A Phase 1, First-In-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, 2 in Patients with Advanced Solid Tumors

Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

AMG 780 in Patients With Advanced Solid Tumors

1 A Phase 1, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, 2 in Patients With Advanced Solid Tumors

3 Afshin Dowlati,1 Gordana Vlahovic,2 Ronald Natale,3 Erik Rasmussen,4 Indrajeet Singh,4 4 Yuying C. Hwang,4,* John Rossi,4,* Michael B. Bass,4,* Gregory Friberg,4 Cheryl A. 5 Pickett4

6 1Case Western Reserve University and University Hospitals Seidman Cancer Center, 7 Cleveland, OH, USA; 2Duke University Medical Center, Durham, NC, USA; 3Cedars 8 Sinai Medical Center, Los Angeles, CA, USA; 4Amgen Inc., Thousand Oaks, CA, USA

9 *Affiliation at the time the research was conducted

10 Running title: AMG 780 in Patients With Advanced Solid Tumors

11 Keywords: angiogenesis, angiopoietin axis, targeted therapy, Tie2 12 receptor, dose escalation

13 Financial support: This study was supported by Amgen Inc.

14 Address correspondence to: Afshin Dowlati, UH Case Medical Center, Department of 15 Medicine—Hematology and Oncology; 11100 Euclid 16 Avenue, Cleveland, OH 44106; Phone: +1-216-844-1228; 17 Fax: +1-216-844-5234; Email: 18 [email protected]

19 Conflicts of interest: Erik Rasmussen, Indrajeet Singh, Gregory Friberg, and 20 Cheryl A. Pickett are employees of and stockholders in 21 Amgen Inc. Yuying C. Hwang, John Rossi, and Michael B. 22 Bass were employees of and stockholders in Amgen Inc. at 23 the time this research was conducted. Afshin Dowlati, 24 Gordana Vlahovic, and Ronald Natale have no conflicts to 25 declare.

26 Previous presentation: The results of this study have not been previously published 27 or submitted for publication elsewhere. The results were 28 presented in part as a poster at the American Society of

Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

AMG 780 in Patients With Advanced Solid Tumors

1 Clinical Oncology 50th Annual Meeting, Chicago, IL, May 30 2 to June 3, 2014.

3 Target journal: Clinical Cancer Research

4 Word count: 4071/5000

5 Figures/tables: 3/3

6 Clinical trial registration: ClinicalTrials.gov, NCT01137552

AMG 780 in Patients With Advanced Solid Tumors

1 Abstract

2 Purpose: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response,

3 and pharmacodynamics of AMG 780, a monoclonal antibody designed to inhibit the interaction

4 between angiopoietin-1 and -2 and the Tie2 receptor.

5 Experimental Design: This was a phase 1 dose-escalation study of patients with advanced

6 solid tumors refractory to standard treatment without previous antiangiogenic treatment.

7 AMG 780 was administered by intravenous infusion every 2 weeks (Q2W) in doses from 0.1 to

8 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse

9 events (AEs), and pharmacokinetics. Secondary endpoints included tumor response, changes

10 in tumor volume and vascularity, and anti–AMG 780 antibody formation.

11 Results: Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs

12 (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no maximum-

13 tolerated dose was reached. Pharmacokinetics of AMG 780 were dose proportional; median

14 terminal elimination half-life was 8 to 13 days. No anti−AMG 780 antibodies were detected. At

15 week 5, 6/16 evaluable patients had a >20% decrease in volume transfer constant (Ktrans),

16 suggesting reduced capillary blood flow/permeability. The most frequent AEs were

17 hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue

18 (27%). Among 35 evaluable patients, none had an objective response; eight achieved stable

19 disease.

20 Conclusions: AMG 780 could be administered at doses up to 30 mg/kg Q2W in patients with

21 advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients.

22 AEs were in line with toxicity associated with antiangiopoietin treatment.

AMG 780 in Patients With Advanced Solid Tumors

1 Abstract word count: 250 (limit, 250)

AMG 780 in Patients With Advanced Solid Tumors

1 Statement of translational relevance

2 Inhibition of angiogenesis can slow tumor growth and improve outcomes for patients with

3 metastatic disease. The angiopoietin axis plays an important role in angiogenesis and is distinct

4 from currently approved angiogenesis inhibitors which target the vascular endothelial growth

5 factor (VEGF) pathway. Several investigational drugs that target the angiopoietin axis are

6 currently in clinical trials. AMG 780 is a monoclonal antibody that binds to angiopoietin-1 and -2

7 (Ang1 and Ang2), preventing their binding to the Tie2 receptor to suppress angiogenesis. In

8 this phase 1 first-in-human study in patients with advanced cancer, AMG 780 was administered

9 once every 2 weeks at doses up to 30 mg/kg, with median terminal elimination half-life ranging

10 from 8 to 13 days and evidence of reduced capillary blood flow. No maximum-tolerated dose

11 was reached. Dosing once every 2 weeks supports both patient convenience and combination

12 with other anticancer regimens.

13 Word count: 142 (limit, 150)

AMG 780 in Patients With Advanced Solid Tumors

1 Introduction

2 Angiogenesis, the process of new blood vessel formation, is required for tumor growth

3 and metastatic spread and is regulated by a number of different pathways (1). Vascular

4 endothelial growth factor (VEGF) pathway family members play a critical role in angiogenesis by

5 stimulating proliferation, migration, and survival of endothelial cells (2). The angiopoietin axis is

6 a distinct angiogenic pathway that activates complementary angiogenic processes through

7 binding of the ligands angiopoietin-1 and -2 (Ang1 and Ang2) to the tyrosine kinase receptor

8 Tie2 (1). Ang1 is primarily involved in the maturation and stabilization of blood vessels,

9 whereas Ang2 contributes to vascular remodeling and new vessel sprouting (3-5). Many tumor

10 cells overexpress Ang1, and transcription of Ang2 is significantly upregulated in tumor-

11 associated endothelium (3). Studies have also identified increased levels of Ang2 in the tumor

12 vasculature across various types of tumors; these elevations have been associated with disease

13 progression and poor prognosis (6-9).

