Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Journal of Clinical Oncology, Vol 25, No 17 (June 10), 2007: pp. 2369-2376
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.07.8170
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rosen, L. S.
Right arrow Articles by Herbst, R. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rosen, L. S.
Right arrow Articles by Herbst, R. S.

Safety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients With Advanced Solid Tumors

Lee S. Rosen, Razelle Kurzrock, Marilyn Mulay, Andy Van Vugt, Michelle Purdom, Chaan Ng, Jeffrey Silverman, Antonis Koutsoukos, Yu-Nien Sun, Michael B. Bass, Ren Y. Xu, Anthony Polverino, Jeffrey S. Wiezorek, David D. Chang, Robert Benjamin, Roy S. Herbst

From the Premiere Oncology, Santa Monica; Landmark Imaging, Los Angeles; Amgen Inc, Thousand Oaks, CA; and the Division of Cancer Medicine Phase 1 Program, Department of Radiology, Department of Sarcoma, and Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Roy S. Herbst, MD, PhD, The University of Texas M.D. Anderson Cancer Center, Thoracic/Head and Neck Medical Oncology, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030; e-mail: rherbst{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Purpose: AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors.

Patients and Methods: AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determined.

Results: Seventy-one patients received AMG 706. The MTD was 125 mg once daily administered continuously. The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%). Plasma AMG 706 concentrations increased in a dose-proportional manner with no accumulation after multiple doses. Five patients (7%) had a partial response, 35 patients (49%) had stable disease (at least through day 50), and 31 patients (44%) had progressive disease. Changes in tumor size correlated significantly with an increase in placental growth factor (P = .003) and a decrease in soluble kinase domain receptor (P = .001).

Conclusion: In this study of patients with advanced refractory solid tumors, AMG 706 was well tolerated and displayed favorable pharmacokinetics and evidence of antitumor activity. Additional studies of AMG 706 as monotherapy and in combination with various agents are ongoing.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Angiogenesis, the formation of new blood vessels from the existing vasculature, is essential for tumor growth and metastasis.1,2 Members of the vascular endothelial growth factor (VEGF) family of cytokines are among the most potent proangiogenic molecules. These cytokines bind and activate VEGF receptors (VEGFr) including VEGFr2 (or KDR, kinase domain receptor) and VEGFr1 (or FLT-1, fms-related tyrosine kinase-1), to induce a stimulatory response in endothelial cells and promote neovascularization.3 In preclinical models of human cancer, blocking angiogenesis inhibits tumor proliferation and induces regression.1,4 A number of antiangiogenic agents such as monoclonal antibodies or small molecule inhibitors have shown clinical activity against advanced solid tumors.5-16

AMG 706 is a novel, orally bioavailable small molecule that selectively inhibits VEGFr1, VEGFr2, VEGFr3, platelet-derived growth factor receptor, and stem-cell factor receptor (Kit).17-19 After activation by cytokines,20 VEGFr1- and VEGFr2-mediated pathways promote angiogenesis, whereas VEGFr3 promotes lymphangiogenesis. Kit- and platelet-derived growth factor receptor–mediated pathways promote cellular proliferation.21 Moreover, Kit mutations, observed in several cancer types, lead to constitutively activated receptors in the absence of ligand binding.22 By inhibiting multiple signaling pathways involved in tumorigenesis, AMG 706 may have broad antitumor activity.

