phase i dose-finding study of pazopanib in hepatocellular … · 10/08/2011 · author manuscript...

Yau et al Pazopanib in hepatocellular carcinoma 1

Phase I Dose-Finding Study of Pazopanib in Hepatocellular Carcinoma: Evaluation of

Early Efficacy, Pharmacokinetics, and Pharmacodynamics

Thomas Yau,1 Pei-Jer Chen,2 Pierre Chan,1 C. Martin Curtis,3 Philip S. Murphy,3

A. Benjamin Suttle,3 Jennifer Gauvin,3 Jeffrey P. Hodge,3 Mohammed M. Dar,3 Ronnie T. Poon1

1Queen Mary Hospital, The University of Hong Kong, Hong Kong; 2National Taiwan University

Hospital, Taipei, Taiwan; 3GlaxoSmithKline Research and Development Oncology Unit,

Research Triangle Park, NC, USA, and Stockley Park, UK

Author email addresses:

Thomas Yau: [email protected]. Pei-Jer Chen: [email protected]

Pierre Chan: [email protected].

C. Martin Curtis: [email protected].

Philip S. Murphy: [email protected].

A. Benjamin Suttle: [email protected].

Jennifer Gauvin: [email protected]

Jeffrey P. Hodge: [email protected]

Mohammed M. Dar: [email protected]

Running Title: Pazopanib in hepatocellular carcinoma

Keywords: hepatocellular carcinoma, pazopanib, dose escalation, DCE MRI, angiogenesis

Research. on March 1, 2021. © 2011 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 10, 2011; DOI: 10.1158/1078-0432.CCR-11-0793

http://clincancerres.aacrjournals.org/


Funding: Financial support for this study and medical editorial assistance was provided by

GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania.

Corresponding author: Professor Ronnie T. Poon

Department of Surgery, The University of Hong Kong Queen Mary Hospital

102 Pokfulam Road; Hong Kong

Tel: 85222553641; Fax: 852-28175475

E-mail: [email protected].

Disclosure: TY has participated in advisory boards for Bayer and Pfizer, for which he was

compensated, but he reports no honoraria, research funding, or other remuneration. PJC has

received honoraria from Novartis and Bristol-Myers Squibb for advisory/consultancy

relationships, and has received research funding from GlaxoSmithKline and Abbott. CMC, PSM,

ABS, JG, JPH, and MMD are employed by GlaxoSmithKline and own company stock. PC and

RTP report no potential conflict of interest.

Previous Publication: These data were previously presented in part at the 45th Annual ASCO

Meeting; May 29-June 2, 2009; Orlando, FL (abstract 3561) and at the Joint ECCO 15 - 34th

ESMO Multidisciplinary Congress; September 20-24, 2009; Berlin, Germany (abstract 1206).

The DCE-MRI results were also previously presented at the Annual Meeting of the International

Society for Magnetic Resonance in Medicine; May 1-7, 2010; Stockholm, Sweden (abstract

2720).

Word Count (limit 5,000) = 3,842 Abstract (limit 250) = 249 Figure/Table Count (limit 6) = 6 References (limit 50) = 27 Includes Supplemental Material





TRANSLATIONAL RELEVANCE

Oral antiangiogenic agents have shown promise in the treatment of hepatocellular

carcinoma (HCC). Notably, oral antiangiogenic agents have demonstrated differences in their

safety and efficacy profiles in clinical studies. Expanding the number of tolerable and effective

agents available for treating patients with HCC may provide additional treatment options with

improved individualized tolerability and efficacy, as well as effective options at recurrence.

Accordingly, this study examined the potential of the oral angiogenesis inhibitor pazopanib,

which has shown antitumor activity in various solid tumors, in patients with HCC. This phase I

study also explores and provides further insights into the use of recently developed DCE-MRI

parameters as a measure of the efficacy of antiangiogenic agents in patients with HCC.





ABSTRACT

Background: A phase I dose-escalating study of pazopanib was conducted to determine the

maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical

activity in patients with advanced hepatocellular carcinoma (HCC).

Design: Asian patients (N=28) were dose-escalated on pazopanib (200-800 mg) once daily

(QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3+3 design.

Changes in tumor vasculature were evaluated by dynamic contrast-enhanced magnetic

resonance imaging (DCE-MRI).

Results: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities

(grade 3 AST/ALT elevations, grade 3 malaise). The MTD in patients with HCC (Child-Pugh

class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most

commonly reported adverse events at the MTD. Mean Cmax and AUC(0-6) of pazopanib and its

metabolites did not increase dose proportionally across the 200-800 mg range. Reductions in

IAUGC and Ktrans were demonstrated at all pazopanib doses evaluated, with the greatest

reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated

with larger C24 and Cmax values, there was no constant relationship between tumor perfusion

decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall,

19 patients (73%) had either partial response or stable disease.

