A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases

Published OnlineFirst March 14, 2014; DOI: 10.1158/1078-0432.CCR-13-1837

Clinical Cancer Cancer Therapy: Clinical Research

Josep Tabernero1, Maria Elena Elez1, Maria Herranz1, Isabel Rico1, Ludmila Prudkin1, Jordi Andreu1, Jose Mateos2, Maria Josep Carreras1, May Han3, James Gifford3, Marc Credi3, Wei Yin3, Shefali Agarwal3, Philip Komarnitsky3, and Jose Baselga4

Abstract Purpose: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases. Patients and Methods: Patients with p-Met (phosphorylated c-Met)–positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed. Results: No dose-limiting toxicities occurred in the 19 patients enrolled (n ¼ 6, 2 mg/kg; n ¼ 7, 10 mg/kg; n ¼ 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n ¼ 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (53%), p-ERK (43%), p-Akt (2%), and increased median HGF levels (þ33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4–10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year. Conclusions: Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle. Clin Cancer Res; 20(10); 2793–804. 2014 AACR.

Introduction tion, invasive growth, and angiogenesis (3–9), and is Activation of the receptor tyrosine kinase c-Met via its observed in many malignancies, including those of the ligand, HGF (1, 2), mediates proliferation, motility, and pancreas, lung, stomach, breast, and kidney (3, 5, 10–16). differentiation in several different cell types (3). Dysregula- c-Met pathway activation has been associated with pro- tion of the HGF/c-Met signaling axis can lead to aberrant cell gression from primary to metastatic disease, particularly proliferation and drug resistance and promote cell migra- with liver metastasis (17–22). Serum HGF levels are elevated in patients with breast cancer with malignant liver lesions (18), and have been correlated with liver metastases versus Authors' Affiliations: 1Vall d'Hebron University Hospital, Vall d'Hebron metastases at other sites (21). Dysregulation of c-Met is Institute of Oncology (VHIO), Universitat Autonoma de Barcelona; 2CRC associated with the presence of liver metastases in patients Hospital Quiron de Barcelona, Barcelona, Spain; 3AVEO Oncology, 4 with gastric (17) and colorectal cancer (22). These findings Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York suggest that targeting the HGF/c-Met pathway may be Note: Supplementary data for this article are available at Clinical Cancer beneficial for patients with advanced solid tumors and liver Research Online (http://clincancerres.aacrjournals.org/). metastases; in addition, patients with liver metastases are likely to have detectable p-Met (phosphorylated c-Met), J. Tabernero and M.E. Elez contributed equally to this article. making it possible to evaluate the p-Met changes in liver Corresponding Author: Josep Tabernero, Medical Oncology Department, metastases after treatment. Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, P. Vall d'Hebron 119–129, 08035 Ficlatuzumab (AV-299; formerly SCH 900105) is a Barcelona, Spain. Phone: 34-93-489-4301; Fax: 34-93-274-6059; E-mail: humanized HGF inhibitory monoclonal antibody that neu- [email protected] tralizes HGF/c-Met binding and HGF-induced c-Met phos- doi: 10.1158/1078-0432.CCR-13-1837 phorylation (23). Ficlatuzumab inhibits HGF-dependent 2014 American Association for Cancer Research. growth of tumors in preclinical tumor xenograft models of

www.aacrjournals.org 2793

Tabernero et al.

serum alanine and/or aspartate aminotransferase 5 Translational Relevance ULN], renal (serum creatinine 1.5 ULN or calculated Dysregulation of the hepatocyte growth factor (HGF)/ creatinine clearance >60 mL/min), and coagulation func- c-Met signaling pathway is observed in many malignan- tion (partial thromboplastin time 1.5 ULN; the inter- cies and associated with progression of primary solid national normalized ratio 1.5 ULN). However, patients tumors to metastatic disease, including with presence of could not have persistent, unresolved grade 2 drug-related liver metastases. Thus, inhibition of the HGF/c-Met toxicity (except alopecia, erectile dysfunction, hot flashes, pathway may be therapeutically beneficial for some decreased libido, and grade 2 sensory peripheral neuropa- patients with cancer. Ficlatuzumab is a humanized HGF thy), HIV infection or HIV-related malignancy, active hep- inhibitory monoclonal antibody that neutralizes HGF/c- atitis B or C, bleeding diathesis, hypersensitivity to any Met binding and HGF-induced c-Met phosphorylation. ficlatuzumab components, active alcohol or illicit drug In addition to evaluation of the safety, tolerability, abuse, or any of the following events 6 months before pharmacokinetic profile, and preliminary antitumor administration of study drug: serious/symptomatic active activity of ficlatuzumab in patients with advanced solid infection (or infection requiring antibiotics 14 days before tumors and liver metastases, this clinical study investi- administration), myocardial infarction, severe/unstable gated the pharmacodynamic effects of ficlatuzumab angina, pectoris, coronary/peripheral artery bypass graft, treatment in serum and tumors of patients. Mean serum symptomatic congestive heart failure, cerebrovascular acci- HGF levels increased with ficlatuzumab dose and num- dent, transient ischemic attack, or seizure disorder. Those ber of treatment cycles. At 20 mg/kg, ficlatuzumab was with any medical or psychiatric condition that might inter- well tolerated and decreases in tumor p-Met, p-Erk, and fere with trial participation or interpretation of study results p-Akt and an increase in HGF were observed, suggesting and those unable to comply with protocol requirements ficlatuzumab can modulate the HGF/c-Met pathway and were also excluded. In addition, patients were excluded if downstream signaling in the tumor. they did not have adequate recovery from prior medical procedures, i.e., major surgical procedure 4 weeks before administration of study drug, radiotherapy 3 weeks prior, and stem cell/bone marrow transplant 6 months prior. glioblastoma (24) and non–small cell lung cancer (NSCLC; Those with participation in any other clinical trials involv- ref. 25). In a first-in-human dose-escalation study, ficlatu- ing therapeutic agents were also excluded. Female patients zumab 20 mg/kg once every 14-day cycle was established as could not be pregnant or breast-feeding, and all women of the recommended phase II dose (RP2D; ref. 26). Ficlatuzu- childbearing potential and men with partners of childbear- mab is in development for the treatment of solid tumors, ing potential were required to use effective contraception including a phase Ib/II study in NSCLC (27, 28). during the study and for 60 days after the last dose. This study reports the safety/tolerability, pharmacodynamic effects in tumors and serum, pharmacokinetic pro- Study design file, and preliminary antitumor activity of ficlatuzumab Primary objectives of this phase I, open-label, single- monotherapy in patients who have solid tumors with liver center study were to evaluate ficlatuzumab safety/tolerabil- metastases that express activated c-Met. ity and its effect on exploratory pharmacodynamic markers in patients with advanced solid tumors and liver metastases. Secondary objectives were to evaluate the pharmacokinetic Patients and Methods profile and antitumor activity of ficlatuzumab. Enrollment criteria Ficlatuzumab was administered once per 14-day cycle. A All patients provided informed consent before enroll- solution of ficlatuzumab (1.0–10.0 mg/mL) in 0.9% sodi- ment. Patients were of the age 18 years with histologically um chloride was administered as a 30-minute intravenous confirmed advanced unresectable colorectal, breast, gastric/ infusion through a low protein binding, 0.22 mmol/L in- esophageal, or pancreatic cancer with liver metastases ame- line filter without premedication. The study was designed to nable to biopsy. Patients had failed standard therapy, include a minimum of 6 patients in each of the three cohorts recurred/progressed following standard therapy, or had no (2, 10, and 20 mg/kg) for safety evaluation, which would standard therapeutic options, and were not currently ame- also allow for a minimum of 3 fully evaluable patients to nable to curative surgical intervention. Key inclusion/exclu- study dose dependence of the pharmacodynamic changes. sion criteria were: Eastern Cooperative Oncology Group Patients with intolerable grade 2 toxicity could have their performance status 1; measurable p-Met by immunohis- dose reduced a level or treatment discontinued (if at the tochemistry (IHC) of a tumor sample; and no previous use lowest dose level). Patients with grade 3/4 toxicity requiring of anti–c-Met or anti-HGF therapy. dose reduction could resume treatment at the lower dose Patients should have had adequate hematologic (hemo- after the adverse event resolved to grade 0/1 or baseline. globin 9 g/dL; white blood cell count 3,000/mm3; The study protocol was approved by the appropriate absolute neutrophil count 1,500/mm3; and platelets ethics committee and was conducted in accordance with 100,000/mm3), hepatic [serum bilirubin 1.5 ULN the principles of Good Clinical Practice and the Declaration (upper limit of normal) except with Gilbert Syndrome; of Helsinki.