In animal models, AMG 706 has demonstrated significant antiangiogenic and antitumor activity.4,23,24 AMG 706 treatment completely inhibited VEGF-induced angiogenesis in a rat corneal model of angiogenesis.4 Furthermore, treatment of tumor xenografts with AMG 706 prevented tumor growth and induced regression of existing tumors.25 On the basis of these data, we initiated a phase I, open-label, sequential dose-escalating study of AMG 706 in patients with advanced solid tumors.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Eligibility Criteria
Key inclusion criteria were age ≥ 18 years; histologically documented advanced tumors refractory to standard treatment or for which no standard therapy was available; Eastern Cooperative Oncology Group performance status ≤ 2; absolute neutrophil count ≥ 1.5 x 109/L; platelet count ≥ 100.0 x 109/L; hemoglobin ≥ 10.0 g/dL; serum creatinine less than 2.0 mg/dL; proteinuria less than 500 mg/24 hours; AST or ALT less than 2.5x the upper limits of normal (ULN; < 5x ULN with liver metastasis). Key exclusion criteria were large central lung tumor lesions (≥ 3 cm unless treated previously with radiation); myocardial infarction within 6 months of study day 1, unstable angina, or congestive heart failure (New York Heart Association functional class > II); uncontrolled hypertension (diastolic > 85 mmHg or systolic > 145 mmHg); coagulation disorders (hypercoagulopathy, bleeding diathesis, or condition requiring therapeutic anticoagulation); chemotherapy within 21 days of study day 1; and prior treatment with a VEGF inhibitor. All patients provided written informed consent before any study-related procedures were performed.

Study Design and Dosing
This was a two-center, phase I, open-label, sequential dose-escalation study. The protocol was approved by each site's institutional review board. Primary end points were to establish the maximum tolerated dose (MTD), characterize dose-limiting toxicities (DLTs), and perform intensive pharmacokinetic (PK) sampling for the generation of AMG 706 PK profiles. Secondary end points included pharmacodynamic response (tumor vascular permeability) and safety profiles (adverse events and changes in laboratory parameters). Exploratory end points included changes in serum levels of proangiogenic markers and tumor response. Results from three PK substudies (food effect, bioavailability, and midazolam metabolism) will be reported in a future publication.

AMG 706 was self-administered orally once daily or bid in 28-day cycles, in accordance with either an intermittent dosing schedule (administration for days 1 to 21 followed by 7 treatment-free days) or a continuous schedule (once-daily dosing for 28 days). In all cohorts the dose was held on day 2 of cycle 1 for PK sampling. Patients were enrolled in one of six sequential, dose-escalating cohorts: 50, 100, 175, or 125 mg intermittent once daily, 25 mg intermittent bid, and 125 mg once daily continuously. Twelve additional patients received 125 mg once daily continuously in the capsule/tablet formulation bioavailability substudy. Initially, three to six patients were assigned to each cohort; additional patients were enrolled if more safety, PK, or pharmacodynamic data were needed. Up to 50 patients could be enrolled at the final MTD level.

Initial dosing (50 mg once daily) was calculated based on a 28-day toxicity study in rats.26 Dose escalation was based on safety, tolerability, and PK data, with maximum dose increments of 100% (< 100% if one of the six initial patients in a cohort experienced a DLT or if two patients experienced grade 2, AMG 706-related toxicities) in the first 28 days of treatment. If ≥ 33% of patients in a cohort experienced DLTs, then lower doses were explored until the MTD was determined. Administration of AMG 706 continued until unacceptable toxicity or disease progression occurred, as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST).

Definition of DLT and MTD
DLTs were defined as follows: related grade 3 fatigue persistent for ≥ 7 days; grade 3 or 4 nausea, diarrhea, and vomiting despite maximum supportive care; grade 3 or 4 neutropenia with fever more than 38.5°C; grade 4 neutropenia for ≥ 7 days; grade 4 thrombocytopenia, anemia, or hypertension; or AST or ALT more than 10x ULN occurring during the first cycle; or any other related grade 3 or 4 toxicities occurring during the first cycle. MTD was defined as the highest dose with an observed incidence of DLT in less than 33% of the patients in the cohort.

Tumor Response and Safety
Tumor measurements were performed within 4 weeks of study day 1 (baseline), on day 50, and every 12 weeks after week 8. Measurable target lesions were evaluated for response using modified RECIST. Confirmation of response by repeat assessments was allowed at any time during the study. For nonmeasurable disease, best medical practice was used to determine time of disease progression. Adverse events were recorded from day 1 through 30 days after the last dose and were graded based on the Common Terminology Criteria for Adverse Events, version 3.0.