14 Inhibition of angiogenesis has been shown to improve outcomes in clinical studies. A

15 number of VEGF pathway inhibitors have been shown to be effective in the treatment of a

16 variety of solid tumor types (10-15). Inhibition of the angiopoietin pathway has been shown to

17 result in tumor growth inhibition in preclinical models, with simultaneous inhibition of Ang1 and

18 Ang2 resulting in greater tumor growth suppression compared with targeting either ligand in

19 isolation (16,17). In early phase clinical studies, treatment with trebananib (AMG 386), a

20 peptibody that inhibits the interaction between Ang1 and Ang2 and the Tie2 receptor (18),

21 showed anticancer activity, reducing tumor size and inducing objective responses in some

22 patients (19-23). In a randomized, double-blind, phase 3 clinical study, trebananib plus weekly

23 paclitaxel prolonged progression-free survival of patients with recurrent ovarian cancer

24 compared with placebo plus paclitaxel (7.2 versus 5.4 months; hazard ratio [HR], 0.66, 95% CI,

AMG 780 in Patients With Advanced Solid Tumors

1 0.57–0.77, P<0.0001) (24). Adverse events (AEs) occurring with greater frequency in the

2 trebananib group included edema, ascites, pleural effusion, and blurred vision (24).

3 AMG 780 is an investigational, intravenously administered fully human monoclonal

4 immunoglobulin G2 antibody that, like trebananib, binds to Ang1 and Ang2, thereby preventing

5 their interaction with the Tie2 receptor. In mice bearing Colo205 human colorectal cancer

6 xenografts, twice weekly administration of AMG 780 significantly inhibited tumor growth (66%),

7 viable tumor fraction (81%), and tumor endothelial cell proliferation (84%) compared with a

8 control antibody (25). The inhibitory activities of AMG 780 (IC50 [nM]: Ang1, 4.5; Ang2, 0.06)

9 were similar to those of trebananib (IC50 [nM]: Ang1, 3.5; Ang2, 0.03) (25). Preclinical studies

10 indicate that AMG 780 and trebananib have similar inhibitory activities and toxicity profiles and

11 that AMG 780, a monoclonal antibody, will have a longer half-life than trebananib, a peptibody,

12 potentially providing longer target inhibition. This report presents results from a first-in-human

13 phase 1 dose-escalation study that assessed the toxicity, pharmacokinetics, tumor vascular

14 response, tumor response, and pharmacodynamics of AMG 780 in patients with advanced solid

15 tumors.

AMG 780 in Patients With Advanced Solid Tumors

1 Methods

2 Patients

3 Eligible patients were ≥18 years of age and had pathologically confirmed advanced solid

4 tumors refractory to standard treatment, or for which standard treatment was not available or

5 had been refused; measurable disease per Response Evaluation Criteria in Solid Tumors

6 (RECIST) version 1.1 (26); and Eastern Cooperative Oncology Group performance status ≤2.

7 Patients were excluded if they had untreated or symptomatic primary central nervous system

8 tumors or metastases; head and neck cancer; history of hematopoietic stem cell transplant;

9 bleeding diathesis or adrenal hemorrhage; stroke, arterial/venous thrombosis, pulmonary

10 embolism, myocardial infarction, or unstable/uncontrolled cardiac disease; pulmonary

11 hemorrhage or gross hemoptysis within 6 months; history of peripheral vascular disease; prior

12 treatment with another agent targeting the angiopoietin-Tie2 pathway; concomitant therapeutic

13 dose anticoagulation therapy (prophylactic therapy was allowed); or inadequate hematologic,

14 hepatic, or renal function. Patients with unexplained clinical signs and symptoms suspicious for

15 adrenal insufficiency (including but not limited to hyperkalemia, hyponatremia and hypotension)

16 had a cosyntropin test performed prior to enrollment and were ineligible if their serum cortisol

17 was ≤18 μg/dL 30 to 60 minutes after stimulation. Patients provided written informed consent,

18 and study procedures were approved by an institutional review board at each site.

19 Study Design and Treatment

20 Patients received AMG 780 by intravenous infusion once every 2 weeks (Q2W)

21 beginning on the first day of treatment in week 1. At week 9, patients did not receive AMG 780;

22 radiologic assessment (see below) was done and, if disease progression had not occurred,

AMG 780 in Patients With Advanced Solid Tumors

1 biweekly treatment recommenced at week 10. Treatment with AMG 780 was discontinued for

2 disease progression per RECIST version 1.1 (26), clinical progression, or intolerance. To

3 determine the maximum tolerated dose (MTD), AMG 780 was administered to patients enrolled

4 sequentially into ascending dose Cohorts 1 to 9 (0.1, 0.3, 0.6, 1.2, 2.5, 5, 10, 20, and 30 mg/kg,

5 respectively). The starting dose was estimated to provide a 2-fold exposure margin over the

6 concentration required for 50% tumor growth inhibition in a mouse Colo205 xenograft model

7 (26). Initially, three patients were enrolled in Cohort 1. If none of the patients had a dose-

8 limiting toxicity (DLT; defined below) during the first 28 days of treatment, then three patients

9 were enrolled in the next dose cohort. If one of the initial three patients had a DLT, the cohort

10 was expanded to six patients. If no additional DLTs occurred in those six patients, then three

11 patients were enrolled in Cohort 2. If two or more of the initial three patients in Cohort 1

12 experienced a DLT, no additional patients were enrolled. Patients who dropped out during the

13 first 28 days of treatment for reasons other than DLT could be replaced. Dose escalation

14 continued until all planned cohorts were enrolled or an MTD (defined as the highest dose level

15 with a DLT patient incidence rate of <33% in a minimum of six patients treated at that dose

16 level) was determined. If the criteria for MTD were not met for any of the cohorts, no MTD was

17 reached. DLT was defined as any treatment-related grade ≥3 AE occurring in the first 28 days

18 of treatment. To be considered a DLT, grade 3 infusion reactions had to last >2 hours, grade 3

19 fatigue had to last >7 days, and grade 3 proteinuria had to last >2 weeks.

20 Endpoints and Analysis

21 The primary endpoints were toxicity, as indicated by patient incidence of DLTs and AEs,

22 and pharmacokinetic parameters of AMG 780. Secondary endpoints were tumor response per

23 RECIST version 1.1 (26), changes in tumor volume, anti−AMG 780 antibody formation, and

24 change in tumor vascularity from baseline to week 5. An exploratory endpoint was

25 pharmacodynamic changes in the levels of angiogenesis-related biomarkers across dose and

AMG 780 in Patients With Advanced Solid Tumors

1 time. All patients who received more than one dose of AMG 780 and had available radiologic

2 imaging at baseline and at least once postbaseline were included in tumor response analysis.