Conclusion: Pazopanib has a manageable safety profile in patients with advanced HCC, and

600 mg was chosen for further development of pazopanib in advanced HCC. Moreover,

pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on

HCC vasculature that might be associated with its antitumor activity.





INTRODUCTION

Advanced hepatocellular carcinoma (HCC) carries a poor prognosis, and systemic

therapy with cytotoxic agents shows no survival benefit (1). The orally available, multi-targeting

receptor tyrosine kinase inhibitor sorafenib is the first agent demonstrating significant

improvement in median overall survival in two randomized phase III trials in advanced HCC (2,

3). Sorafenib may exert its antiangiogenic effects by targeting receptors for vascular endothelial

growth factor (VEGFR-2, VEGFR-3) and platelet-derived growth factor (PDGFR), and may block

tumor cell proliferation by targeting the RAF/MEK/ERK signaling pathway (4, 5).

In the era of personalized medicine, improving treatment outcomes for patients with

advanced HCC requires the development of additional active agents/regimens with tolerable

safety profiles, and the identification of drug mechanism of action and biomarkers capable of

predicting tumor response and/or resistance to treatment. Pazopanib is a potent, oral,

multikinase angiogenesis inhibitor targeting VEGFR-1, -2, and -3, PDGFR-α and -β, and c-Kit

that has demonstrated efficacy and tolerability in treating various tumor types (6-8). In a phase I

pazopanib study, clinical benefits were seen in patients with solid tumors who received

pazopanib 800 mg or more once daily (QD) or 300 mg twice daily (BID) (6). Moreover, when

pazopanib 800 mg QD was administrated as a single agent, evidence of antitumor activity was

observed in various phase II studies in several tumor types, including soft tissue sarcoma, renal

cell carcinoma, ovarian cancer, and non-small cell lung cancer (9-12).

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive

quantitative method that facilitates the evaluation of microvascular structure by tracking the

pharmacokinetics of injected low-molecular-weight contrast agents. The technique is sensitive

to alterations in vascular permeability, extracellular, extravascular, and vascular volumes, and

blood flow, and has potential advantages over computed tomography (CT) and positron





emission tomography in evaluating tumor angiogenesis (6, 13). It has been increasingly used as

a biomarker of drug efficacy in clinical trials of various angiogenesis inhibitors.

The objective of this multidisciplinary phase I study of pazopanib was to assess safety,

pharmacokinetics, pharmacodynamics, and clinical activity of pazopanib, in patients with

advanced HCC. Candidate biomarkers potentially correlating with clinical efficacy were explored

by comparing clinical outcome with DCE-MRI parameters.





PATIENTS AND METHODS

This phase I, open-label, dose-finding study (VEG107200; clinicaltrials.govdentifier

NCT00370513) was conducted in two phases: a dose-escalation and a cohort-expansion

phase, at three international centers. The study complied with the Helsinki Declaration

principles; study protocol and amendments were reviewed and approved by the appropriate

national, regional, or investigational center Ethics Committee or Institutional Review Board. All

patients provided written informed consent.

Patients

Eligible patients were at least 18 years of age, satisfied European Association for the

Study of the Liver diagnostic criteria for diagnosis of HCC (14), and had advanced (local

unresectable and/or metastatic) disease not amenable to surgery or local therapy. Prior

systemic or local therapy was permitted, provided it was completed within the protocol-specified

time frame as follows: > 4 weeks since prior systemic therapy, radiotherapy, or major surgery;

> 6 weeks since administration of nitrosoureas, mitomycin, or prior local-ablative therapy; > 60

days since completion of prior radiofrequency ablation. Patients who received prior therapy had

to show evidence of disease progression and must have fully recovered from previous therapy.

Additional eligibility criteria included an Eastern Cooperative Oncology Group performance

status of 0 or 1; at least one target lesion according to Response Evaluation Criteria for Solid

Tumors (RECIST) (15); adequate hematologic and renal function; and Child-Pugh A cirrhosis

with adequate hepatic parameters (serum albumin ≥ 2.8 g/dL, serum bilirubin < 2.0 mg/mL;

aspartate aminotransferase [AST] ≤ 2.0 × ULN; and alanine aminotransferase [ALT] ≤ 2.0 ×

ULN).

Major exclusion criteria included underlying malabsorption syndrome, any condition that

interfered with oral administration of the study drug, Child-Pugh B or C cirrhosis, previous

therapy with any VEGF-directed angiogenesis inhibitor, and previous history of portal vein





thrombosis or bleeding esophageal varices. Additional exclusion criteria included poorly

controlled hypertension; QTc prolongation (defined as a QTc interval > 470 msec); previous

Class III or IV heart failure; history of cerebrovascular events within 6 months; history of

myocardial infarction, hospitalization for unstable angina, or cardiac angioplasty or stenting

within 6 months; or untreated venous thrombosis.