PK
Intensive PK blood sampling was performed on days 1 and 21 with samples drawn predose, at 15 and 30 minutes, and at 1, 2, 4, 6, 8, 12, 24, and 48 hours postdose (48 hours for day 1 only). Additional blood samples were taken predose and 1 hour postdose on days 8 and 43. AMG 706 concentrations in plasma were determined using liquid chromatography coupled to tandem mass spectrometry. The lower limit of quantification for AMG 706 was 0.1 ng/mL. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods (WInNonlin; Professional Version 4.1e; Pharsight Corp, Mountain View, CA).

Exploratory Biomarker Analyses and Dynamic Contrast-Enhanced Magnetic Resonance Imaging
Blood samples for serum biomarker analysis were available from 69 patients predose on day 1 (baseline) and on days 2, 8, and 22 during cycle 1. Placental growth factor (PlGF), VEGF, basic fibroblast growth factor, and soluble VEGFr1 (sVEGFr1) were measured using a four-plex assay; soluble VEGFr2 (sVEGFr2) and Kit (sKit) were measured using a duplex assay (Meso Scale Discovery [MSD], Gaithersburg, MD). Biomarkers were quantified in parallel within each assay and correlated to AMG 706 exposure and percentage change in the sum of the longest diameters (SLD) in target lesions by day 50 using a Spearman rank correlation test. Statistical significance was determined from the regression using an F test; P values were not corrected for multiple comparisons.

Tumor vascular permeability was measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) within 72 hours of the first administration of AMG 706 (baseline), and at 1 to 9 hours after dosing on days 3 and 21 during cycle 1. A dynamic contrast technique was used to acquire functional MRI data for assessment of the volume transfer constant (Ktrans) and initial area under the curve (IAUC).

Statistical Analysis
Descriptive statistics are provided for all end points presented. Continuous measurements are summarized using mean, standard deviation, median, range, interquartile range, and number of patients. Graphical summaries of assessments over time are presented by dose cohort and for individual patients.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Patient Characteristics and Disposition
Seventy-one patients with advanced solid refractory tumors were enrolled. Demographics and clinical characteristics are summarized in Table 1. All patients received at least one dose of AMG 706 and were evaluated for safety and tolerability. Four patients discontinued treatment due to DLTs. Five deaths occurred during the study; all were attributed to disease progression.


View this table:
[in this window]
[in a new window]

  		Table 1. Baseline Demographic and Clinical Characteristics

 
Dose Escalation, DLT, and MTD
Patients were enrolled sequentially onto each of the intermittent-dosing cohorts and in parallel within each dosing cohort (Appendix Fig A1; Table A1, online only). No DLTs occurred in the 50-mg once-daily (n = 3) and 100-mg once-daily (n = 6) cohorts. Six patients were then enrolled onto the 175-mg once-daily dose cohort, with three patients (50%) experiencing a grade 3 DLT: fatigue, hyperbilirubinemia, and encephalopathy (one patient each). Fatigue occurred in a thyroid cancer patient who resumed AMG 706 at 100 mg once daily (after withholding AMG 706 for 7 days) and subsequently had a partial response (PR). Encephalopathy occurred in a patient with GI stromal tumor and hyperbilirubinemia occurred in a colon cancer patient. All events resolved after AMG 706 was discontinued (the patient with hyperbilirubinemia was removed from the study). Because 175 mg once daily exceeded the MTD, six patients were enrolled onto the 125-mg once-daily intermittent cohort. One patient experienced a DLT (grade 3 hyponatremia and grade 3 elevated serum creatinine of 4.3 mg/dL), which improved after withholding AMG 706 for 20 days. The patient continued receiving a lower dose (50 mg once daily). Three additional patients were then enrolled onto this cohort, and no additional DLTs were observed. Finally, six patients were enrolled onto the 125-mg once-daily continuous cohort. No DLTs were observed. The 125-mg once-daily continuous dose was determined to be the MTD for AMG 706. Consequently, this cohort was expanded to 28 patients for collection of additional safety and PK data. No additional DLTs occurred. Seven patients were enrolled onto the 25-mg bid cohort; no DLTs were observed. After review of preliminary PK data, the investigators and sponsor decided to pursue once-daily dosing in this trial and bid dosing in future studies. Median overall treatment duration for all dose cohorts was 114 days (range, 6 to 914 days).