3 Adverse Events

4 All AEs occurring from study day 1 until 4 weeks after the last dose of AMG 780 (end of

5 study) were recorded and graded according to the National Cancer Institute Common

6 Terminology Criteria for Adverse Events version 4.0 by investigators. In preclinical studies,

7 histologic changes were noted in the liver, pancreas, and adrenal cortex of rats receiving

8 AMG 780 (Amgen Inc., data on file). Therefore, in addition to routine safety laboratory

9 assessment, which included alanine aminotransferase (ALT), aspartate aminotransferase

10 (AST), and bilirubin, for evaluation of liver function, we also evaluated pancreatic function by

11 monitoring amylase, lipase, and adrenal function by monitoring both baseline cosyntropin-

12 stimulated cortisol concentrations. Cosyntropin testing was conducted with measurement of

13 baseline and stimulated cortisol levels (serum cortisol before and 30–60 minutes after an

14 intravenous injection of 0.25 mg of cosyntropin) at screening, predose at week 5, at weeks 9

15 and 18, and every 8 weeks thereafter. A Jonckheere-Terpstra test (27) was used to evaluate

16 associations between AMG 780 dose and amylase/lipase levels.

17 Pharmacokinetics

18 Serum samples for evaluation of AMG 780 pharmacokinetics were collected immediately

19 before and after infusion of AMG 780 at weeks 1, 3, 5, 7, 10, Q2W beginning at week 12, and

20 every 8 weeks after week 18. Additional samples were collected at week 1 at 0.5, 8, 24, 72,

21 168, and 240 hours postdose, at week 5 at 48 and 168 hours postdose, and at week 7 at 8, 24,

22 72, 168, and 336 hours postdose. Pharmacokinetic analyses were conducted using

23 noncompartmental methods with Phoenix® WinNonlin® version 6.3 software on Citrix

24 (Pharsight®, St. Louis, MO).

AMG 780 in Patients With Advanced Solid Tumors

1 Immunogenicity

2 Anti-drug antibodies were detected using a modified electrochemiluminescent bridging

3 immunoassay as previously described for trebananib (28). Serum samples were collected for

4 evaluation of anti–AMG 780 antibodies at week 1 (predose); weeks 5, 9, and 10; every 8 weeks

5 thereafter; and at the end-of-study visit. Samples were first analyzed for anti–AMG 780

6 antibodies using a validated immunoassay. Positive samples were subsequently tested with a

7 validated receptor-binding assay to determine if these antibodies neutralized the activity of

8 AMG 780.

9 Tumor Vascular Response

10 To evaluate changes in tumor perfusion and vessel permeability, dynamic contrast-

11 enhanced magnetic resonance imaging (DCE-MRI) was performed at baseline and postdose at

12 week 5 using either ProHance® or MultiHance® as contrast agents (both from Bracco Imaging,

13 Monroe Township, NJ). DCE-MRI was analyzed by an independent core laboratory that

14 evaluated percentage change from baseline in the volume transfer constant (Ktrans) and blood-

15 normalized area under the enhancement curve (IAUC) (29).

16 Tumor Response

17 Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI)

18 was performed at baseline, weeks 9 and 18, and every 8 weeks thereafter. The same imaging

19 modality used for baseline studies was employed for subsequent scans. Tumor response was

20 evaluated by investigators per RECIST version 1.1 (26). Radiologic imaging was also submitted

21 to an independent imaging core laboratory for assessment of tumor volume.

AMG 780 in Patients With Advanced Solid Tumors

1 Pharmacodynamics

2 Serum samples for evaluation of circulating angiogenic cytokines were collected at day 1

3 (predose), and days 4, 11, 15 (predose), 29 (predose), 31, 43 (predose), 46, 57, every 8 weeks

4 thereafter, and at the end-of-study visit. Circulating angiogenic cytokines assessed included

5 soluble VEGF receptor 2 (sVEGFR2), placental growth factor (PLGF), VEGF, soluble Kit,

6 soluble VEGF receptor 1 (sVEGFR1), soluble vascular cell adhesion molecule-1 (sVCAM-1),

7 Ang1, Ang2, and soluble Tie2. A detailed description of these biomarker assays was previously

8 reported (30).

9 Results

10 Patients

11 Between August 2010 and December 2013, 45 patients were enrolled across each of

12 the nine dose cohorts (0.1−30 mg/kg; Supplementary Figure S1). All patients received at least

13 one dose of AMG 780 except for one patient in the 10-mg/kg dose cohort who withdrew consent

14 before receiving AMG 780 and was not included in the analyses. The median (range) number

15 of doses of AMG 780 administered was 4 (1–20). At the time of analysis, all patients had

16 discontinued AMG 780 because of disease progression (n=35), AEs (n=5), death (n=1),

17 withdrawal of consent (n=2), and other reasons (n=2). Patient characteristics are described in

18 Table 1. The median (range) age was 63 (45–76) years and 57% of patients were female.

19 Patients who received AMG 780 most frequently had cancer of the large intestine (27%), non–

20 small-cell lung cancer (21%), ovarian cancer (11%), or mesothelioma (9%).

AMG 780 in Patients With Advanced Solid Tumors

1 Dose Escalation and Toxicity

2 Three patients had DLTs. One patient in the 0.6-mg/kg dose cohort had treatment-

3 related grade 3 thrombocytopenia beginning on day 18 that resulted in discontinuation of

4 AMG 780. One patient in the 10-mg/kg dose cohort had treatment-related grade 2 proteinuria

5 beginning on day 2 that worsened to a DLT of grade 3 proteinuria on day 15, and resulted in

6 discontinuation of AMG 780. Finally, one patient in the 30-mg/kg dose cohort with NSCLC who

7 entered the study with a mild pericardial effusion was hospitalized for dyspnea on day 4 (post

8 one dose of AMG 780) and found to have worsening of the pericardial effusion to a grade 3

9 serious AE and in addition had an obstructing lesion in the left upper lung lobe and a possible

10 pneumonia. The pericardial effusion continued to worsen over the next several days and was

11 treated with placement of a pericardial window and drain. The investigator reported there was a

12 reasonable possibility the worsening effusion was related to AMG 780. The patient

13 discontinued AMG 780 because of disease progression. None of these DLTs prevented dose

14 escalation and no other DLTs occurred in any of the other cohorts; therefore, an MTD was not

15 reached in this study.