Study Design and Treatment

Dose-Escalation Phase

Pazopanib dose escalation ranged from 200 to 800 mg QD during the dose-escalation

phase, with a minimum of three patients enrolled in each cohort; a modified 3+3 design

specified that at least three to six patients could be enrolled in a given cohort. Patients were not

enrolled in subsequent cohorts until all patients in the previous cohort completed 21 days of

therapy (ie, one cycle), and the toxicity profile and pharmacokinetics results from cycle 1 were

available. Dose escalation continued at 100% of the preceding dose level until a dose-limiting

toxicity (DLT) was observed or the maximum dose level of 800 mg QD was achieved in the

absence of DLTs. The maximum tolerated dose (MTD) was defined as the highest daily dose of

pazopanib at which no more than one of six patients experienced a DLT.

In addition to the standard definitions of DLTs (any grade 3 or 4 clinically significant non-

hematologic toxicity except alopecia) employed in other studies of pazopanib monotherapy,

additional adverse events (AEs) relevant to the population under study were defined as DLTs.

These included liver toxicity for which clinical and radiologic criteria supported either progressive

disease or viral reactivation as the cause of increased hepatic dysfunction, and an increase in

the Child-Pugh score by 2 or more in association with liver toxicity considered to be related to

pazopanib (see Supplemental Methods for a complete list).

Cohort-Expansion Phase





Once the MTD was determined, up to 10 additional patients could be enrolled at the

MTD to further evaluate the safety and tolerability of pazopanib and acquire additional and

pharmacokinetics data.

Study Objectives

The primary objectives of this study were the safety, tolerability, and MTD of pazopanib

in patients with HCC. Secondary objectives included characterization of pharmacokinetics,

evaluation of changes in tumor vasculature based on DCE-MRI, serial serum alpha fetoprotein

(AFP) measurements, and evaluation of contrast-enhanced CT scans or MRI for response per

RECIST guidelines (15).

Safety Assessments and Disease Evaluation

Clinical assessments were performed at least every 3 weeks and more frequently during

the first three cycles for all patients on treatment. Adverse events were reported in accordance

with National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0

(16). Viral hepatitis replication parameters were assessed at the start of each cycle. Radiologic

assessments, either CT or MRI scans, were performed at baseline and at 6-week intervals

thereafter.

Pharmacokinetics

To characterize the pharmacokinetics of pazopanib after single and multiple doses,

serial blood samples were collected over 6 hours on Day 15 during the dose-escalation phase,

over 72 hours after pazopanib administration on Day 1, and over 24 hours on Day 15 during the

expansion-cohort phase. Concentrations of plasma pazopanib and pazopanib metabolites

(GSK1268992, GSK1268997, GSK1071306) were measured by tandem high-performance

liquid chromatography mass spectrometry.





Pharmacokinetic parameters included area under the concentration-time curve (AUC)

from 0 to 6 hours (AUC(0-6)) , maximum plasma concentration (Cmax), time to maximum observed

concentration (tmax), and 24-hour plasma concentration (C24) of pazopanib on study Day 15.

Pharmacokinetic analyses of concentration-time data for plasma pazopanib and pazopanib

metabolite were conducted using the noncompartmental Model 200 (for extravascular

administration) of WinNonlin Professional Edition version 5.2 (Pharsight Corporation, Mountain

View, California).

DCE-MRI

Changes in tumor vascular parameters in response to pazopanib were characterized by

DCE-MRI. Specifically, DCE-MRI was used to determine the contrast agent transfer coefficient

(Ktrans) and the initial area under the tissue gadolinium concentration-time curve (IAUGC) at

baseline and on Day 22 after pazopanib treatment. Two DCE-MRIs, at least 24 hours apart,

were performed during screening, within 7 days of Day 1 of cycle 1 to evaluate measurement

variability. A third DCE-MRI was performed on Day 1 of cycle 2 (study Day 22). The pazopanib

dose and exposure parameters at Day 22 were compared with baseline (defined by the mean of

the two baseline measurements) using Ktrans and IAUGC.

The IAUGC was derived from the area under the tissue gadolinium concentration-time

curve over 60 seconds following bolus arrival (IAUGC60). Tumors were manually outlined and all

DCE-MRI parameters were calculated within the enhancing portion of the tumor.

A standardized DCE-MRI protocol was implemented at three clinical trial sites and all the

images were centrally analyzed by a group blinded to study treatment (Imaging Science and

Biomedical Engineering, University of Manchester, UK). Additional details of the DCE-MRI

methods and analysis protocol are provided in Supplemental Methods.