Safety
All 71 patients (100%) experienced at least one adverse event, which were mostly grade 1 or 2 and reversible (Table 2). Hypertension was the most common grade 3 event and was manageable with blood pressure monitoring and antihypertensive therapy. There were no grade 4 or 5 hypertensive events, and no therapy discontinuations due to hypertension. Treatment-related adverse events (mostly mild to moderate; no grade 4 or 5 events) were reported in 59 patients (83%), with grade 3 treatment-related hypertension (n = 14; 20%) and diarrhea (n = 4; 6%) occurring in ≥ 5% of patients. There were two treatment-related adverse events of posterior reversible encephalopathy syndrome (one patient each in the 125- and 175-mg once-daily cohorts). There were three patient cases of cholecystitis. The relationship to AMG 706 is still under investigation.


View this table:
[in this window]
[in a new window]

  		Table 2. Incidence of Adverse Events in at Least 10% of All Patients, and Grade 3 and 4 Laboratory Changes in at Least 3% of Patients

 
Grade 3 or 4 changes in laboratory values are summarized in Table 2. Hyponatremia, elevated alkaline phosphatase, and hyperglycemia were generally asymptomatic and not considered related to AMG 706 treatment. Grade 4 neutropenia occurred during the safety follow-up in a patient receiving gemcitabine, but not AMG 706. One patient with a history of idiopathic thrombocytopenic purpura, who previously required intravenous immunoglobulin, developed grade 4 thrombocytopenia. Other toxicities previously associated with antiangiogenic agents were grade 3 vaginal and GI bleeding (n = 1 each). During the safety follow-up period, one patient with progressive disease (PD) developed deep venous thrombosis and pulmonary embolism.

Pharmacokinetics
The PK of AMG 706 was approximately dose proportional (Table 3). After single and multiple doses, AMG 706 was absorbed rapidly, with an overall median time to maximum observed plasma concentration (Tmax) ranging from 0.6 to 2.0 hours. The mean terminal-phase elimination half-life values ranged from 5.1 to 7.7 hours after single-dose administration and from 4.5 to 7.0 hours after multiple-dose administration; these values did not seem to be time or dose dependent. Oral clearance was also evaluated in relation to body-surface area and no trends were identified (data not shown). Plasma concentrations of AMG 706 on days 1 and 21 after administration are shown in Appendix Figure A2 (online only).


View this table:
[in this window]
[in a new window]

  		Table 3. PK Parameters of AMG 706 on Days 1 and 21

 
The mean Cmax and AUC0-24 values were approximately dose proportional after single-and multiple-dose administration (Table 3). Mean observed plasma concentrations at 24 hours after dosing for doses ≥ 125 mg would provide continuous coverage above the concentration that inhibits 50% of proliferation in human umbilical vein endothelial cells in vitro (Amgen Inc, Thousand Oaks, CA; data on file). To achieve higher predose plasma concentration values, bid dosing regimens will be explored further in future studies. No evidence of accumulation was observed after multiple-dose administrations of AMG 706, as indicated by mean observed concentrations at 24 hours after dosing, Cmax, and AUC0-24 values at day 21 relative to those at day 1. AMG 706 did not seem to induce its own metabolism.

Efficacy
Sixty-seven of 71 patients were assessable for tumor response by modified RECIST (measurable disease at baseline). The remaining four patients had nonmeasurable disease and were included in the calculation of stable disease (SD) and PD rates only. Five of 71 patients (one of whom had nonmeasurable disease at baseline) discontinued treatment before the study day 50 evaluation without having an assessment of disease response. These patients were classified as having PD.

Of the 67 assessable patients, five patients (7%) had a PR (one unconfirmed) and 31 patients (44%) had PD (Fig 1). Of the responders, three had thyroid cancer (medullary, papillary, and follicular carcinoma; AMG 706 treatment lasted for 482, 529, and 564 days, respectively), and one each had renal cell carcinoma and leiomyosarcoma. Figure 2 shows the PR in a patient with medullary thyroid cancer. Thirty-five patients (49%) had evidence of SD; three of these had thyroid cancer (Hürthle cell carcinoma, n = 1; papillary carcinoma, n = 2; AMG 706 treatment for 124, 141, and 141 days, respectively). Nineteen patients (27%) with SD had a decrease in SLD from baseline that did not meet modified RECIST criteria for PR. Median duration of treatment for patients with SD was 142 days (range, 84 to 876 days). Details of patients receiving treatment for more than 1 year are summarized in Appendix Table A2 (online only).