2794 Clin Cancer Res; 20(10) May 15, 2014 Clinical Cancer Research

Ficlatuzumab in Solid Tumor Patients with Liver Metastases

Safety evaluations Tumor sample preparation has been described previously All patients who received 1 dose of ficlatuzumab were (30). Collected biopsies were fixed in 10% formalin for 12 considered evaluable for safety analyses. Adverse event to 16 hours followed by a series of alcohol, xylene, and reporting occurred at screening, during treatment, and 1 paraffin solution exchanges until final embedding in a month after the final dose; other safety evaluations occurred paraffin block. Expression of HGF, c-Met, p-Met, p-ERK at screening, the beginning of each treatment cycle, end of (phosphorylated extracellular-signal-regulated kinase), p- treatment (EOT), and 1 month after treatment discontin- Akt (phosphorylated Akt), p-S6K, cleaved caspase-3, CD31, uation. Toxicities were graded using the National Cancer and Ki-67 in tumor samples was analyzed by IHC, using Institute Common Terminology Criteria for Adverse Events, automated staining system [Dako Autostainer and Dako version 3.0 (29). Envision Flex Kit (K8012) detection system from Dako Dose-limiting toxicities (DLT) were defined as any of the Colorado, Inc.] and immunodetection with commercially following toxicities: grade 3 toxicities (except nausea or available antibodies according to the manufacturer’s vomiting, diarrhea, fever without neutropenia, and alanine instructions (Supplementary Table S1). The percentage of or aspartate aminotransferase abnormalities lasting 48 positive cells was reported for Ki-67 and cleaved caspase-3; hours); grade 3 neutropenia with an absolute neutrophil CD31 was quantified as a percentage of positive area within count 500/mm3 and <1,000/mm3 lasting 5 days; grade 3 tumor tissue per high power field. H-scores (31) were thrombocytopenia associated with bleeding; grade 4 hema- calculated for all other pharmacodynamic parameters using tologic or nonhematologic toxicities; drug-related toxicities the formula: (% weak-stained cells) 1 þ (% intermediate- of any grade that occurred during the first 2 cycles and stained cells) 2 þ (% strong-stained cells) 3. Results required a dose reduction during the next scheduled study were presented as percentage change from baseline, calcu- drug administration; and drug-related toxicities of any lated as: [100 (cycle "X" value baseline value)/baseline grade that resulted in interruption of treatment for >2 value]. weeks. Accrual to the next cohort occurred if 1 of 6 patients Sequential blood samples were collected predose and at 3 experienced a DLT during the first 2 cycles; dose escalation hours postdose on cycle 1 day 1; cycle 1 days 3 to 4; predose was terminated if 2 patients in a cohort experienced a DLT. and at 2 hours postdose on cycle 2 day 1; and on cycle 3 days Antidrug antibodies (ADA) against ficlatuzumab were 8 to 14. Serum HGF was measured using an ELISA (R&D evaluated in serum at cycle 1 day 1 predose and at EOT Systems). c-Met levels were measured using a bridging using a validated bridging electrochemiluminescence assay. electrochemiluminescence assay. Briefly, streptavidin-coat- Briefly, biotinylated ficlatuzumab and sulfo-tag ficlatuzu- ed plates (MSD) were coated with a biotinylated goat mab (Meso Scale Discovery, MSD) were added to diluted polyclonal Met antibody (R&D Systems). c-Met present in serum samples and incubated overnight. Samples were serum samples was captured and subsequently detected added to the wells of a streptavidin-coated plate (MSD) to using goat polyclonal c-Met antibody (R&D Systems) capture the biotinylated ficlatuzumab in the complex. Only labeled with sulfo-tag (MSD). c-Met extracellular domain samples containing antibody bound to both biotinylated (R&D Systems) was used as a standard. ficlatuzumab and sulfo-tag ficlatuzumab generated the Tumor metabolic activity was followed by positron emis- electrochemiluminescence signal. The specificity of the sion tomography (PET) computed tomography (CT) with ADA signal was verified by ficlatuzumab spike-in. If the [18F]fluorodeoxyglucose at baseline (cycle 1 day 1 preinfu- reading was reduced by half and/or was below the assay sion and before the first liver biopsy), on day 3 or 4 (48–72 cutoff point after spike-in, then the sample was considered hours after the first dose of study drug; only performed in positive for ADA. patients with evaluable PET CT scan lesions clearly distinct from the biopsy site), and during cycle 3 (at the time of the Pharmacodynamic evaluations first disease assessment). For pharmacodynamic biomarker analyses, a minimum of 3 patients per cohort had to meet the criteria for the Pharmacokinetic evaluations pharmacodynamic evaluable population, defined as Whole-blood samples for serum evaluations were col- patients with p-Met–positive tumors (i.e., H-score 30) by lected predose, immediately postdose, and at 1, 3, 6, and 8 IHC at baseline predose and with 1 postdose p-Met result. hours postdose on cycle 1 day 1; cycle 1 days 3 to 4; predose, This threshold for p-Met positivity was selected conserva- postdose, and at 2 hours postdose on cycle 2 day 1; predose tively, to minimize inclusion of false-positive patients (par- and postdose on cycle 3 day 1; cycle 3 days 8 to 14; and EOT. ticularly as archival specimens were used for eligibility Ficlatuzumab serum concentrations were measured in determination for several patients), and was based on prior serum using an ELISA method validated according to Good observation that known low/negative tissue microarray Laboratory Practice guidelines (with mean inter- and samples typically score below this cutoff, whereas the rest intraassay precision of 9.99% and 6.27%, respectively). score above it; of note, literature guides were not available Briefly, ficlatuzumab was captured from serum samples by for threshold determination at the time of the study design. recombinant HGF (R&D Systems) bound on a microtiter Sequential tumor biopsies from liver metastases were plate, and captured ficlatuzumab was detected with perox- collected at baseline predose, cycle 1 days 3 to 8, and cycle idase-labeled rabbit anti-human antibody (Dako) and tet- 3 days 8 to 14; archived tumor tissue was also collected. ramethylbenzidine as substrate.