Statistical Analysis





Survival analysis was computed by the Kaplan-Meier method. Progression-free survival

(PFS) was calculated from the date of commencement of study drugs to the date of

documented progression or death, and was performed on intent-to-treat basis. All statistical

analysis was performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina).





RESULTS

Patients

Median patient age was 61 years, and 24 patients (86%) were male (Table 1). Twenty-

two patients (79%) met the cyto-histologic criteria defined by European Association for the

Study of the Liver for HCC, and six patients (21%) met the European Association for the Study

of the Liver noninvasive criteria (restricted to cirrhotic patients) for HCC. Twenty-eight patients

received pazopanib QD. Median days (minimum-maximum) on study were 133.5 (42-798), 55

(8-295), 127 (4-289), and 169 (9-274) for pazopanib 200 mg (n = 4), 400 mg (n = 11), 600 mg

(n = 8), and 800 mg (n = 5) QD doses, respectively.

Dose-Escalation Phase and Dose-Limiting Toxicity

Overall, 21 patients were enrolled in the dose-escalation phase and three patients

experienced DLTs. At the pazopanib 800 mg QD dose level, two patients experienced DLTs

(grade 3 AST/ALT elevations and grade 3 malaise) and the MTD was exceeded. Six patients

were subsequently enrolled at pazopanib 600 mg in the dose-escalation phase of the study,

according to the protocol. This dose met the protocol-defined MTD, in that one of the six

patients enrolled at this dose level experienced a DLT (ie, unable to receive > 75% of dose

during cycle 1 because of grade 2 neutropenia, grade 2 AST elevation, and grade 2

hyperbilirubinemia). Thus, the MTD was defined as 600 mg according to the protocol.

Cohort-Expansion Phase

Although not specified as part of the original study design, due to insufficient DCE-MRI

data available that met pre-specified technical requirements from the original five patients

enrolled at the 400 mg dose level during the dose-escalation phase, an additional six patients

were enrolled at this dose, rather than the MTD of 600 mg during the cohort-expansion phase.

After completion of cycle 1 and acquisition of DCE-MRI data, and in the absence of DLTs, these





patients were permitted to escalate to the MTD of 600 mg QD. However, two additional patients

were enrolled to receive pazopanib at the MTD of 600 mg starting from cycle 1 in the cohort-

expansion phase. Nevertheless, one of these patients experienced a grade 4 gastrointestinal

hemorrhage during the first 21 days of dosing, related in part to occult metastases invading the

gastrointestinal tract, and withdrew from the study. The second patient enrolled in the cohort-

expansion phase at 600 mg starting from cycle 1 was not evaluable for treatment-related

toxicities because of rapid disease progression and withdrawal from the study after receiving

two doses of pazopanib. No additional patients were enrolled in the cohort-expansion phase at

the 600 mg dose level, because of slow accrual and in light of additional patients having been

exposed to 600 mg QD as a result of intra-patient dose modification (ie, ten patients received

600 mg for the majority of their on-study duration).

Safety

The most commonly reported AEs (Table 2) were diarrhea (17 patients; 61%),

hypertension (10 patients; 36%), AST elevation (9 patients; 32%), and ALT elevation (6

patients; 21%). The most commonly reported AEs at the MTD were diarrhea (4 patients; 50%),

skin hypopigmentation (4 patients; 50%), and AST elevation (3 patients; 38%). Most toxicities

were grade 1 or 2 and resolved after discontinuation of pazopanib. Hypertension was the most

common AE with a maximum toxicity of grade 3 or higher across all treatment groups.

The most common treatment-emergent hematologic laboratory abnormalities were

lymphopenia (10 patients; 53%), leukopenia (13 patients; 46%), and neutropenia (8 patients;

42%). The most common treatment-emergent clinical chemistry abnormalities were AST

elevation (20 patients; 71%), hyperbilirubinemia (19 patients; 68%), ALT elevation (15 patients;

54%), lipase elevation (13 patients; 50%), and hyperglycemia (14 patients; 50%). Maximum

changes in hepatobiliary parameters from baseline are shown in Table 3.





Overall, six patients were withdrawn from the study because of AEs that included

AST/ALT elevation, AST/bilirubin elevation, malaise, gastrointestinal hemorrhage, hepatic

function abnormality, and myocardial ischemia (one patient each). Nine patients experienced

AEs that required dose interruption of pazopanib. The most common AEs leading to dose

interruptions were AST/ALT elevations. Moreover, six patients had pazopanib dose reductions.

The most common AEs leading to dose reductions were AST/ALT elevations and diarrhea.