Figure 1
View larger version (17K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 1. Best tumor response by modified Response Evaluation Criteria in Solid Tumors. Not shown, n = 9 due to unavailability of tumor measurement data (n = 2 with stable disease [SD]) or clinical progression (PD; n = 7). *Includes 12 patients from the capsule/tablet formulation cohort. {dagger}0% change in tumor measurement (n = 3, SD). {ddagger}Unconfirmed. PR, partial response; RCC, renal cell carcinoma.

 

Figure 2
View larger version (18K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 2. Computed tomography scan of a partial response in a patient with medullary thyroid cancer metastatic to the liver, treated with AMG 706. (A) Baseline; (B) week 73.

 
Proangiogenic Biomarkers and DCE-MRI
Levels of PlGF increased with increasing AMG 706 exposure at days 2 and 22 (Figs 3A and 3B), and plateaued after the AUC of AMG 706 was ≥ 4 µg·h/mL. Forty-four patients had biomarker and day-50 tumor measurement. Changes in serum PlGF and sVEGFr2 concentrations at day 22 both appeared to correlate with change in SLD at day 50 (Figs 3C and 3D). No differences in serum levels relative to AMG 706 exposure or correlations to response were observed for sKit-1, basic fibroblast growth factor, or sVEGFr1. A correlation of AMG 706 AUC with change in SLD at day 50 was observed (Spearman rank, 0.27; P = .0004). Additional analysis showed that AMG 706 AUC rather than dose correlated best with biomarker levels and change in SLD.


Figure 3
View larger version (17K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 3. Correlation of platelet growth factor (PlGF) levels with AMG 706 exposure at (A) day 2 and (B) day 22. Correlation of (C) PlGF levels and (D) soluble vascular endothelial growth factor (sVEGFr2) levels with change in tumor size, calculated from biomarker measurements at baseline and day 22, and tumor size measurements at baseline and day 50 (n = 44 patients). R2 and P values were not corrected for multiple comparisons. AUC, area under the curve.

 
DCE-MRI data at baseline and days 3 and 21 of cycle 1 were available for 19 patients (27%). Fifteen patients (21%) had assessable scans only for day 3; 17 patients (24%) had assessable scans only for day 21. Changes in Ktrans or IAUC ranged from –52% to +62%, but there was no significant correlation of either Ktrans or IAUC with AMG 706 AUC at either day 3 or 21 (Amgen Inc, Thousand Oaks, CA; data on file).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
AMG 706 was generally well tolerated, as supported by the adverse event profile and length of treatment of some study patients. Most of the treatment-related adverse events were consistent with those previously observed for anti-VEGF therapy, including hypertension, fatigue, and diarrhea, and were reversible during the study.6,7,10,12 VEGF inhibition seems to induce hypertension,10,11 possibly by inhibiting nitric oxide production, which then causes vasodilation.27 Several clinical studies of angiogenesis inhibitors reported incidence rates of hypertension similar to those observed in our study (16% to 61%), indicating a class effect.6,7,10,12 Likewise, hematologic toxicities have been observed with other antiangiogenic multikinase inhibitors, such as sunitinib6 and PTK787/ZK 222584.12 For example, grade 3 neutropenia has been reported in up to 18% of patients treated at the respective MTDs,6 whereas grade 3 or 4 thrombocytopenia has been seen in up to 20% of patients receiving sunitinib.6 In contrast, only 3% and 1% of patients developed grade 3 or 4 neutropenia and thrombocytopenia, respectively, in the study presented here, suggesting possible differences in toxicity among different multikinase inhibitors.