www.aacrjournals.org Clin Cancer Res; 20(10) May 15, 2014 2795

Tabernero et al.

Pharmacokinetic parameters calculated for ficlatuzumab tion Criteria in Solid Tumors, version 1.1 (32), at screening, included minimum and maximum plasma concentration the cycle 3 days 8 to 14 visit, and approximately every 6 (Cmin and Cmax), time to peak plasma concentration (tmax), weeks thereafter. Efficacy parameters included overall area under the plasma concentration-time curve from time response rate, duration of response, and time to progression (AUC0!t,AUC0!¥), clearance, half-life (t1/2), apparent vol- (TTP). Time-to-event endpoints were estimated using ume of distribution (Vd), and the percentage of coefficient of Kaplan–Meier methodology. variation (% CV), using noncompartmental analysis (Phoe- nix WinNonLin version 6.2; Pharsight Corporation). Results Patients Tumor response evaluations From August 2009 to March 2011, 19 patients were The efficacy evaluable population included those who enrolled across three dose cohorts: n ¼ 6, the 2-mg/kg received 3 cycles of ficlatuzumab or were withdrawn due cohort; n ¼ 7, the 10-mg/kg cohort; and n ¼ 6, the 20- to progressive disease before completing cycle 3. Disease mg/kg cohort (baseline characteristics in Table 1). The most and tumor response were assessed using Response Evalua- common primary diagnosis was colorectal cancer (79%).

Table 1. Patient demographic and disease characteristics at baseline

2 mg/kg 10 mg/kg 20 mg/kg Total Parameter (n ¼ 6) (n ¼ 7) (n ¼ 6) (n ¼ 19) Mean age (range), y 57 (46–68) 59 (46–65) 63 (52–74) 60 (46–74) Sex, n (%) Male 5 5 5 15 (79) Female 1214(21) Caucasian race, n (%) 6 (100) 7 (100) 6 (100) 19 (100) Mean BMI (range), kg/m2 26 (24–28) 24 (20–28) 26 (22–31) 25 (20–31) ECOG PS, n (%) 0 1348(42) 1 5 4 2 11 (58) Median no. prior antitumor therapies 4454 Cancer diagnosis (%) Colorectal 5 5 5 15 (79) Pancreas 1102(11) Breast 0101(5) Esophageal adenocarcinoma 0011(5) No. of target lesions, n (%) 2–3 3 5 5 13 (68) >3 3216(32) Target lesion location, n (%) Liver 6 7 6 19 (100) Lung 4318(42) Lymph nodes 0224(21) Abdomen 1001(5) Other 1102(11) No. of nontarget lesions, n (%) 1 0022(11) 2–3 6 5 4 15 (79) >3 0202(11) Nontarget lesion location, n (%) Bone 0101(5) Liver 5 7 6 18 (95) Lung 5 6 3 14 (74) Lymph nodes 3328(42) Othera 1203(16)

Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; PS, performance status. aOther target lesion locations included the following: 2 mg/kg, mediastinum (aorta-lung window lymph node); 10 mg/kg, pancreas (local recurrence).

2796 Clin Cancer Res; 20(10) May 15, 2014 Clinical Cancer Research

Ficlatuzumab in Solid Tumor Patients with Liver Metastases

All patients had stage IV disease with measurable target Albumin level in the patient with grade 3 hypoalbumine- lesions at screening, including in the liver; all had 1 mia was 26.9 g/L at screening (grade 2) and decreased nontarget lesion. throughout the study. Grade 4 TEAEs included hyperbilir- Median (range) treatment duration was 6 (2–59) weeks. ubinemia associated with worsening liver metastasis result- Fifteen patients (79%) received ﬁclatuzumab for 2 weeks to ing in discontinuation and respiratory failure due to disease 2 months, 3 patients (16%) for >2 to 6 months, and 1 progression (n ¼ 1 each). Five patients (26%) had one dose patient (5%) for >6 months. All patients discontinued: 18 delay each for adverse event management. patients (95%) for progressive disease and 1 patient (5%) Laboratory abnormalities reported as TEAEs (all grades) for grade 4 adverse event (hyperbilirubinemia; unlikely included hypokalemia, hypomagnesemia, hypoalbumine- related to treatment). mia, anemia, leukopenia, hypocalcemia, hyponatremia, proteinuria, hyperglycemia, increased gamma-glutamyl Safety and tolerability transpeptidase, and neutropenia. One patient had an The safety population included all patients. No DLTs abnormal change in urinalysis results (epithelial cells) were reported. Eighteen patients (95%) experienced 1 considered clinically signiﬁcant. treatment-emergent adverse event (TEAE), including 1 con- Five patients (26%) experienced serious unrelated sidered possibly drug related (grade 1 pyrexia during cycle 1 adverse events: hyperbilirubinemia (n ¼ 1; 2 mg/kg); in the 2-mg/kg cohort). The most common TEAEs were fatigue and intestinal obstruction (n ¼ 1 each; 10 mg/kg), asthenia, peripheral edema, hepatic pain, and cough (Table gastrointestinal hemorrhage (n ¼ 1; 20 mg/kg), and intes- 2). Four patients (21%) experienced grade 3/4 unrelated tinal obstruction, hepatic pain, and respiratory failure (n ¼ TEAEs. Grade 3 TEAEs included asthenia, hypoalbumine- 1; 20 mg/kg). The last patient died due to grade 4 respiratory mia, hypokalemia, proteinuria, and dyspnea (n ¼ 1 each). failure considered related to disease progression.