16 All patients who received AMG 780 had at least one treatment-emergent AE. The most

17 frequently occurring treatment-emergent AEs were hypoalbuminemia, peripheral edema,

18 decreased appetite, and fatigue (Table 2). Twenty-seven patients (61%) had grade ≥3

19 treatment-emergent AEs; there did not appear to be an association between incidence of grade

20 ≥3 events and dose. Two patients had grade 4 AEs (esophageal ulcer and sepsis); both

21 occurred in the 10-mg/kg cohort and neither was considered related to administration of AMG

22 780 by the investigators. The patient with esophageal ulcers had a history of hepatocellular

23 carcinoma, cirrhosis and hepatitis B. Three months after entering the study, he was

24 hospitalized for nausea, vomiting and gastrointestinal bleeding. Esophageal duodenoscopy

25 revealed severe portal gastropathy in addition to esophageal ulcers. The patient with grade 4

AMG 780 in Patients With Advanced Solid Tumors

1 sepsis (non-specific, NOS) had metastatic colorectal cancer; the patient had received two doses

2 of AMG 780 at the time of the AE. An etiology for the septic picture was not identified. Three

3 patients died during the study: one from suicide (2.5-mg/kg cohort), one from breast cancer

4 (10-mg/kg cohort), and another from malignant lung neoplasm (30-mg/kg cohort). The latter of

5 these patients had earlier developed a DLT of pericardial effusion (described above). None of

6 the deaths were considered to be related to administration of AMG 780 by the investigators.

7 Twenty-eight patients (64%) had treatment-related AEs; all were grade ≤3 (Supplementary

8 Table S1). Sixteen patients (36%) had serious AEs. Those that occurred in more than one

9 patient were ascites, dyspnea, and pleural effusion (all n=2). Only one patient had a serious AE

10 considered by the investigator to be related to treatment (pericardial effusion). Sixteen patients

11 (36%) had AEs that led to discontinuation of AMG 780.

12 Several AEs have previously been reported to occur with the dual Ang1/Ang2 inhibitor

13 trebananib, including edema, ascites, pleural effusion, hypokalemia, proteinuria, and blurred

14 vision (19-21,24,31), and were therefore of interest in this study of AMG 780. In this first-in-

15 human study, thirteen patients (30%) had peripheral edema. Six patients had peripheral edema

16 that was considered by the investigator to be related to AMG 780. All peripheral edema events

17 were of grade 1 or 2. Six patients (14%) had pleural effusion (two grade 3 events), six patients

18 (14%) had hypokalemia (two grade 3 events, one of which was treatment related), six patients

19 (14%) had proteinuria (one treatment-related grade 3 event), and five patients (11%) had

20 ascites (two grade 3 events). Blurred vision (grade 1) occurred in one patient in the 30-mg/kg

21 cohort. AEs that are typically associated with angiogenic inhibitors targeting the VEGF

22 pathway, such as hypertension, hemorrhage, delayed wound healing, and thromboembolism

23 (32), were not common during AMG 780 treatment. Hypertension occurred in three patients

24 (7%). One patient (2%) had hematemesis; no other hemorrhage events and no delayed wound

25 healing events were reported. Three patients (7%) had venous thromboembolic events. One

26 patient had superior vena cava syndrome.

AMG 780 in Patients With Advanced Solid Tumors

1 Alanine aminotransferase and AST levels were elevated (≥3 times the upper limit of

2 normal) for three patients in the 2.5-mg/kg cohort and one patient each in the 10-mg/kg and 30-

3 mg/kg cohorts. Two of the three patients with elevated ALT and AST levels in the 2.5-mg/kg

4 cohort also had elevated bilirubin levels (ie, ≥2 times the upper limit of normal). However, both

5 patients had grade 3 elevations in alkaline phosphatase indicative of hepatobiliary disease;

6 therefore, neither met the criteria for Hy’s law. There was no trend for increase or decrease in

7 amylase or lipase levels with increasing dose of AMG 780 per Jonckheere-Terpstra test

8 performed at each patient visit. One patient in the 5-mg/kg cohort had an elevated postbaseline

9 serum amylase level >150 IU/L that resolved by the end-of-study visit. One patient in the 30-

10 mg/kg cohort had serum lipase ≥800 IU/L that resulted in discontinuation of AMG 780 but was

11 not considered related to treatment by investigators. No significant decreases in serum cortisol

12 levels, either before or after cosyntropin stimulation, were observed at any of the doses or time

13 points tested.

14 Pharmacokinetics

15 AMG 780 exhibited linear pharmacokinetics after single-dose administrations over the

16 dose range of 0.1 to 30 mg/kg (Figure 1). Exposure (as measured by mean maximal plasma

17 concentration [Cmax] and area under the concentration-time curve during the dosing interval [tau;

18 AUCtau], with tau equal to 336 hours) increased in a dose-proportional manner up to a dose of

19 30 mg/kg (Table 3). Median time to Cmax (ie, tmax) was equal to 1 hour across all doses. The

20 mean volume of distribution at steady state (Vss) at all dose levels was 31.4 mL/kg. For doses

21 from 0.6 to 30 mg/kg, the estimated mean serum clearance after intravenous infusion was

22 0.16 mL/h/kg. Steady state was reached after three doses of AMG 780 (Figure 1), with a mean

23 accumulation ratio of 1.6. At doses of 2.5 mg/kg and above, median terminal elimination half-

24 life (t1/2,z) was between 8 and 13 days, and minimum plasma concentration (Cmin) exceeded the

AMG 780 in Patients With Advanced Solid Tumors

1 50% (1.2 µg/mL) and 90% (10.4 µg/mL) inhibitory concentrations obtained in a mouse Colo205

2 xenograft model (Amgen Inc., data on file).