In this heavily pretreated patient population, five patients had PR and 37 patients had SD after receiving AMG 706. There was evidence of clinical benefit in patients who did not meet modified RECIST criteria for PR. Sixteen patients (23%) had disease stabilization for more than 6 months. Data from larger studies of other agents in this class indicate that long-term disease stabilization correlates well with markers of clinical benefit such as confirmed response, durable progression-free survival, and perhaps even overall survival.26,27 There was no significant correlation between changes in Ktrans or IAUC and AMG 706 AUC by DCE-MRI. This result may reflect either the lack of usefulness of the DCE-MRI technique or may be due to the timing of the scan on day 3 (no AMG 706 dose on day 2 to obtain 48-hour PK after first dose) and/or poor accrual to this portion of the study.

PlGF and sVEGFr2 are potential biomarkers of AMG 706 therapy. The VEGF family member PlGF binds VEGFr1 and may increase endothelial cell sensitivity to VEGF.28 PlGF may displace VEGF from VEGFr1, resulting in more available VEGF to bind and activate VEGFr2.28 Serum concentrations of PlGF increased proportionally to AMG 706 exposure up to AMG 706 AUC more than 4.0 µg·h/mL before reaching a plateau, possibly reflecting maximum VEGFr inhibition. An increase in serum PlGF or a reduction in sVEGFr2 correlated with changes in tumor size at day 50. Similar to our findings, decreases in sVEGFr2 levels were observed in patients receiving sunitinib.6 The function of sVEGFr2 is currently unknown and needs to be explored in additional studies.

In conclusion, in this phase I study, oral administration of AMG 706 in patients with refractory advanced solid tumors was generally well tolerated, with dosing to a maximum of 914 days at the time of this report (treatment still ongoing). PK and antitumor activity data support additional trials evaluating efficacy and safety of AMG 706 once daily or bid as monotherapy or in combination with chemotherapy and other targeted therapies.


   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Antonis Koutsoukos, Amgen Inc; Yu-Nien Sun, Amgen Inc; Michael B. Bass, Amgen Inc; Ren Y. Xu, Amgen Inc; Anthony Polverino, Amgen Inc; Jeffrey S. Wiezorek, Amgen Inc; David D. Chang, Amgen Inc Leadership: N/A Consultant: Roy S. Herbst, Amgen Inc Stock: Antonis Koutsoukos, Amgen Inc; Yu-Nien Sun, Amgen Inc; Michael B. Bass, Amgen Inc; Ren Y. Xu, Angen Inc; Anthony Polverino, Amgen Inc; Jeffrey S. Wiezorek, Amgen Inc; David D. Chang, Amgen Inc Honoraria: Roy S. Herbst, Amgen Inc Research Funds: Lee S. Rosen, Amgen Inc; Razelle Kurzrock, Amgen Inc; Roy S. Herbst, Amgen Inc Testimony: N/A Other: N/A


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
Appendix
 REFERENCES
 
Conception and design: Lee S. Rosen, Marilyn Mulay, Andy Van Vugt, Jeffrey Silverman, Antonis Koutsoukos, Anthony Polverino, Jeffrey S. Wiezorek, David D. Chang, Roy S. Herbst

Administrative support: Marilyn Mulay, Andy Van Vugt, Jeffrey Silverman

Provision of study materials or patients: Lee S. Rosen, Razelle Kurzrock, Roy S. Herbst

Collection and assembly of data: Lee S. Rosen, Marilyn Mulay, Andy Van Vugt, Michelle A. Purdom, Jeffrey Silverman, Yu-Nien Sun, Jeffrey S. Wiezorek, Roy S. Herbst

Data analysis and interpretation: Lee S. Rosen, Marilyn Mulay, Andy Van Vugt, Chaan Ng, Jeffrey Silverman, Antonis Koutsoukos, Yu-Nien Sun, Michael B. Bass, Ren Y. Xu, Anthony Polverino, Jeffrey S. Wiezorek, David D. Chang, Roy S. Herbst

Manuscript writing: Lee S. Rosen, Yu-Nien Sun, Ren Y. Xu, Jeffrey S. Wiezorek, David D. Chang, Roy S. Herbst

Final approval of manuscript: Lee S. Rosen, Razelle Kurzrock, Chaan Ng, Antonis Koutsoukos, Yu-Nien Sun, Michael B. Bass, Anthony Polverino, Jeffrey S. Wiezorek, David D. Chang, Robert Benjamin, Roy S. Herbst