Clinical Activity

Twenty-six patients were evaluable for treatment response (two patients were withdrawn

during cycle 1 because of treatment-related toxicity and were not evaluable for response).

Among evaluable patients, two patients (8%) had confirmed partial responses, 17 patients

(65%) had stable disease, and seven patients (27%) had progressive disease. The partial

responses (one patient each at the 400 and 800 mg dose levels) were maintained for at least 12

weeks. Overall, 19 patients (73%) had either partial response or stable disease while receiving

pazopanib treatment.

The median estimation of PFS for the entire study population was 17.7 weeks (95%

confidence interval: 11.9 - 23.9 weeks; Fig. 1A). The best percent change from baseline in the

sum of the longest diameters of target lesions according to pazopanib dose received on the

largest number of days (ie, modal dose rather than the originally assigned dose) is displayed in

Fig. 1B to provide a more accurate picture of the association between dose and antitumor

activity. Of the patients with a modal dose of 600 mg QD, one patient had a confirmed partial

response, six patients had stable disease, and one patient had progressive disease.

Serial Alpha Fetoprotein Changes

Of the 16 patients who had elevation in baseline AFP (ie, > 20 µg/L); ten patients (63%)

showed a 20% or greater decline in AFP compared with baseline during the study, while two





patients had no post-baseline AFP measurements (Supplemental Table 1). Among the ten

patients who had elevated AFP at baseline and achieved a partial response or stable disease

as their best response, eight patients had a 20% or greater decline in AFP compared with

baseline, and two patients had an increase in AFP compared with baseline. Additionally, among

the six patients who had elevated AFP and achieved PFS of 17.7 weeks or longer, five patients

had a 20% or greater decline in AFP compared with baseline, and only one patient had an

increase in AFP compared with baseline.

Pharmacokinetics

After repeated oral administration of pazopanib 200, 400, 600, or 800 mg QD in the

Dose-Escalation phase, median tmax values ranged from 2 to 3 hours (Supplemental Table 2).

The highest AUC(0-6), Cmax, and C24 values were observed in the pazopanib 800 mg QD cohort.

However, systemic exposure (AUC(0-6)) to pazopanib did not increase in a dose-proportional

manner when the pazopanib dose was increased, and ranged from 151 µg·hr/mL at pazopanib

200 mg QD to 214 µg·hr/mL at pazopanib 800 mg QD. Similarly, the mean Cmax values for

pazopanib did not vary widely across the range of pazopanib doses used in this study (29.8

g/mL at pazopanib 200 mg QD; 31.6 g/mL at pazopanib 400 mg QD; 28.8 g/mL at pazopanib

600 mg QD; 39.5 g/mL at pazopanib 800 mg QD). The trough plasma C24 was above 15 µg/mL

for all doses tested and was highest at the pazopanib 800 mg QD dose level (28.1µg/mL).

After 14 days of QD administration, metabolites in the pazopanib 800 mg cohort were

greater than or equal to the mean values observed in the 200, 400, and 600 mg dose cohorts.

Similar to pazopanib, systemic exposure to pazopanib metabolites did not increase in a dose

proportional fashion when the dose of pazopanib was increased from 200 to 800 mg QD.





DCE-MRI Findings

Seventeen of 28 patients treated with pazopanib 200 mg (n = 4), 400 mg (n = 5), 600 mg

(n = 5), or 800 mg (n = 3) successfully completed both baseline and Day 22 DCE-MRI

acquisitions. Baseline scanning was repeated to estimate measurement variability. The mean

percent (standard deviation) differences between two baseline scans for IAUGC60 and Ktrans

were 17.8% (17.3%) and 24.8% (23.1%), respectively. Median percent changes from baseline

in IAUGC60 were –17.3, –15.9, –39.6, and –60.0, whereas median percent changes from

baseline in Ktrans were –36.3, –23.0, –44.6, and –73.8 for the pazopanib 200 mg, 400 mg, 600

mg, and 800 mg QD doses, respectively (Table 4). The percent changes from baseline in

IAUGC and Ktrans were variable across observed pazopanib C24 and Cmax values; however, the

largest decrease from baseline in Ktrans occurred in patients with C24 values above 20 µg/mL

(Fig. 2A). Decreases of 40% or greater from baseline in IAUGC60 were observed only in patients

with C24 of approximately 20 µg/mL or higher. One patient receiving pazopanib 800 mg QD had

a best response of partial response, achieved C24 of approximately 30 µg/mL, and had large

decreases from baseline in IAUGC (∼60%) and Ktrans (∼74%; Fig. 2B). All three patients who had

a best response of progressive disease and underwent paired DCE-MRI acquisitions achieved

C24 values below 30 µg/mL and less than 40% decreases from baseline in IAUGC or Ktrans. A

similar trend was observed for Cmax.