3 Tumor Vascular Response

4 Baseline dynamic contrast-enhanced magnetic resonance imaging was conducted in 41

5 consenting patients (three patients did not have DCE-MRI per their decision). Among these 41

6 patients, 22 had baseline and at least one postbaseline scan after AMG 780 was administered

7 whereas the remainder lacked a postbaseline scan because they were off-study at week 5 (14),

8 their lesions were too small at baseline (3), or they lacked baseline scans (2). Sixteen of these

9 22 patients were considered evaluable in that they had interpretable data from baseline as well

10 as from both the predose and the postdose week 5 scans. In two of these 16 patients, two

11 evaluable lesions were present. Data were considered not interpretable (evaluable) in six

12 patients because of either week 5 predose and/or postdose scans were not evaluable (n=4) or

13 baseline scans were inadequate (n=2). At week 5, six patients had a >20% decrease in Ktrans (a

14 measure of capillary blood flow), and five patients had IAUC decreased by >20% relative to

15 baseline (Figure 2). Four patients had a >20% decrease in both Ktrans and IAUC. There were

16 no effects on tumor vascularity among the other patients.

17 Tumor Response

18 Thirty-five patients were evaluable for tumor response. No patients achieved a complete

19 or partial response. Eight patients had a best response of stable disease (one each receiving

20 AMG 780 0.1, 0.3, 0.6, 2.5, 20, and 30 mg/kg, and two receiving AMG 780 10 mg/kg). Stable

21 disease lasted >6 months for the patient in the 0.6-mg/kg cohort (a patient with non–small-cell

22 lung cancer); however, there was no reduction in tumor volume. The remaining 27 patients had

23 progressive disease. Tumor size decreased relative to baseline in four patients (all had stable

24 disease as best response). Best response reductions in tumor size were 3.8% in a patient with

AMG 780 in Patients With Advanced Solid Tumors

1 a tumor of the large intestine (2.5-mg/kg cohort; evaluated as having stable disease that lasted

2 33 weeks), 4.5% in a patient with ovarian cancer (2.5-mg/kg cohort; progressive disease at

3 initial scan), 7.4% in a patient with non−small-cell lung cancer (0.6-mg/kg cohort; stable disease

4 lasting 3 weeks), and 25% in a patient with endometrial cancer (30-mg/kg cohort; stable disease

5 lasting 8 weeks). Across all patients, tumor size changes relative to baseline ranged from −25%

6 to 135%.

7 Anti−AMG 780 Antibodies

8 For anti−AMG 780 antibody analyses, serum samples were available for all 44 patients

9 at baseline and for 33 patients postbaseline. No patients developed binding or neutralizing

10 anti−AMG 780 antibodies during the study. One patient had preexisting neutralizing,

11 anti−AMG 780 binding antibodies at baseline, but did not test positive for anti−AMG 780

12 antibodies at any other point during the study. The presence of these neutralizing antibodies

13 did not affect AMG 780 concentrations.

14 Pharmacodynamics (Biomarkers)

15 Dose-proportional changes in biomarkers were observed for sVCAM-1 and PLGF during

16 AMG 780 treatment (Figures 3A and B). Maximum increases occurred at treatment day 4 for

17 PLGF and treatment day 11 for sVCAM-1. There was also a small decrease in sVEGFR2 over

18 the first 57 days of treatment with AMG 780; this decrease was not dose proportional

19 (Figure 3C). None of the measured circulating angiogenic factors were associated with

20 baseline tumor measurements or changes in tumor size during treatment. All evaluable patients

21 (n=38) expressed detectable levels of Ang1 and Ang2. Mean (SD) serum baseline Ang1 and

22 Ang2 concentrations were 27.8 (10.3) ng/mL and 3.50 (2.24) ng/mL, respectively.

AMG 780 in Patients With Advanced Solid Tumors

1 Discussion

2 In this first-in-human, phase 1 dose-escalation study, we found that AMG 780, a

3 monoclonal antibody that blocks the interaction between Ang1 and Ang2 and the Tie2 receptor,

4 could be administered at doses up to 30 mg/kg, had pharmacologic characteristics that allowed

5 for dosing once every 2 weeks, and had biologic effects consistent with an antiangiogenic

6 mechanism of action. An MTD was not reached at the highest dose administered (30 mg/kg

7 Q2W). Three patients had DLTs (thrombocytopenia, proteinuria, pleural effusion), none of

8 which prevented dose escalation. There were two grade 4 events (esophageal ulcer and

9 sepsis) and three on-study deaths (two disease progressions and one suicide), none of which

10 were considered related to AMG 780. All other AEs were of grade ≤3, and there did not appear

11 to be an association between dose and AE severity.

12 Patterns of toxicity occurring during the study were consistent with those anticipated for

13 an antiangiopoietin agent. Peripheral edema, which has been reported during treatment with

14 trebananib (19-24,31,33), occurred in 30% of patients, although all events were grade 1 or 2.

15 The mechanism by which peripheral edema might occur during AMG 780 and trebananib

16 treatment is uncertain. There did not appear to be an association between administration of

17 AMG 780 and hepatic, pancreatic, or adrenal cortex functioning. Although two patients had

18 significant hepatic laboratory abnormalities, the presence of grade 3 elevations in alkaline

19 phosphatase is suggestive of underlying hepatobiliary tract disease rather than drug-induced

20 liver injury. Events typically associated with anti-VEGF therapy (eg, bleeding events,

21 hypertension, thromboembolic events, and delayed wound healing) occurred either infrequently

22 or not at all. Since AMG 780 inhibits the angiopoietin pathway, its mechanism of action and

23 adverse event profile are unique and different from those of angiogenesis inhibitors targeting the

AMG 780 in Patients With Advanced Solid Tumors

1 VEGF pathway. This is consistent with what has been observed and in studies evaluating other

2 agents targeting the angiopoietin pathway (24).

3 AMG 780 had approximately dose-linear pharmacokinetics, with steady state reached

4 after three Q2W doses and no evidence of accumulation. At doses of 2.5 mg/kg and above,

5 median t1/2,z was between 8 and 13 days for this monoclonal antibody compared with 3.1 to 6.3

6 days for the peptibody trebananib (19). This difference in half-life is due to molecular weight

7 and size differences between the two molecules (antibody versus peptibody). Although an MTD

8 was not reached (as frequently occurs in phase 1 studies evaluating biologic agents) (34),

9 AMG 780 concentrations remained above the IC90 for tumor growth inhibition in xenograft

10 models throughout a 2-week cycle. Thus, Q2W administration of AMG 780 is feasible and

11 provides serum concentrations at levels required for antitumor activity. Dosing once every 2

12 weeks supports both patient convenience and combination with chemotherapy regimens

13 administered at this interval.

14 Dynamic contrast-enhanced magnetic resonance imaging has been used in clinical

15 development of antiangiogenic drugs to evaluate their effects on tumor vasculature (29,35).