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
REFERENCES
 
Go


View this table:
[in this window]
[in a new window]

  		Table A1. Dose Cohort Enrollment and DLT

 
Go


View this table:
[in this window]
[in a new window]

  		Table A2. Patients Receiving AMG 706 for > 1 Year

 
Go


Figure 4
View larger version (27K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig A1. Dose escalation scheme. Cohort 7 (125 mg once daily, capsule/tablet; see Table A1) not shown. DLT, dose-limiting toxicity. (*) AMG 706 was administered for days 1 to 21 followed by seven treatment-free days.

 
Go


Figure 5
View larger version (22K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig A2. Pharmacokinetic profile of AMG 706 on (A) day 1 and (B) day 21. Mean (+ SD) plasma concentrations (in nanograms per milliliter) of AMG 706 were plotted for each cohort during a 24-hour pharmacokinetic sampling period after day 1 administration. Error bars represent standard deviation.

 


   ACKNOWLEDGMENTS
 
We thank Deborah Boughton for collection and assembly of data; Megan Ingram and Mandy Parson for study management; Michael Eschenberg for statistical support; Daisy Wang for statistical programming support; Becki Cepeda Rebeca Melara, and Shekman Wong, PhD, for pharmacokinetic analyses; Kimberly Hamic; Sid Suggs, PhD, Yun Lan, Jenny Wu, and Scott D. Patterson, PhD, for biomarker assays and analyses; Sharon McBee and Berta Grigorian for clinical data management; Jeff Evelhoch, PhD, for assistance with DCE-MRI analyses; David Reese, MD, and Rafael Amado, MD, for critical review of this manuscript; Mee Rhan Kim, PhD, for assistance with the writing and preparation of this manuscript; and Beate Quednau, PhD, and Bich Tran for assistance with the preparation of this manuscript.


   NOTES
 
Supported by Amgen Inc and the Cancer Center Support Core Grant No. 5P30 CA016672-30 (R.S.H.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
1. Fidler IJ, Kerbel RS, Ellis LM: Biology of cancer: Angiogenesis, in Devita VT, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 2001, pp 137-147

2. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27-31, 1995[CrossRef][Medline]

3. Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368-4380, 2002[Abstract/Free Full Text]

4. Coxon A, Starnes C, Bready J, et al: The effect of AMG 706, a novel multi-kinase inhibitor, on angiogenesis and tumor growth in preclinical models. Proc Am Assoc Cancer Res 47:889, 2006 (abstr 3779)

5. Ahmad T, Eisen T: Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res 10:6388S-6392S, 2004[Abstract/Free Full Text]

6. Faivre S, Delbaldo C, Vera K, et al: Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25-35, 2006[Abstract/Free Full Text]

7. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004[Abstract/Free Full Text]

8. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al: Bevacizumab in combination with fluorouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502-3508, 2005[Abstract/Free Full Text]

9. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003[Abstract/Free Full Text]

10. Rugo HS, Herbst RS, Liu G, et al: Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: Pharmacokinetic and clinical results. J Clin Oncol 23:5474-5483, 2005[Abstract/Free Full Text]

11. Sakamoto KM: Su-11248 Sugen. Curr Opin Investig Drugs 5:1329-1339, 2004[Medline]

12. Thomas AL, Morgan B, Horsfield MA, et al: Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23:4162-4171, 2005[Abstract/Free Full Text]

13. Miller KD, Wang M, Gralow J, et al: E2100: A randomized phase III trial of paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL; Educational Session, 2005

14. Rhee J, Hoff PM: Angiogenesis inhibitors in the treatment of cancer. Expert Opin Pharmacother 6:1701-1711, 2005[CrossRef][Medline]

15. Sandler A, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel plus carboplatin with or without bevacizumab in patients with advanced non-squamous non-small cell lung cancer: An Eastern Cooperative Oncology Group Trial- E4599. J Clin Oncol 23:2s, 2005 (suppl; abstr LBA416)