DISCUSSION

For patients with advanced HCC in Child-Pugh class A, the MTD for pazopanib was 600

mg QD, on the basis of DLT frequency during the first 21 days of pazopanib in the dose

escalation phase. During the cohort-expansion phase of the study (pazopanib 600 mg QD), one

patient died and another experienced grade 4 gastrointestinal bleeding. Both the death and the

gastrointestinal bleeding were likely related to rapid disease progression and occult metastases

invading the gastrointestinal tract, respectively. Overall, 10 patients received pazopanib 600 mg

for the majority of their time on treatment, and appeared to tolerate this dose (with the exception

of the two patients described above). Although a potential contribution of study drug to the

serious AEs observed in the two patients receiving 600 mg during the cohort-expansion phase

cannot be excluded, based on available data, pazopanib 600 mg QD was determined to be both

the protocol-defined MTD and the recommended dose for further development in patients with

advanced HCC.

Notably, in view of the potential hepatotoxicity reported in the phase 1 pazopanib study

(6), the current study specified that an increase of 2 or more in the Child-Pugh score was one of

the criteria defining DLT if the liver toxicity was considered to be related to pazopanib. In fact,

the frequency of transaminase and bilirubin elevations was higher in the current study than

other pazopanib studies (6). This observed increase in the incidence of liver toxicities may be

related to exacerbation of hepatic AEs in a population with underlying disease (HCC) that

compromised liver function. Nevertheless, the overall safety profile of patients with HCC treated

with pazopanib appeared to be similar to the profiles reported in other pazopanib monotherapy

studies with regard to the frequency of serious AEs, as well as the frequency of AEs leading to

withdrawal from the study, dose interruption, or dose reduction (6).





There may be important differences in the AE profile of the targeted agents in the

treatment of advanced HCC (2, 3, 17-20). For instance, hypertension, hepatobiliary laboratory

abnormalities, and diarrhea occurred at a higher frequency in this study compared with that

reported for sorafenib. Nevertheless, it is important to note that such cross-study comparisons

are limited by sample size, differences in baseline disease characteristics (eg, tumor stage,

association with hepatitis B vs C), on-study duration, and study design (phase I vs phase II/III),

and should be undertaken with care.

Although the relationship between pazopanib pharmacokinetic parameters and DCE-

MRI endpoints in the current study was not constant, greater decreases in DCE-MRI

parameters were associated with higher pazopanib C24 values. All patients with an

approximately 40% or greater decrease in IAUGC had a pazopanib C24 of 20 µg/mL or higher.

Results from a previous pazopanib study (6) demonstrated that patients with C24 of 15 µg/mL or

higher, compared to patients with C24 below 15 µg/mL, had a markedly higher rate of developing

hypertension (77% vs 39%), which is a predominant AE associated with VEGF inhibition

observed in clinical trials of anti-VEGF therapy (21, 22). The similarity of plasma pazopanib C24

at which the effects on blood pressure and DCE-MRI parameters are observed suggests that

effects consistent with anti-VEGF activity occur when plasma pazopanib concentrations are

maintained above a target of approximately 20 µg/mL.

Preliminary clinical activity was observed with pazopanib in this study of patients with

HCC. The overall response rate was 8% and the median PFS was 17.7 weeks. Overall, 73% of

patients had a best response of either a partial response or stable disease while on pazopanib

treatment, and among patients with elevations in baseline AFP, those with a 20% or greater

decline in AFP seemed to benefit more from pazopanib treatment compared with patients

without this decline. Notably, at the time this study was conducted, RECIST guidelines remain

the standard for assessing tumor response (15). As yet, there is no consensus in the HCC

community about whether modified RECIST would be a better method to assess response in





patients with HCC receiving targeted therapy alone. Nevertheless, there may be an even higher

rate of radiological response if the results of the study are evaluated by modified RECIST

guidelines (23), which take into account tumor necrosis.

To measure the changes in HCC tumor vessel function, we used DCE-MRI, a technique

widely used to evaluate changes in the vasculature in response to antiangiogenic therapies.

Parameters such as Ktrans are considered related to vascular permeability and are considered

biomarker candidates because they can detect functional changes in tumor vasculature after

treatment with anti-VEGF agents (24-27). To our knowledge, this is one of the few published

studies to evaluate functional changes in HCC tumor vasculature in response to a range of

doses of an antiangiogenic agent. Notably, in the current study the extent of decrease in both

Ktrans and IAUGC was greater in patients with clinical benefit, suggesting that control of vessel

leakage may be a determinant of HCC tumor response to pazopanib. However, the predictive

value of imaging biomarkers remains to be standardized and validated in larger studies.