Table 2. TEAEs of any grade occurring in 3 patients and laboratory abnormalities of grade 3 severity occurring in 1 patient

2 mg/kg 10 mg/kg 20 mg/kg Total Event, n (%) (n ¼ 6) (n ¼ 7) (n ¼ 6) (n ¼ 19) TEAEa Asthenia 2 3 1 6 (32) Hepatic pain 2 3 1 6 (32) Peripheral edema 1 3 2 6 (32) Cough 1 2 2 5 (26) Abdominal distension 1 2 1 4 (21) Abdominal pain 1 2 1 4 (21) Constipation 0 2 1 3 (16) Decreased appetite 1 2 0 3 (16) Dyspnea 0 2 1 3 (16) Anemia 0 2 1 3 (16) Increased GGTb 3 0 0 3 (16) Grade 3 laboratory abnormalities Hyperuricemia 2 2 1 5 (26) Increased alkaline phosphatase 1 1 2 4 (21) Hypoalbuminemiac 0 1 1 2 (11) Hyperbilirubinemiad 1001(5) Hyperglycemia 1 0 0 1 (5) Hypocalcemia 0 0 1 1 (5) Grade 4 laboratory abnormalities Hyperbilirubinemia 1 0 0 1 (5)

Abbreviation: GGT, gamma-glutamyl transferase. aGrade 3/4 TEAEs included hypoalbuminemia and proteinuria (n ¼ 1 each) in the 2-mg/kg cohort; hypoalbuminemia and hypokalemia (n ¼ 1 each) in the 10-mg/kg cohort; and asthenia, dyspnea, and respiratory failure (n ¼ 1 each) in the 20-mg/cohort. bNo patient experienced a GGT laboratory abnormality of grade >2. cSerum albumin decreased to below normal for the majority of patients by the EOT visit and trended toward recovery at the follow-up visit. dLikely related to liver metastasis biopsy procedures.

www.aacrjournals.org Clin Cancer Res; 20(10) May 15, 2014 2797

Tabernero et al.

The most frequently occurring laboratory abnormalities c-Met signal transduction. No dose- or time-dependent were hepatobiliary events; average levels of lactate dehy- pattern could be identified in the changes in CD31- drogenase, alkaline phosphatase, alanine aminotransferase, positive microvessel density upon initiation of treatment and aspartate aminotransferase were high at baseline and with ficlatuzumab (Supplementary Table S2). No changes throughout the study. Grade 3 abnormalities included in serum c-Met levels were observed postdose. elevated alkaline phosphatase for 4 patients (21%) and All patients who had PET CT scans performed had elevated total bilirubin for 1 patient (5%), which worsened [18F]fluorodioxyglucose avid tumors at baseline, consistent to grade 4 (Table 2). Other changes in laboratory para- with metabolically active neoplastic disease. Fourteen meters included grade 2 increased lymphocytes, partial patients had both a baseline and cycle 3 PET CT scans and thromboplastin time, and potassium, and grade 3 increased were evaluable for pharmacodynamic analyses; the remain- blood glucose and decreased albumin. ing 5 patients did not have a cycle 3 PET CT scan. Among In a retrospective analysis, serum albumin levels these 14 evaluable patients, 4 patients had stable disease, decreased in all patients to below the lower limit of normal and 10 patients had increased [18F]fluorodioxyglucose by study completion. Mean (SD) albumin levels decreased uptake consistent with progression at cycle 3. Of note, 1 from 36.8 (4.46) to 30.5 (6.70) g/L during treatment, patient had a decrease in [18F]fluorodeoxyglucose update reaching minimum levels at EOT. Three patients (n ¼ 1, after 3 days of ficlatuzumab, which correlated with 10 mg/kg; n ¼ 2, 20 mg/kg) experienced serum albumin decreased p-Met, p-MAPK (phosphorylated mitogen-acti- decreases to grade 3 at the end of cycle 2, coinciding with vated protein kinase), Ki-67, CD31, and tumor HGF expres- EOT for all 3 patients. Mean (SD) albumin level increased sion as assessed by IHC staining; however, this patient had during the 30-day follow-up period for all cohorts to 31.1 disease progression by the first tumor evaluation and was (4.67) g/L but remained below normal. withdrawn from the study before the cycle 4 dose. Antidrug antibodies were measured for 13 patients at the One patient with colorectal carcinoma had dramatic EOT and ficlatuzumab was not immunogenic. No patient decreases in nearly all pharmacodynamic markers (Fig. had clinically significant abnormal electrocardiograms. 2A–D) and an increase in HGF (Fig. 2E). This patient Changes in body mass index were small and not clinically received three treatment cycles and was withdrawn from meaningful. the study due to a new lesion observed by CT (negative by PET). Pharmacodynamic analyses The tumor pharmacodynamic evaluable population Pharmacokinetic analyses comprised 12 patients (n ¼ 4, 2 mg/kg; n ¼ 3, 10 mg/kg; Pharmacokinetic parameters are listed by the dose cohort and n ¼ 5, 20 mg/kg). All patients had measurable baseline in Table 3. Ficlatuzumab exposure (assessed by Cmax and p-Met by IHC (H-score 30); median (range) H-score was AUC) increased in an approximately dose-proportional 115 (40–260). manner (Fig. 3). No significant changes in the mean clear- H-score changes from baseline for selected pharmaco- ance and t1/2 across doses were observed (P ¼ 0.092 and dynamic markers are shown in Fig. 1 (marker summary in 0.167, respectively, by ANOVA), suggesting linear pharma- Supplementary Table S2). More pronounced and consis- cokinetics for the 2 to 20 mg/kg dose range. Ficlatuzumab tent decrease in p-Met from baseline was apparent at the exhibited low clearance (0.178–0.261 mL/h/kg) leading to RP2D (20 mg/kg) of ficlatuzumab versus lower doses. At a long terminal t1/2 (7.4–10 days), with significant accu- cycles 1 and 3, respectively, median (range) relative mulation of ficlatuzumab from cycle 1 to cycle 3. Mean (SD) changes were: at 20 mg/kg, 21% (42 to 17) and Vd ranged from 61 (18) to 75 (15) mL/kg, suggesting limited 53% (81 to 9); at 10 mg/kg, 11% (11–11) and 22% distribution of ficlatuzumab to the extravascular compart- (11–80); and at 2 mg/kg, 40% (0–50) and 17% (23 to ment (33). 9; Fig. 1A). Similarly, at 20 mg/kg there was a decrease in p-ERK with median (range) change of 38% (59 to Antitumor activity 34) and 43% (78 to 15) and to lesser extent p-Akt, Eighteen patients were evaluable for efficacy (n ¼ 5, 2 with a median (range) change of 40% (48 to 91) and mg/kg; n ¼ 7, 10 mg/kg; n ¼ 6, 20 mg/kg); no patient had 2% (45 to 12) at both time points (Fig. 1B, and C). At an objective response. Five patients (28%) achieved stable 20 mg/kg, there was an increase in tumor HGF level with disease; median duration was 2.6 months [95% confi- median (range) change of 17% (0–125) and 33% (10 to dence interval (CI), 1.5–13.7]. Four of these patients had 138) at the same time points (Fig. 1D). Increased serum colorectal adenocarcinoma with stable disease duration HGF levels were also observed in a time- and dose- from 1.5 to 2.7 months, and 1 patient had pancreatic dependent manner (Fig. 1E; Supplementary Table S3). acinar cell carcinoma with stable disease lasting 13.7 At 10 mg/kg, there was an increase in median change p- months (this particular tumor type usually has a more Met and p-ERK at both time points for reasons unknown. indolent course than pancreatic ductal adenocarcinoma). Further, changes in p-ERK expression correlated with Median TTP was 1.4 months (95% CI, 1.3–1.5). No changes in tumor p-Met (Spearman correlation coeffi- significant relationship was found between TTP and max- cient r ¼ 0.48, P ¼ 0.044; n ¼ 18; Fig. 1F), suggesting imum percentage change from baseline for any measured that changes in p-ERK could result from changes in HGF/ pharmacodynamic marker.