16. Wakelee HA, Schiller JH: Targeting angiogenesis with vascular endothelial growth factor receptor small-molecule inhibitors: Novel agents with potential in lung cancer. Clin Lung Cancer 7:S31-S38, 2005 (suppl 1)[Medline]

17. Herbst R, Bass MB, Kurzrock R, et al: Serum levels of placental growth factor (PlGF) and soluble kinase domain receptor (sKDR) correlate with exposure and tumor response to AMG 706 in patients with advanced malignancy. Eur J Cancer 3:421a, 2005 (suppl 2; abstr 1455)

18. Herbst RS, Kurzrock R, Parson M, et al: AMG 706 first in human, open-label, dose-finding study evaluating the safety and pharmacokinetics (PK) in subjects with advance solid tumors. Eur J Cancer 2:48a, 2004 (suppl 8; abstr 151)

19. Rosen L, Kurzrock E, Jackson L, et al: Safety and pharmacokinetics of AMG 706 in patients with advanced solid tumors. J Clin Oncol 23:195s, 2005 (suppl; abstr 3013)

20. Yancopoulos GD, Davis S, Gale NW, et al: Vascular-specific growth factors and blood vessel formation. Nature 407:242-248, 2000[CrossRef][Medline]

21. Wandzioch E, Edling CE, Palmer RH, et al: Activation of the MAP kinase pathway by c-Kit is PI-3 kinase dependent in hematopoietic progenitor/stem cell lines. Blood 104:51-57, 2004[Medline]

22. Tian Q, Frierson HF Jr, Krystal GW, et al: Activating c-kit gene mutations in human germ cell tumors. Am J Pathol 154:1643-1647, 1999[Abstract/Free Full Text]

23. Jackson EF, Esparza-Coss E, Bankson JA, et al: The effect of AMG 706, a novel tyrosine kinase inhibitor, on vascular permeability and blood flow as assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in an in vivo preclinical tumor model. Proc AACR-NCI-EORTC 131a, Philadelphia, PA, November 14-18, 2005 (abstr B20)

24. Starnes C, Coxon A, Scully S, et al: Antitumor activity of AMG 706, a multi-kinase inhibitor, against multiple established human tumor xenograft models in nude mice. Proc AACR-NCI-EORTC 129a, Philadelphia, PA, November 14-18, 2005 (abstr B13)

25. Polverino A, Coxon A, Starnes C, et al: AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 66:8715-8721, 2006[Abstract/Free Full Text]

26. DeGeorge JJ, Ahn CH, Andrews PA, et al: Regulatory considerations for preclinical development of anticancer drugs. Cancer Chemother Pharmacol 41:173-185, 1998[CrossRef][Medline]

27. Bouloumi A, Schini-Kerth VB, Busse R: Vascular endothelial growth factor up-regulates nitric oxide synthase expression in endothelial cells. Cardiovasc Res 41:773-780, 1999[CrossRef][Medline]

28. Luttun A, Carmeliet P: Soluble VEGF receptor Flt1: The elusive preeclampsia factor discovered? J Clin Invest 111:600-602, 2003[CrossRef][Medline]

Submitted June 15, 2006; accepted January 26, 2007.




This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
A. Coxon, T. Bush, D. Saffran, S. Kaufman, B. Belmontes, K. Rex, P. Hughes, S. Caenepeel, J. B. Rottman, A. Tasker, et al.
Broad Antitumor Activity in Breast Cancer Xenografts by Motesanib, a Highly Selective, Oral Inhibitor of Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors
Clin. Cancer Res., January 1, 2009; 15(1): 110 - 118.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
S. I. Sherman, L. J. Wirth, J.-P. Droz, M. Hofmann, L. Bastholt, R. G. Martins, L. Licitra, M. J. Eschenberg, Y.-N. Sun, T. Juan, et al.
Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer
N. Engl. J. Med., July 3, 2008; 359(1): 31 - 42.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. Verweij and M. de Jonge
Multitarget Tyrosine Kinase Inhibition: [And the Winner Is...]
J. Clin. Oncol., June 10, 2007; 25(17): 2340 - 2342.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rosen, L. S.
Right arrow Articles by Herbst, R. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rosen, L. S.
Right arrow Articles by Herbst, R. S.

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online