18 6.8 collected to measure fi clatuzumab, anti-drug antibodies (ADAs), s-Met, HGF, and Ras P MAP Anemia 0 2 1 3 (16) kinases Figure 6. Example of Pharmacodynamic Changes Pre- and Post-Ficlatuzumab Treatment HGF/fi clatuzumab complex levels by enzyme-linked immunosorbent assay (ELISA). Gab-1 Cell 10 mg/kg P proliferation Increased gamma-glutamyl STAT Results: Nineteen pts received fi clatuzumab: 15 men/4 women; mean age 60 years; a 3 0 0 3 (16) P Shc Branched transferase (GGT) n 7 7 6 6 6 6 p-MET p-MAPK Ki67 CD31 Tumor HGF morphogenesis Eastern Cooperative Oncology Group Performance Status (ECOG PS) PLC-γ P a No patient experienced GGT laboratory abnormality of Grade >2. Signal P Mean 173 1.5 40.52 0.261 207 75.4 0/1 (8/11 pts). The most frequent treatment-emergent adverse events (TEAEs) were amplification Before asthenia (32%), peripheral edema (32%), hepatic pain (32%), and cough (26%). (SD) (39.9) (0.58-3.6) (11.24) (0.0637) (46.1) (15.1) ficlatuzumab There were no dose-limiting toxicities (DLTs) or ADAs. Serum albumin decreased to Table 3. All TEAEs ≥ Grade 3 %CV 23 NA 28 24 22 20 below normal for the majority of pts at end of treatment and trended toward recovery 2 mg/kg 10 mg/kg 20 mg/kg Total (%) 20 mg/kg at the follow-up visit. Best overall response was stable disease (SD) (5/18 pts) and After disease progression (13/18 pts), and median duration of treatment was 6 wks (range Study Objectives n=6 n=7 n=6 n=19 n 6 6 4 4 4 4 ficlatuzumab 2-59). PK analysis revealed dose-proportional drug exposure with a low systemic Asthenia 0 0 1 1 (5) Mean 443 1.0 117.0 0.178 239 61.2 clearance leading to a terminal half-life of 7.4 to 10.0 days and a low volume of Dyspnea 0 0 1 1 (5) (SD) (111) (0.5-1.5) (27.76) (0.0398) (43.3) (17.8) distribution approximating the plasma volume. Ficlatuzumab treatment increased Primary objective • The pt was diagnosed with advanced colorectal carcinoma with lung and liver metastasis a %CV 23 NA 24 22 18 29 the total serum HGF and HGF/fi clatuzumab complex levels. Increasing dose of Evaluate the safety and tolerability of fi clatuzumab and investigate the effect of Hyperbilirubinemia 1 0 0 1 (5) • The pt experienced pharmacodynamic changes in nearly all the markers tested • • Pt received 3 cycles of ficlatuzumab at 20 mg/kg and had progressive disease due to suspected new fi clatuzumab resulted in progressive decreases in p-Met and p-Akt. At RP2D, the fi clatuzumab on exploratory pharmacodynamic markers in the serum and within the tumor a Hypoalbuminemia 0 1 0 1 (5) Median (minimum, maximum) presented for tmax. liver lesion by CT; however, the new lesion was not detected with PET majority of pts experienced ≥25% decrease from baseline in p-Met, p-Akt, p-ERK, bOnly pts with PK profi les evaluable for complete non-compartmental analysis were included. Secondary objective Hypokalemia 0 1 0 1 (5) AUC =area under the concentration-time curve extrapolated to infi nite time; CL=clearance; Ki67, and CD31. 0-∞ C =maximum plasma concentration; h=hour; NA=not applicable; SD=standard deviation; Evaluate the PK profi le of fi clatuzumab and study the preliminary anti-tumor activity max Conclusions: Ficlatuzumab is well tolerated in this population. The PK of fi clatuzumab • Proteinuria 1 0 0 1 (5) t =time to maximum plasma concentration; t =terminal elimination half-life; V =volume of distribution; of fi clatuzumab max 1/2 d Summary of Results in this study was consistent with that reported previously. Increase in post-dose serum Respiratory failure 0 0 1 1 (5) %CV=percent coeffi cient of variation. HGF and HGF/fi clatuzumab complex levels indicates target engagement. At RP2D, a aLikely related to liver metastasis biopsy procedures. majority of pts experienced decreases in key cell signaling pharmacodynamic markers. Study Design • The most frequent TEAEs were asthenia (32%), peripheral edema (32%), hepatic pain This study supports the selection of the 20-mg/kg fi clatuzumab dose as RP2D. Figure 3. Change in Serum HGF Levels from Baseline (32%), and cough (26%) Table 4. Lab Abnormalities ≥ Grade 3 • There were no DLTs or ADAs detected • A single-center, open-label study 2 mg/kg 10 mg/kg 20 mg/kg Total (%) 20 20 mg/kg • The best overall response was SD (5/18 pts) and disease progression (13/18 pts), and • Ficlatuzumab was administered as a 30-minute IV infusion once per cycle 18 10 mg/kg median duration of treatment was 6 wks (range 2-59) (1 cycle=14 days) n=6 n=7 n=6 n=19 16 Background 2 mg/kg • The PK of fi clatuzumab was characterized by low CL and a long t of 7 to 10 days; 1/2 • Pts were sequentially enrolled into cohorts of 2 mg/kg (n=6); 10 mg/kg (n=7); and 20 Uric acid 2 2 1 5 (26) 14 12 fi clatuzumab exhibited linear PK across all dose levels tested mg/kg (n=6), which was the RP2D defi ned in a previous study Alkaline phosphatase 1 1 2 4 (21) 10 • Ficlatuzumab treatment resulted in dose- and time-dependent increase in serum HGF • Ficlatuzumab (AV-299, formerly SCH 900105) is a humanized HGF IgG1 inhibitory • Target pathway modulation was assessed by measuring the following pharmacodynamic Hypoalbuminemiaa 0 1 1 2 (11) 8 • At 20 mg/kg, the majority of pts experienced ≥25% decrease from baseline in p-Met, monoclonal antibody that markers by IHC in biopsies of liver metastases: p-Met, p-Akt, p-ERK, p-S6K, HGF, 6 Hyperglycemia 1 0 0 1 (5) from baseline p-ERK, p-Akt, Ki67, and CD31 and increased HGF in the tumor Neutralizes all HGF biological activities tested, such as HGF/c-Met binding, 4 - c-Met, Ki67, cleaved caspase-3, and CD31 HGF-fold change All pts treated with 20 mg/kg fi clatuzumab had a decrease of p-ERK in the tumor HGF-induced c-Met phosphorylation, cell proliferation, invasion, and migration1 Hypocalcemia 0 0 1 1 (5) 2 • • Serum was collected to measure fi clatuzumab, ADAs, s-Met, and HGF levels by ELISA 0 biopsies post-treatment 2-4 b - Inhibits tumor growth in autocrine and paracrine HGF-driven tumor models Total bilirubin 1 0 0 1 (5) 0 10203040 Key Inclusion Criteria • Changes in p-Met were correlated with changes in p-S6K and p-ERK • HGF/c-Met pathway dysregulation is an important driver of cancer and contributes to a Serum albumin decreased to below normal for the majority of pts at end of treatment and trended toward Days after ficlatuzumab treatment resistance to targeted anti-cancer agents • Advanced metastatic colorectal, breast, gastric/esophageal, or pancreatic cancer recovery at the follow-up visit.
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