2798 Clin Cancer Res; 20(10) May 15, 2014 Clinical Cancer Research

Ficlatuzumab in Solid Tumor Patients with Liver Metastases

A B 80 200 60 150 40 20 100 0 50 –20 –40 0 –60 –50 –80 p-Met Change from baseline (%) –100 p-ERK Change from baseline (%) –100

21020 21020 Dose, mg/kg Dose, mg/kg

Biopsy timepoint Cycle 1 Day 3–8 Cycle 3 Day 8–14 Biopsy timepoint Cycle 1 Day 3–8 Cycle 3 Day 8–14 C D 100 700 80 600 60 500 40 400 20 300 0 200 –20 100 –40 0 HGF change from baseline (%) p-Akt Change from baseline (%) –60 –100 21020 21020 Dose, mg/kg Dose, mg/kg

Biopsy timepoint Cycle 1 Day 3–8 Cycle 3 Day 8–14 Biopsy timepoint Cycle 1 Day 3–8 Cycle 3 Day 8–14 E F p-Met versus p-ERK 20 200 18 n = 18 r = 0.456 16 P = 0.057 14 100 12 10 8 6 0 4 2

Fold change in HGF from baseline Fold 0 –100

0 10203040p-ERK H-score Change frombaseline (%) –90 –80 –70 –60 –50 –40 –30 –20 –10 0 10 20 30 40 50 60 70 80 Time since ficlatuzumab treatment (d) p-Met H-score Change from baseline (%)

Ficlatuzumab dose 2 mg/kg 10 mg/kg 20 mg/kg Ficlatuzumab dose 2 mg/kg 10 mg/kg 20 mg/kg

Figure 1. Pharmacodynamic analyses. Median percentage changes from baseline for p-Met (A), p-ERK (B), p-Akt (C), and HGF (D) H-scores in the tumor samples for each cohort are depicted in box plots. Medians (horizontal lines) are shown with their ﬁrst and third quartile values (boxes) and ranges (vertical lines). E, change in serum HGF levels from baseline over time for each cohort. F, percentage changes from baseline for p-ERK H-scores versus percentage change from baseline for p-Met H-score are plotted for each cohort. Data points were offset slightly for improved visibility of the error bars.

Discussion pathway pharmacodynamic markers in the tumor and In a previous ficlatuzumab phase I study in patients with serum, and had a good pharmacokinetic profile that was advanced solid tumors, the recommended treatment dose consistent with a previous study (34). was 20 mg/kg once every 2 weeks (14-day cycle; ref. 34). In The overall safety profile of ficlatuzumab observed in this study, the same ficlatuzumab regimen was well toler- this study, characterized by peripheral edema, hypoalbu- ated without DLTs; ficlatuzumab modulated HGF/c-Met minemia, cough, and gastrointestinal adverse events,

www.aacrjournals.org Clin Cancer Res; 20(10) May 15, 2014 2799

Tabernero et al.