In conclusion, we established a tolerable dose of pazopanib and provided initial

evidence of antitumor activity in selected patients with advanced HCC. Pazopanib reduces

tumor vessel leakage, as estimated by DCE-MRI, indicating a direct effect on HCC vasculature

that might be associated with clinical benefit. With the manageable safety profile of pazopanib

demonstrated in this study of selected patients with HCC, further evaluation of pazopanib in

phase II trials is warranted.





ACKNOWLEDGMENTS

Imaging was supported by Frank Stornanti, Perceptive Informatics, Billerica, and Dr.

Brandon Whitcher, GlaxoSmithKline Clinical Imaging Centre, London. Image analysis was

conducted by Dr. Caleb Roberts and Professor Geoff Parker, Imaging Science and Biomedical

Engineering, University of Manchester, UK. We thank Bret Wing, PhD, ProEd Communications,

Inc.®, for his medical editorial assistance with this manuscript.

FUNDING

This study was sponsored by GlaxoSmithKline Research and Development and

GlaxoSmithKline provided funding for medical editorial assistance.





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TABLES

Table 1. Patient Baseline Characteristics and Disposition Baseline Characteristics N = 28 Age, median years (range) 61 (38 - 76) Sex, n (%) Female Male

4 (14)

24 (86) Race, n (%) Asian—Japanese/East Asian/Southeast Asian Asian—Central/South Asian

27 (96)

1 (4) ECOG performance status, n (%) 0 1

17 (61) 11 (39)

Hepatitis serology, n (%) Hepatitis B (+) Hepatitis B surface antigen (+) Hepatitis C (+) Hepatitis B (+) AND hepatitis C (+) Hepatitis B (–) AND hepatitis C (–)

23 (82) 19 (68) 3 (11) 2 (7)

4 (14) Baseline AFP level, n (%) ≤ 400 µg/L > 400 µg/L

20 (71) 8 (29)

AJCC disease stage at study entry, n (%) I IIIA IIIC IV

1 (4) 2 (7) 2 (7)

23 (82) Distant metastases, n (%) Lung Lymph nodes Adrenals Abdomen Bone Kidney

15 (54) 8 (29) 4 (14) 2 (7) 2 (7) 2 (7)

Prior surgical treatment, n (%) Liver resection Liver transplant

18 (64)

0 (0) Local ablative procedure, n (%) TACE RFA Alcohol injection

15 (54) 5 (18) 1 (4)





Prior systemic therapy, n (%) Chemotherapy Biologic therapy Hormonal therapy

8 (29) 4 (14) 1 (4)

Disposition Patients, n Pazopanib dose-escalation phase (n = 21) 200 mg QD 400 mg QD 600 mg QD 800 mg QD

4 5 6 5

Pazopanib cohort-expansion phase (n = 7) 400 mg QD 600 mg QD

6 2

Abbreviations: AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; (+), positive; (–), negative.





Table 2. Summary of Adverse Events (Any Grade) Occurring in ≥ 10% of All Patients Across All Treatment Groups and Adverse Events ≥ Grade 3

Patients, n (%)

Pazopanib (mg) Treatment Groups Total

(N = 28) Adverse Event (preferred terms)

200 (n = 4)

400 (n = 11)

600 (n = 8)

800 (n = 5)

Any Grade

Diarrhea 2 (50) 9 (82) 4 (50) 2 (40) 17 (61)

Hypertension 2 (50) 2 (18) 2 (25) 4 (80) 10 (36)

AST increased 0 5 (45) 3 (28) 1 (20) 9 (32)

ALT increased 0 3 (27) 2 (25) 1 (20) 6 (21)

Cough 2 (50) 2 (18) 1 (13) 0 5 (18)

Skin hypopigmentation 0 1 (9) 4 (50) 0 5 (18)

Weight decreased 0 2 (18) 2 (25) 1 (20) 5 (18)

Alopecia 1 (25) 0 1 (13) 2 (40) 4 (14)

Anorexia 1 (25) 3 (27) 0 0 4 (14)

Dizziness 1 (25) 1 (9) 1 (13) 1 (20) 4 (14)

Hair depigmentation 0 1 (9) 0 3 (60) 4 (14)

Hyperbilirubinemia 0 1 (9) 2 (25) 1 (20) 4 (14)

Malaise 1 (25) 2 (18) 0 1 (20) 4 (14)

Abdominal distension 1 (25) 0 2 (25) 0 3 (11)

Abdominal pain 0 1 (9) 2 (25) 0 3 (11)

Fatigue 1 (25) 1 (9) 1 (13) 0 3 (11)

Leukopenia 0 2 (18) 1 (13) 0 3 (11)

Muscle spasms 0 0 2 (25) 1 (20) 3 (11)

Nausea 2 (50) 0 0 1 (20) 3 (11)