16 The reductions in Ktrans and IAUC reported in this study suggest that AMG 780 induced the

17 anticipated effects on tumor perfusion and vessel permeability (as measured by Ktrans and

18 IAUC), with effects observed across a variety of tumor types. Notably, the magnitude of

19 reductions in Ktrans and IAUC was similar to those occurring with trebananib (19) and smaller

20 than what has been measured with agents targeting the VEGF pathway (29,36-38).

21 Further evidence of the biologic effects of AMG 780 on angiogenic pathways was

22 provided by evaluation of circulating angiogenic factors. During AMG 780 treatment, serum

23 concentrations of PLGF and sVCAM-1 were increased, whereas serum sVEGFR2 decreased.

24 PLGF is a ligand for VEGFR1 (39), VCAM-1 is expressed by endothelial cells in response to

25 VEGF (40), and sVEGFR2 is a VEGF receptor variant that appears to have

26 antilymphangiogenic activity (41). The observed changes in these molecules are indicative not

AMG 780 in Patients With Advanced Solid Tumors

1 only of effects of AMG 780 on angiogenesis but also of interactions between the angiopoietin

2 axis and VEGF pathway. Although we did not see an association between change from

3 baseline in PLGF, sVCAM-1, and sVEGFR2 and outcomes, it must be noted that the small

4 magnitude of changes in tumor size, which is not unexpected for a heavily pretreated patient

5 population with advanced disease, may have made it difficult to identify such associations if they

6 exist. It is also possible that identification of a biomarker for AMG 780 activity will require

7 evaluation of alternative biomarkers. For example, it has been suggested that tumor expression

8 of a panel of proteins (Ang1, epidermal growth factor, and Emmprin) may have predictive value

9 for tumor growth inhibition by the anti-Ang2 monoclonal antibody CVX-060 (42). Evaluation of

10 tumor expression of other components of the angiopoietin pathway (including Tie2) might also

11 be appropriate. However, such analyses may be challenging given the need to localize

12 expression within tumor versus endothelial versus stromal cells and the heterogeneity of

13 expression of Tie2 (43).

14 Tumor response was a secondary endpoint in this phase 1 dose-escalation study.

15 Although no patients met the criteria for complete or partial response, four patients had

16 reductions in tumor size during AMG 780 treatment and one patient, who had been treated with

17 surgery, radiation, and seven prior anticancer regimens (including one course of bevacizumab),

18 had stable disease lasting 7 months. The lack of complete or partial responses must be

19 evaluated in the context of the enrolled population of patients with advanced solid tumors

20 refractory to available therapy.

21 The angiopoietin pathway represents an attractive target in the treatment of cancer.

22 Both Ang1 and Ang2 play key roles in neovascularization, with Ang1 regulating maturation of

23 new blood vessels while Ang2 regulates vascular remodeling and sprouting of new vessels (3-

24 5). In addition to the extensive data on the role of the angiopoietin pathway in angiogenesis,

25 several studies have demonstrated increased expression of Tie2 in cancer cells and in cancer-

26 associated stromal cells. This, coupled with the expression of Ang1 and/or Ang2 by cancer cells

AMG 780 in Patients With Advanced Solid Tumors

1 and studies of these cell lines and in vivo tumor models, suggests that Tie2 activation may

2 contribute to cancer cell growth via additional autocrine mechanisms that promote a stem cell–

3 like phenotype with enhanced adhesion, invasion and metastatic potential (44-46).

4 Results from the phase 3 TRINOVA-1 study of trebananib plus paclitaxel versus placebo

5 plus paclitaxel in women with recurrent ovarian cancer have validated the angiopoietin pathway

6 as a target in the treatment of cancer (24). In addition to trebananib and AMG 780 (which target

7 the interaction between Ang1 and Ang2 and Tie2), agents employing a diverse range of

8 alternative strategies to inhibit the angiopoietin pathway have been evaluated in the treatment of

9 cancer (47). Agents investigated in clinical studies include CVX-060, a fusion of a peptide and a

10 carrier antibody scaffold that blocks the interaction between Ang2 and Tie2 interaction (42);

11 CEP-11981, a small molecule inhibitor of VEGF receptor 1, VEGF receptor 2, and Tie2 (48);

12 MEDI3617 (49) and REGN910 (50), monoclonal antibodies that bind Ang2 to prevent its

13 interaction with the Tie2 receptor; and small molecule inhibitors such as regorafenib (51,52),

14 cabozantinib (53), MGCD265 (54), and foretinib (55) that block the activity of multiple protein

15 kinases, including Tie2 and VEGF receptors. All of these agents focus on inhibition of Ang2 or

16 Tie2, either alone or in combination with sometimes multiple other targets, but none aim at

17 inhibiting both Ang1 and Ang2, alone. The potential role of targeting angiopoetins and other

18 angiogenic factors outside of the well-studied VEGF pathway in the treatment of cancer

19 continues to be an area of scientific interest (56,57). Although treatment with anti-VEGF or anti-

20 VEGF receptor agents has been shown to result in objective responses in some patients

21 (particularly when combined with chemotherapy), not all patients respond and tumor shrinkage

22 has not always translated into improvements in overall survival in phase 3 studies (57). As a

23 result, some have suggested that combinations employing agents targeting both the VEGF and

24 angiopoietin pathways may be worthy of investigation (58). In conclusion, AMG 780 could be

25 administered at doses up to 30 mg/kg once every 2 weeks with toxicity as anticipated for an

26 antiangiopoietin agent. No MTD was reached. AMG 780 had dose-proportional

AMG 780 in Patients With Advanced Solid Tumors

1 pharmacokinetics with serum concentrations remaining above levels anticipated for an

2 antitumor effect (based on preclinical studies) throughout a 2-week treatment cycle.

3 Acknowledgments

4 The authors would like to thank Don Zhong, PhD (Amgen Inc.), for performing anti–AMG 780

5 antibody measurements and data analysis; and Terrance J. Williams, PhD (formerly of Amgen

6 Inc.), and Ali Hassan, PhD (Complete Healthcare Communications, Inc.), whose work was funded

7 by Amgen Inc., for assistance in the preparation of this manuscript.