sistent with the previous phase I study (34) and the profile of other humanized immunoglobulin G1 antibodies (38). Ficlatuzumab exhibited linear pharmacokinetics across all dose levels tested. A maximum tolerated dose was not reached with ficlatuzumab, making the determination of the RP2D challeng- ing; this is similar to reports of other HGF/c-Met inhibitory antibodies, including onartuzumab (37), rilotumumab (35), and TAK701 (36). The objective of this study was to determine whether ficlatuzumab treatment could result in pharmacodynamic target modulation in the tumor to max- imize antitumor activity at the doses tested. Activation of the c-Met pathway, indicated by p-Met levels, tends to increase with disease progression (17– 22), and tends to be higher in liver metastases than in the primary tumor site. In this study, ficlatuzumab inhibition of p-Met and subsequent downstream signaling was investi- gated in patients with advanced tumors with liver metastases accessible to repeat biopsies. Patients with positive p- Met in archival tumor biopsies were also enrolled. Predose baseline liver tumor biopsies for all patients had measurable p-Met. Ficlatuzumab treatment led to consistently decreased levels of p-Met only at 20 mg/kg, confirming that it can modulate HGF/c-Met pathway function in the tumor at the RP2D of 20 mg/kg. These findings support a mechanism proposed by previous in vitro and in vivo studies (23– 25), in which ficlatuzumab inhibits c-Met signaling. The observed decrease in p-Akt and p-ERK only at 20 mg/ kg suggests that ficlatuzumab may decrease cellular proliferation and survival signals at RP2D. Changes in p-ERK that correlated with changes in p-Met suggested that changes observed in p-ERK may indeed result from changes in p-Met following ficlatuzumab treatment. Treatment with 20 mg/kg ficlatuzumab also resulted in mild increases in HGF levels in liver metastases (17%–33%) and more pronounced increases in serum (4.0-fold by cycle 1, days 3–4). Although no measurable increase in tumor HGF expression levels was observed for the 2- or 10-mg/kg cohorts, the increase was observed in serum by 2.66- and 3.51-fold, respectively, by the same time postdose. Increased serum HGF after ficlatuzumab administration, indicating target engagement, is consistent with previous Figure 2. Pharmacodynamic changes in liver tumor biopsies. Liver biopsies from a single patient predose (left-hand side of A–E) and 3 days observations (26). The increase in HGF in tumor and more after ficlatuzumab 20 mg/kg (right-hand side of A–E) to detect levels of p- pronounced and consistent increase in serum is likely due to Met (A), p-MAPK (B), Ki-67 (C), CD31 (D), and tumor HGF(E). the stabilization of HGF upon complex formation with ficlatuzumab and/or compensatory increase in HGF pro- matches that observed for other antibodies targeting the duction (39). HGF/c-Met pathway (i.e., rilotumumab, onartuzumab, Similarly, decreased HGF/c-Met pathway–related signal- and TAK701; refs. 35–37). Edema was also among the ing, as indicated by reductions in p-Met and p-ERK, was most common adverse events observed for the ALK/c-Met more pronounced in the 20-mg/kg cohort, despite a high inhibitor crizotinib (38). Slow recovery of albumin levels ficlatuzumab serum trough concentration (mean Cmin: after EOT is consistent with the long half-life of ficlatuzu- 7.15, 40.7, and 128 mg/mL at 2, 10, and 20 mg/kg, respec- mab. In this study, gastrointestinal adverse events (e.g., tively) in all cohorts well exceeding the IC50 of approxi- abdominal pain, abdominal distention, and constipation), mately 1 mg/mL in most cellular assays (23). This discrep- were among the most common TEAEs, consistent with the ancy between tumor and serum pharmacodynamic marker disease state. modulations is likely due to limited antibody penetration The pharmacokinetics of ficlatuzumab was characterized into the tumor milieu, emphasizing the importance of by low clearance and a long half-life (7.4–10 days), con- establishing an effective dosing regimen using paired

2800 Clin Cancer Res; 20(10) May 15, 2014 Clinical Cancer Research

Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2014 American Association for Cancer Research. www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org Published OnlineFirstMarch14,2014;DOI:10.1158/1078-0432.CCR-13-1837

Table 3. Ficlatuzumab pharmacokinetic parameters by treatment group in cycle 1

a Parameter Cmax (mg/mL) tmax (h) AUC0! t (mg h/mL) AUC0-¥ (mg h/mL) CL (mL/h/kg) t1/2 (h) Vd (mL/kg) Cmin (mg/mL) 2 mg/kg n 66 6 4a 4 445 on October 2,2021. ©2014 American Association forCancer Research. Mean, SD 39.05 (13.94) 1.5 (0.58–3.5) 4.365 (2.678) 8.382 (1.594) 0.2452 (0.04838) 177.5 (32.72) 61.25 (4.168) 7.15 (4.587) % CV 35.7 57.4 61.3 19 19.7 18.4 6.8 64.2 10 mg/kg n 7 7 7 6 6 666 Mean, SD 173.3 (39.85) 1.5 (0.58–3.58) 24.66 (9.613) 40.52 (11.24) 0.2610 (0.06366) 206.5 (46.12) 75.43 (15.06) 40.67 (13.79) % CV 23 63.4 39.0 27.7 24.4 22.3 20.0 33.9

20 mg/kg Metastases Liver with Patients Tumor Solid in Ficlatuzumab n 6 6 6 4 4 444 Mean, SD 443 (100.7) 1.04 (0.5–1.5) 54.27 (32.08) 117.0 (27.76) 0.1780 (0.03984) 239 (43.34) 61.15 (17.83) 128.2 (27.98) % CV 22.7 51.3 59.1 23.7 22.4 18.1 29.2 21.8

NOTE: Only patients with pharmacokinetic proﬁles evaluable for complete noncompartmental analysis were included. Abbreviations: AUC0!t, area under the concentration-time curve from time zero to the end of the dosing interval; AUC0! ¥, area under the concentration-time curve extrapolated to inﬁnite time; CL, clearance; SD, stable disease.

lnCne e;2(0 a 5 2014 15, May 20(10) Res; Cancer Clin a tmax is reported as median (range). 2801 Published OnlineFirst March 14, 2014; DOI: 10.1158/1078-0432.CCR-13-1837

Tabernero et al.

A Ficlatuzumab dose

2 mg/kg 10 mg/kg 20 mg/kg 1,000

100

Figure 3. Ficlatuzumab pharmacokinetics. A, 10 concentration time profiles. Serum concentrations of ficlatuzumab are Ficlatuzumab concentration (μg/mL) Ficlatuzumab plotted as a function of treatment visit for each patient. Dashed lines 0 7 14 21 28 35 0 7 14 21 28 35 0 7 14 21 28 35 indicate expected dosing times for cycle 1 day 1, cycle 2 day 1, and Nominal time since first ficlatuzumab dose (d) cycle 3 day 1 (0, 14, and 28 doses since the first ficlatuzumab dose, Mean Individual respectively). Four patients who B C withdrew before their cycle 2 dose were included up to their last 600 recorded sample point. r 2 = 0.87 150 r 2 = 0.853 Ficlatuzumab Cmax (B) and 500 AUC0!¥ (C) as a function of cycle 1 dose. AUC0!¥, area under the h/mL) 400 • concentration-time curve 100 (μg/mL) (mg extrapolated to infinite time. max 0-∞ 300