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Upper respiratory tract infection 0 2 (18) 1 (13) 0 3 (11)

Grade 3

Hypertension 2 (50) 2 (18) 1 (13) 2 (40) 7 (25)

AST increased 0 1 (9) 1 (13) 1 (20) 3 (11)

ALT increased 0 1 (9) 0 1 (20) 2 (7)

Diarrhea 0 2 (18) 0 0 2 (7)

Hypercholesterolemia 0 0 1 (13) 0 1 (4)

Hypokalemia 0 0 0 1 (20) 1 (4)

Hyponatremia 1 (25) 0 0 0 1 (4)

Lipase increased 0 1 (9) 0 0 1 (4)

Malaise 0 0 0 1 (20) 1 (4)

Grade 4

Gastrointestinal hemorrhage 0 0 1 (13) 0 1 (4)

Hypoglycemia 0 0 1 (13) 0 1 (4)

Transaminases increased 0 0 1 (13) 0 1 (4)

Grade 5

Hepatic function abnormal 0 0 1 (13)a 0 1 (4) a Patient had rapid disease progression in the liver.

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Table 3. Summary of Treatment-Emergent Shifts from Baseline to Maximum Toxicity Grade in Hepatobiliary Parameters

Hepatobiliary Marker

Maximum Toxicity Grade

Patients, n

Total Patients, n (%)

Pazopanib Treatment Groups (N = 28)

200 mg (n = 4)

400 mg (n = 11)

600 mg (n = 8)

800 mg (n = 5)

AST elevation

1 2 2 0 2

20 (71) 2 1 4 1 1

3 0 1 3 2

4 0 0 1 0

Hyperbilirubinemia

1 2 5 2 1

19 (68) 2 1 1 2 2

3 0 0 1 0

4 0 0 2 0

ALT elevation

1 2 4 1 2

15 (54) 2 0 1 1 0

3 0 1 1 1

4 0 0 1 0

ALP elevation

1 0 3 3 2

10 (36) 2 0 0 1 0

3 0 1 0 0

Note: Table includes only data for patients whose worst grade during the study was higher than their baseline grade. Abbreviation: ALP, alkaline phosphatase.

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Table 4. Pharmacokinetic/Pharmacodynamic Relationships with Respect to Pazopanib Dose Pazopanib Dose, mg

200 (n = 4)

400 (n = 11)

600 (n = 8)

800 (n = 5)

C24,a median μg/mL

(min, max) 15.4

(13, 26) 21.4b

(10.5, 31.1) 21.8c

(1.63, 36.8) 28.7d

(24.6, 30.9) Ktrans, median % change (min, max)

–36.3 (–70.0, –22.9)

–23e (–76.8, –9.5)

–44.6e (–45.6, 9.2)

–73.8f (–86.2, –37.5)

IAUGC60, median % change (min, max)

–17.3 (–24.7, –11.7)

–15.9e (–47.9, 30.3)

–39.6e (–56.0, 12.6)

–60.0f (–78.4, 10.8)

Number of days on studyg, median days (min, max)

133.5 (40, 788)

43 (6, 294)

116.5 (2, 289)

169 (9, 274)

Abbreviations: C24, steady state concentration; Ktrans, volume transfer coefficient; IAUGC60, initial area under the gadolinium curve over 60 seconds after bolus arrival. a C24 was defined as the predose plasma drug concentration on day 15. b n = 10. c n = 6. d n = 4. e n = 5. f n = 4 g Number of days on study counts the number of days from first dose to last dose of study drug.





FIGURE LEGENDS

Fig. 1. (A) Kaplan Meier estimation of progression-free survival. Gray and thin lines represent

95% confidence intervals. (B) Best percent change from baseline in the sum of the longest

diameters of target lesions. Data on patients are presented according to modal dose (dose,

including a zero dose, administered on the largest number of days while on-study) rather than

the original assigned dose.

Fig. 2. (A). Relationship of the IAUGC to pazopanib trough concentration and best response by

RECIST. (B) Representative magnetic resonance images of T1-weighted tumor enhancement

and maps of Ktrans before and after administration of pazopanib 800 mg, demonstrating a

dramatic reduction in both tumor size and Ktrans after 3 weeks of treatment.




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0 4 168 12 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116

28 24 1419 15 10 7 5 4 4 3 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Time, weeks

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Perc

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5,000 10,000 15,000 20,000

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Published OnlineFirst August 10, 2011.Clin Cancer Res Thomas CC Yau, Pei-Jer Chen, Pierre Chan, et al. PharmacodynamicsCarcinoma: Evaluation of Early Efficacy, Pharmacokinetics, and Phase I Dose-Finding Study of Pazopanib in Hepatocellular

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