AMG 780 in Patients With Advanced Solid Tumors

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AMG 780 in Patients With Advanced Solid Tumors

1 Tables

2 Table 1. Demographics and Clinical Characteristics

All Patients Characteristic (N=44) Median (range) age, y 63 (45–76)

Sex, n (%) Female 25 (57) Male 19 (43)

Race, n (%) White 41 (93) Asian 1 (2) Black or African American 1 (2) Hispanic or Latino 1 (2)

Primary tumor type, n (%) Large intestine/colorectal 12 (27) Non–small-cell lung 9 (21) Ovarian 5 (11) Mesothelioma 4 (9) Pancreatic 2 (5) Thymic 2 (5) Uterine/Endometrial 2 (5) Bone sarcoma 1 (2) Breast 1 (2) Small-cell lung 1 (2) Soft tissue sarcoma 1 (2) Stomach 1 (2) Appendiceal mucinous adenocarcinoma 1 (2) Abdominal mass-mucinous adenocarcinoma 1 (2) Hepatocellular carcinoma 1 (2)

Stage, n (%) Stage II 1 (2.3) Stage III 5 (11.4) Stage IV 37 (84.1) Unknown 1 (2.3)

AMG 780 in Patients With Advanced Solid Tumors

ECOG performance status, n (%) 0 16 (36.4) 1 27 (61.4) 2 1 (2.3) 1 ECOG=Eastern Cooperative Oncology Group.

Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. AMG 780 in Patients With Advanced Solid Tumors Downloaded from Table 2. Patient Incidence of Treatment-Emergent AEs Irrespective of Relationship to Treatment Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Author ManuscriptPublishedOnlineFirstonApril13,2016;DOI:10.1158/1078-0432.CCR-15-2145

AMG 780 Dose Cohort

clincancerres.aacrjournals.org All AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 Patients 0.1 mg/kg 0.3 mg/kg 0.6 mg/kg 1.2 mg/kg 2.5 mg/kg 5 mg/kg 10 mg/kg 20 mg/kg 30 mg/kg (N=44) (n=3) (n=3) (n=6) (n=3) (n=6) (n=3) (n=9) (n=3) (n=8) Any AE, n (%) 44 (100) 3 (100) 3 (100) 6 (100) 3 (100) 6 (100) 3 (100) 9 (100) 3 (100) 8 (100) Grade 3 22 (50) 2 (67) 1 (33) 3 (50) 1 (33) 3 (50) 2 (67) 4 (44) 2 (67) 4 (50) Grade 4* 2 (5) 0 0 0 0 0 0 2 (22) 0 0 Grade 5† 3 (7) 0 0 0 0 1 (17) 0 1 (11) 0 1 (13) AEs occurring in >10% of patients, n (%) Hypoalbuminemia 15 (34) 1 (33) 1 (33) 3 (50) 2 (67) 3 (50) 1 (33) 3 (33) 0 1 (13)

Research. Peripheral edema 13 (30) 1 (33) 1 (33) 3 (50) 1 (33) 2 (33) 1 (33) 3 (33) 0 1 (13) Decreased appetite 12 (27) 1 (33) 0 0 2 (67) 2 (33) 1 (33) 4 (44) 1 (33) 1 (13) Fatigue 12 (27) 1 (33) 1 (33) 3 (50) 0 1 (17) 1 (33) 4 (44) 0 1 (13) Grade 3 1 (2) 0 0 0 0 1 (17) 0 0 0 0 Hyponatremia 9 (20) 1 (33) 0 2 (33) 1 (33) 2 (33) 0 2 (22) 0 1 (13) Grade 3 3 (7) 1 (33) 0 0 0 2 (33) 0 0 0 0 Lymphopenia 9 (21) 2 (67) 1 (33) 1 (17) 1 (33) 1 (17) 0 0 2 (67) 1 (13) Grade 3 2 (5) 0 0 1 (17) 1 (33) 0 0 0 0 0 Nausea 9 (21) 1 (33) 1 (33) 1 (17) 1 (33) 2 (33) 0 3 (33) 0 0 Cough 8 (18) 2 (67) 0 0 0 1 (17) 1 (33) 2 (22) 0 2 (25) Dyspnea 8 (18) 1 (33) 0 1 (17) 1 (33) 1 (17) 0 2 (22) 0 2 (25) Grade 3 1 (2) 0 0 0 0 0 0 1 (11) 0 0 Headache 8 (18) 1 (33) 1 (33) 1 (17) 0 0 0 2 (22) 0 3 (38) Abdominal pain 7 (16) 0 1 (33) 0 2 (67) 1 (17) 0 1 (11) 1 (33) 1 (13) Grade 3 1 (2) 0 0 0 0 0 0 1 (11) 0 0 Constipation 7 (16) 0 1 (33) 0 1 (33) 2 (33) 0 2 (22) 1 (33) 0 Grade 3 1 (2) 0 0 0 0 1 (17) 0 0 0 0 Anemia 6 (14) 1 (33) 0 0 0 1 (17) 1 (33) 1 (11) 0 2 (25) Blood alkaline phosphatase increased 6 (14) 0 0 1 (17) 0 2 (33) 1 (33) 1 (11) 1 (33) 0 Grade 3 4 (9) 0 0 0 0 2 (33) 1 (33) 1 (11) 0 0 Dizziness 6 (14) 0 0 1 (17) 1 (33) 0 0 2 (22) 1 (33) 1 (13) Hypokalemia 6 (14) 1 (33) 0 0 1 (33) 1 (17) 1 (33) 1 (11) 0 1 (13)

30 AMG 780 in Patients With Advanced Solid Tumors Downloaded from AMG 780 Dose Cohort

All AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 AMG 780 Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Patients 0.1 mg/kg 0.3 mg/kg 0.6 mg/kg 1.2 mg/kg 2.5 mg/kg 5 mg/kg 10 mg/kg 20 mg/kg 30 mg/kg Author ManuscriptPublishedOnlineFirstonApril13,2016;DOI:10.1158/1078-0432.CCR-15-2145 (N=44) (n=3) (n=3) (n=6) (n=3) (n=6) (n=3) (n=9) (n=3) (n=8) Grade 3 2 (5) 0 0 0 1 (33) 0 0 0 0 1 (13)