200 50 Ficlatuzumab C Ficlatuzumab Ficlatuzumab AUC Ficlatuzumab 100

0 0 2 5 10 15 20 25 10 15 20 Ficlatuzumab dose (mg/kg) Ficlatuzumab dose (mg/kg)

predose and postdose tumor biopsies rather than solely Disclosure of Potential Conflicts of Interest relying on exposure in the serum. M. Han is an employee of and has ownership interest (including patents) in AVEO. P. Komarnitsky has ownership interest (including Given the small number of patients at each dose and time patents) in AVEO. No potential conflicts of interest were disclosed by point, the results need to be interpreted with caution. the other authors. However, collectively, at 20 mg/kg ficlatuzumab, there is decrease in median tumor p-Met, p-Erk, and p-Akt, and an increase in HGF at both time points; this pattern is consis- Authors' Contributions tent with the mechanism of action of an anti-HGF antibody. Conception and design: J. Tabernero, J. Andreu, M. Han, P. Komarnitsky, J. Baselga These changes likely indicate that ficlatuzumab 20 mg/kg Development of methodology: J. Tabernero, M.E. Elez, J. Andreu, M. Han, induced pharmacodynamic modulation of the HGF/c-Met W. Yin, P. Komarnitsky, J. Baselga Acquisition of data (provided animals, acquired and managed patients, pathway and downstream signaling. provided facilities, etc.): J. Tabernero, M.E. Elez, M. Herranz, L. Prudkin, J. Overall, ficlatuzumab monotherapy was well tolerated in Andreu, J. Mateos, M.J. Carreras, J. Gifford, W. Yin, S. Agarwal, P. Komar- patients with solid tumors and liver metastases. The study nitsky, J. Baselga Analysis and interpretation of data (e.g., statistical analysis, biosta- confirmed the validity of 20 mg/kg as the appropriate RP2D tistics, computational analysis): J. Tabernero, M.E. Elez, J. Andreu, M. for ficlatuzumab based on pharmacodynamic target mod- Han, J. Gifford, W. Yin, S. Agarwal, P. Komarnitsky, J. Baselga ulation in the tumor. These results support the clinical Writing, review, and/or revision of the manuscript: J. Tabernero, M.E. Elez, L. Prudkin, J. Andreu, J. Mateos, M.J. Carreras, M. Han, M. Credi, W. Yin, evaluation of ficlatuzumab for treating patients with S. Agarwal, P. Komarnitsky, J. Baselga advanced solid tumors. A randomized phase Ib/II trial Administrative, technical, or material support (i.e., reporting or orga- nizing data, constructing databases): M. Herranz, I. Rico, J. Gifford, M. exploring ficlatuzumab in combination with gefitinib Credi, S. Agarwal (27, 28) is ongoing. Study supervision: J. Tabernero, J. Baselga

2802 Clin Cancer Res; 20(10) May 15, 2014 Clinical Cancer Research

Ficlatuzumab in Solid Tumor Patients with Liver Metastases

Acknowledgments Grant Support The authors thank all of the participating patients and their families as This study was supported by AVEO Pharmaceuticals, Inc. well as the global network of investigators, research nurses, study coordi- The costs of publication of this article were defrayed in part by the nators, and operations staff. Medical writing support was provided by payment of page charges. This article must therefore be hereby marked Kimberly Brooks, of SciFluent. advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Trial registration: Received July 9, 2013; revised February 12, 2014; accepted February 22, This trial was registered at ClinicalTrials.gov (NCT00969410). 2014; published OnlineFirst March 14, 2014.

References 1. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande 19. EichbaumMH,deRossiTM,KaulS,BrucknerT,SchneeweissA, Woude GF, et al. Identification of the hepatocyte growth factor Sohn C. Serum levels of hepatocyte growth factor/scatter factor in receptor as the c-met proto-oncogene product. Science 1991;251: patients with liver metastases from breast cancer. Tumour Biol 802–4. 2007;28:36–44. 2. Weidner KM, Sachs M, Birchmeier W. The Met receptor tyrosine kinase 20. Hansel DE, Rahman A, House M, Ashfaq R, Berg K, Yeo CJ, et al. transduces motility, proliferation, and morphogenic signals of scatter Met protooncogene and insulin-like growth factor binding protein 3 factor/hepatocyte growth factor in epithelial cells. J Cell Biol 1993; overexpression correlates with metastatic ability in well-differenti- 121:145–54. ated pancreatic endocrine neoplasms. Clin Cancer Res 2004;10: 3. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, 6152–8. metastasis, motility, and more. Nat Rev Mol Cell Biol 2003;4:915–25. 21. Maemura M, Iino Y, Yokoe T, Horiguchi J, Takei H, Koibuchi Y, et al. 4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Serum concentration of hepatocyte growth factor in patients with Cell 2011;144:646–74. metastatic breast cancer. Cancer Lett 1998;126:215–20. 5. Trusolino L, Comoglio PM. Scatter-factor and semaphorin recep- 22. Zeng ZS, Weiser MR, Kuntz E, Chen CT, Khan SA, Forslund A, et al. tors: cell signalling for invasive growth. Nat Rev Cancer 2002;2: c-Met gene amplification is associated with advanced stage colorectal 289–300. cancer and liver metastases. Cancer Lett 2008;265:258–69. 6. Engelman JA, Janne PA. Mechanisms of acquired resistance to 23. Han M, Breault L, Wright K, Moore C, Knuehl C, Lin J, et al. In vivo epidermal growth factor receptor tyrosine kinase inhibitors in non– genetic screens designed to complement loss of HER2 or kRas small cell lung cancer. Clin Cancer Res 2008;14:2895–9. functions identify c-Met/HGF pathway as potent driver of growth/ 7. Gentile A, Trusolino L, Comoglio PM. The Met tyrosine kinase survival in solid tumor models. AACR Meeting Abstracts 2007:4887. receptor in development and cancer. Cancer Metastasis Rev 2008; 24. Meetze KA, Connolly K, Boudrow A, Venkataraman S, Medicherla S, 27:85–94. Gyuris J, et al. Preclinical efficacy and pharmacodynamics of SCH 8. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, 900105 (AV-299) an anti-HGF antibody in an intracranial glioblastoma et al. MET amplification leads to gefitinib resistance in lung cancer by model. Mol Cancer Ther 2009;8:C181. activating ERBB3 signaling. Science 2007;316:1039–43. 25. Meetze KA, Boudrow A, Connolly K, Huang R, Rideout W, Gyuris J, 9. Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. et al. Anti-tumor activity of SCH 900105 (AV299), an anti-HGF anti- Widespread potential for growth-factor-driven resistance to antican- body, in non–small cell lung cancer models. Mol Cancer Ther 2009;8: cer kinase inhibitors. Nature 2012;487:505–9. C173. 10. Drebber U, Baldus SE, Nolden B, Grass G, Bollschweiler E, Dienes HP, 26. Patnaik A, Weiss GJ, Papadopoulos R, Tibes R, Tolcher AW, Payumo et al. The overexpression of c-met as a prognostic indicator for gastric FC, et al. Phase I study of SCH 900105, an anti-hepatocyte growth carcinoma compared to p53 and p21 nuclear accumulation. Oncol Rep factor monoclonal antibody, as a single agent and in combination with 2008;19:1477–83. erlotinib in patients with advanced solid tumors. J Clin Oncol 11. Ponzo MG, Lesurf R, Petkiewicz S, O'Malley FP, Pinnaduwage D, 2010;28:2525. Andrulis IL, et al. Met induces mammary tumors with diverse histol- 27. Mok T, Tan E, Park K, Jac J, Han M, Payumo FC, et al. Randomized ogies and is associated with poor outcome and human basal breast phase II study of ficlatuzumab (formerly AV-299), an anti-hepatocyte cancer. Proc Natl Acad Sci U S A 2009;106:12903–8. growth factor (HGF) monoclonal antibody (MAb) in combination with 12. Pour L, Svachova H, Adam Z, Mikulkova Z, Buresova L, Kovarova L, gefitinib (G) in Asian patients (pts) with NSCLC. J Clin Oncol 2011;29: et al. Pretreatment hepatocyte growth factor and thrombospondin-1 TPS213. levels predict response to high-dose chemotherapy for multiple mye- 28. Tan E, Park K, Lim WT, Ahn M, Ng QS, Ahn JS, et al. Phase Ib study of loma. Neoplasma 2010;57:29–34. ficlatuzumab (formerly AV-299), an anti-hepatocyte growth factor 13. Betsunoh H, Mukai S, Akiyama Y, Fukushima T, Minamiguchi N, Hasui monoclonal antibody in combination with gefitinib in Asian patients Y, et al. Clinical relevance of hepsin and hepatocyte growth factor with NSCLC. J Clin Oncol 2011;29:7571. activator inhibitor type 2 expression in renal cell carcinoma. Cancer Sci 29. National Cancer Institute (2006) Common Terminology Criteria for 2007;98:491–8. Adverse Events v3.0 (CTCAE). http://www.eortc.be/services/doc/ctc/ 14. Hepatocyte growth factor/scatter factor (HGF/SF), MET and cancer ctcaev3.pdf. references. 2011. http://www.vai.org/met/. 30. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, et al. Dose- 15. Salgia R. Role of c-Met in cancer: emphasis on lung cancer. Semin and schedule-dependent inhibition of the mammalian target of rapa- Oncol 2009;36:S52-S58. mycin pathway with everolimus: a phase I tumor pharmacodynamic 16. Christensen JG, Burrows J, Salgia R. c-Met as a target for human study in patients with advanced solid tumors. J Clin Oncol 2008; cancer and characterization of inhibitors for therapeutic intervention. 26:1603–10. Cancer Lett 2005;225:1–26. 31. Detre S, Saclani JG, Dowsett M. A "quickscore" method for immuno- 17. Amemiya H, Kono K, Itakura J, Tang RF, Takahashi A, An FQ, et al. c- histochemical semiquantitation: validation for oestrogen receptor in Met expression in gastric cancer with liver metastasis. Oncology breast carcinomas. J Clin Pathol 1995;48:876–8. 2002;63:286–96. 32. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford 18. Coskun U, Bukan N, Sancak B, Gunel N, Ozenirler S, Unal A, et al. R, et al. New response evaluation criteria in solid tumours: revised Serum hepatocyte growth factor and interleukin-6 levels can distin- RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. guish patients with primary or metastatic liver tumors from those with 33. Davies B, Morris T. Physiological parameters in laboratory animals and benign liver lesions. Neoplasma 2004;51:209–13. humans. Pharm Res 1993;10:1093–5.

www.aacrjournals.org Clin Cancer Res; 20(10) May 15, 2014 2803

Tabernero et al.

34. Ramanathan RK, Payumo FC, Papadopoulos KP, Weiss GJ, Cham- 37. Salgia R, Peterson A, Eppler S, Yu W, Polite B, Geary D, et al. A phase I, bers G, Iyengar T, et al. A phase 1, first in human, study of SCH 900105, open-label, dose-escalation study of the safety and pharmacology of an antihepatocyte growth factor (HGF) monoclonal antibody, in sub- MetMAb, a monovalent antagonist antibody to the receptor Met, jects with advanced solid tumors. Mol Cancer Ther 2009;8:A100. administered IV in patients with locally advanced or metastatic solid 35. Gordon MS, Sweeney CS, Mendelson DS, Eckhardt SG, Anderson A, tumors [abstract]. In: Proceedings of the 20th European Organisation Beaupre DM, et al. Safety, pharmacokinetics, and pharmacodynamics for Research and Treatment of Cancer-National Cancer Institute- of AMG 102, a fully human hepatocyte growth factor-neutralizing American Association for Cancer Research Symposium; 2008 Oct monoclonal antibody, in a first-in-human study of patients with 21–24; Geneva, Switzerland: AACR; 2008. Abstract nr 411. advanced solid tumors. Clin Cancer Res 2010;16:699–710. 38. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmaco- 36. Jones SF, Cohen RB, Bendell JC, Denlinger CS, Harvey RD, Para- kinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet suraman S, et al. Safety, tolerability, and pharmacokinetics of TAK- 2010;49:493–507. 701, a humanized anti-hepatocyte growth factor (HGF) monoclonal 39. Penuel E, Li C, Parab V, Burton L, Cowan KJ, Merchant M, Yauch RL, antibody, in patients with advanced nonhematologic malignancies: et al. HGF as a circulating biomarker of onartuzumab treatment in first-in-human phase I dose-escalation study. J Clin Oncol 2010; patients with advanced solid tumors. Mol Cancer Ther 2013;12: 28:3081. 1122–3.

2804 Clin Cancer Res; 20(10) May 15, 2014 Clinical Cancer Research

A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases

Josep Tabernero, Maria Elena Elez, Maria Herranz, et al.

Clin Cancer Res 2014;20:2793-2804. Published OnlineFirst March 14, 2014.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-13-1837

Supplementary Access the most recent supplemental material at: Material http://clincancerres.aacrjournals.org/content/suppl/2014/03/14/1078-0432.CCR-13-1837.DC1

Cited articles This article cites 35 articles, 10 of which you can access for free at: http://clincancerres.aacrjournals.org/content/20/10/2793.full#ref-list-1

Citing articles This article has been cited by 1 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/20/10/2793.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at Subscriptions [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/20/10/2793. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.