clincancerres.aacrjournals.org Pain in extremity 6 (14) 0 1 (33) 0 0 2 (33) 0 1 (11) 0 2 (25) Pleural effusion 6 (14) 0 0 1 (17) 0 1 (17) 0 3 (33) 0 1 (13) Grade 3 2 (5) 0 0 1 (17) 0 0 0 1 (11) 0 0 Proteinuria 6 (14) 0 0 0 0 2 (33) 0 2 (22) 0 2 (25) Grade 3 1 (2) 0 0 0 0 0 0 1 (11) 0 0 Vomiting 6 (14) 0 1 (33) 0 0 2 (33) 0 3 (33) 0 0 Ascites 5 (11) 0 0 0 0 3 (50) 0 1 (11) 0 1 (13) Grade 3 2 (5) 0 0 0 0 2 (33) 0 0 0 0 AST increased 5 (11) 0 1 (33) 0 0 1 (17) 0 0 1 (33) 2 (25) Grade 3 1 (2) 0 0 0 0 0 0 0 0 1 (13) Back pain 5 (11) 1 (33) 0 0 0 1 (17) 1 (33) 1 (11) 0 1 (13) on September 24, 2021. © 2016American Association for Cancer Diarrhea 5 (11) 0 0 1 (17) 0 0 0 1 (11) 1 (33) 2 (25) Research. Grade 3 1 (2) 0 0 1 (17) 0 0 0 0 0 0 Hypoglycemia 5 (11) 0 1 (33) 1 (17) 0 1 (17) 0 0 2 (67) 0 Myalgia 5 (11) 0 0 2 (33) 0 2 (33) 0 0 1 (33) 0 AE=adverse event; AST=aspartate aminotransferase. *Two patients had grade 4 AEs (esophageal ulcer and sepsis). †There were three fatal AEs (completed suicide, malignant lung neoplasm, and dyspnea). None were considered to be related to treatment.

31 AMG 780 in Patients With Advanced Solid Tumors Downloaded from 1 Table 3. AMG 780 Pharmacokinetic Parameters Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Author ManuscriptPublishedOnlineFirstonApril13,2016;DOI:10.1158/1078-0432.CCR-15-2145

Week 1 Week 7 clincancerres.aacrjournals.org

Dose Cmax AUCtau t1/2,z Cmax AUCtau CL Vss (mg/kg) (µg/mL) (mg•h/mL) (h) (µg/mL) (mg•h/mL) (mL/h/kg) (mL/kg)

n Mean CV Mean CV (%) Mean CV (%) n Mean CV (%) Mean CV (%) Mean CV (%) Mean CV (%)

0.1 3 2.46 22.2 210 50.4 55.9 58.0 2 2.38 20.2 260 77.0 0.547 77.0 36.8 24

0.6 6 16.0 15.1 1860 35.5 79.7 47.1 4 19.8 10.3 2570 33.3 0.255 35.6 32.2 12

1.2 3 40.8 37.1 6310 42.6 147 16.3 3 55.6 27.5 7730 20.6 0.159 18.2 26.3 42

2.5 4 55.9 26.7 8600 29.5 198 31.0 3 98.0 18.4 15,700 17.7 0.161 18.3 31.6 17

5 3 121 15.9 19,500 6.3 240 62.8 1 202 – 36,300 – 0.135 – 32.8 –

10 9 265 29.3 35,900 41.3 179 23.7 2 394 6.1 56,600 32.0 0.186 32.3 34.3 37

20 3 431 14.6 75,800 16.1 300 25.2 2 811 13.6 165,000 28.6 0.126 29.3 30.2 27

30 8 724 15.7 113,000 19.9 289 53.4 4 1360 20.6 243,000 29.9 0.132 32.1 29.0 23

32 AMG 780 in Patients With Advanced Solid Tumors Downloaded from 3 AUCtau=area under the concentration-time curve during the dosing interval; CL=serum clearance after intravenous

4 infusion; Cmax=maximum observed plasma concentration; Cmin=minimum observed plasma concentration; Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited.

5 CV=coefficient of variation; t1/2,z=terminal elimination half-life; Vss=volume of distribution at steady state. Author ManuscriptPublishedOnlineFirstonApril13,2016;DOI:10.1158/1078-0432.CCR-15-2145 6 clincancerres.aacrjournals.org on September 24, 2021. © 2016American Association for Cancer Research.

33 Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

AMG 780 in Patients With Advanced Solid Tumors

7 Figure Legends

8 Figure 1. Concentration of AMG 780 in the serum during treatment in each dose cohort. 9 IV=intravenous

10 Figure 2. Changes in tumor vascularity as assessed by dynamic contrast-enhanced 11 magnetic resonance imaging as measured by Ktrans (A) and IAUC (B) at week 5 12 for each patient (all, n=16). *Patient in the 0.1 mg/kg cohort with a 0% change 13 from baseline. Append AdCC=appendicular adenocarcinoma; CRC=colorectal 14 cancer; HPCC=hepatocellular carcinoma; IAUC= blood-normalized area under 15 the enhancement curve; Ktrans=percentage change from baseline in the volume 16 transfer constant; NSCLC=non–small-cell lung cancer; Syn Sarc=synovial 17 sarcoma.

18 Figure 3. Pharmacodynamic effects of AMG 780 on the circulating angiogenic factors 19 sVCAM-1 (A), PLGF (B), and sVEGFR2 (C). Arrows indicate AMG 780 20 administration. EOS=end of study; PLGF=placental growth factor; sVCAM- 21 1=soluble vascular cell adhesion molecule-1; sVEGFR2=soluble vascular 22 endothelial growth factor receptor 2.

Figure 1

10000

1000

100 0.1 mg/kg (n=2–3) 0.3 mg/kg (n=1–3) 0.6 mg/kg (n=3–6) 10 1.2 mg/kg (n=2–3) 2.5 mg/kg (n=2–6) 5 mg/kg (n=1–3) 10 mg/kg (n=1–9) 1 20 mg/kg (n=2–3) 30 mg/kg (n=1–8)

0.1 Mean (SD) Serum AMG 780 Concentration, µg/mL 0.01 0 7 14 21 28 35 42 49 56

1st Dose 2nd Dose 3rd Dose 4th Dose Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Time Postdose,Research. days Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

A Phase 1, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients With Advanced Solid Tumors

Afshin Dowlati, Gordana Vlahovic, Ron Natale, et al.

Clin Cancer Res Published OnlineFirst April 13, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-15-2145

Supplementary Access the most recent supplemental material at: Material http://clincancerres.aacrjournals.org/content/suppl/2016/04/13/1078-0432.CCR-15-2145.DC1

Author Author manuscripts have been peer reviewed and accepted for publication but have not yet been Manuscript edited.

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