Given Every 21 Days in Patients with Advanced Solid...

Phase I Study of Pazopanib in Combination with Paclitaxel and Carboplatin Given Every 21 Days in Patients with Advanced Solid Tumors

Howard A. Burris III1, Afshin Dowlati2, Rebecca A. Moss3, Jeffrey R. Infante1, Suzanne F. Jones1, David R. Spigel1, Kelly T. Levinson3, Diana Lindquist3, Shelby D. Gainer4, Mohammed

M. Dar4, A. Benjamin Suttle4, Howard A. Ball4, Antoinette R.Tan3

1Sarah Cannon Research Institute, Nashville, TN; 2Case Western Reserve University, Cleveland, OH; 3The Cancer Institute of New Jersey, New Brunswick, NJ;

4GlaxoSmithKline, Research Triangle Park, NC, and Upper Providence, PA

Running Title: Phase I study of pazopanib, paclitaxel, and carboplatin

Keywords: pazopanib, paclitaxel, carboplatin, phase I, pharmacokinetics

Abbreviations: ANOVA, analysis of variance; AUC(0-23), area under the curve from 0 to 23 hours; AUC5, dosed at area under the curve 5 (carboplatin); AUC6, dosed at area under the curve 6 (carboplatin); CI, confidence interval; Cmax, maximal concentration; DLT, dose-limiting toxicity; ECOG, Eastern Cooperative Oncology Group; MTR, maximum tolerated regimen; NSCLC, non-small-cell lung cancer; VEGF and VEGFR, vascular endothelial growth factor and VEGF receptor.

Financial/Grant Support: This study was funded by GlaxoSmithKline Pharmaceuticals. Standard study-related costs to all investigators were supported, and no funding was provided to investigators.

Corresponding Author: Howard A. Burris III, MD Sarah Cannon Research Institute 250 25th Ave North, Suite 110 Nashville, TN 37203-1632 Phone: 615-320-5090 Facsimile: 615-320-1225 E-mail: [email protected]

Disclosure of Potential Conflicts of Interest: H.A. Burris, A. Dowlati, R.A. Moss, J.R. Infante, S.F. Jones, D.R. Spigel, K.T. Levinson, D. Lindquist, and A.R. Tan report no relevant financial relationships.

Previous Publication: Portions of the data were presented at the 2009 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (abstract A6).

Word Counts: Text only (limit 5,000 words) = 3,043 Abstract (limit: 250 words) = 242 Number of Figures/Tables (limit 6 total): 6 Number of References (limit 50): 26

on January 2, 2020. © 2012 American Association for Cancer Research. mct.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 June 7, 2012; DOI: 10.1158/1535-7163.MCT-11-0997

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Burris et al Phase I study of pazopanib, paclitaxel, and carboplatin

ABSTRACT

Several phase III trials have demonstrated that the addition of an antiangiogenic agent to

conventional chemotherapy can improve clinical benefit in patients with advanced solid tumors.

This study examined the feasibility of combining pazopanib (Votrient), an oral antiangiogenic

agent, with paclitaxel and carboplatin. This 3 + 3 dose-escalation phase I study evaluated the

maximum tolerated regimen (MTR) of daily pazopanib in combination with paclitaxel 175 mg/m2

and carboplatin (dosed at area under the curve [AUC] 5 or 6) given every 21 days in patients

with advanced solid tumors. Plasma samples were collected to evaluate the effect of pazopanib

on the pharmacokinetics of paclitaxel and carboplatin. Thirty-four patients were enrolled. The

MTR was paclitaxel 175 mg/m2 and carboplatin AUC5 with pazopanib 200 mg. The most

common dose-limiting toxicities were neutropenia and thrombocytopenia. Two patients with

esophageal cancer had a complete response and four patients, one each with breast, small-cell

lung, pancreatic, and gastroesophageal junction cancer, had partial responses. Pazopanib at

200 mg increased paclitaxel maximal concentration (Cmax) by 43% and carboplatin (AUC5 or

AUC6) Cmax by 54%. Paclitaxel and carboplatin given every 21 days at standard doses was not

feasible in combination with the monotherapy pazopanib dose of 800 mg daily because of dose-

limiting myelosuppression. Coadministration of pazopanib increased exposure to paclitaxel and

carboplatin and likely contributed to this effect. Given the antitumor activity of this regimen,

further studies are underway to determine a clinically tolerable schedule of pazopanib with

paclitaxel and carboplatin.





INTRODUCTION

Angiogenesis is an important process for tumor growth (1,2). Therefore, the addition of

angiogenesis inhibitors to chemotherapy is a potential approach to enhance antitumor activity.

In addition to inhibiting tumor-mediated angiogenesis, antiangiogenic agents may normalize

“leaky” tumor vasculature and increase the delivery of chemotherapy agents to the tumor site

and enhance their efficacy (3). The addition of bevacizumab (Avastin), an anti-vascular

endothelial growth factor (VEGF) antibody, to chemotherapy has been shown to improve clinical

benefit in several tumor types, including metastatic colon cancer (4,5), non-small-cell lung

cancer (NSCLC) (6), and breast cancer (7,8).

Pazopanib (Votrient) is an oral agent that inhibits the tyrosine kinases of the VEGF

receptor (VEGFR), platelet-derived growth factor receptor, and c-Kit (9). Pazopanib given at 800

mg once daily has demonstrated single-agent activity in multiple tumor types (10-15), and is

approved for the treatment of advanced renal cell carcinoma in the United States and other

countries. The multikinase activity of pazopanib may potentially improve tumor control

compared with other angiogenesis inhibitors such as bevacizumab, which targets a single

component of the angiogenesis pathway. Paclitaxel combined with carboplatin is a common

chemotherapy backbone for the treatment of NSCLC and ovarian cancer (16,17). This phase I

study explored the feasibility and efficacy of adding daily pazopanib to the combination of

paclitaxel and carboplatin given every 21 days in patients with advanced solid tumors.





METHODS

Patients

Eligible patients had a confirmed histologic or cytologic diagnosis of cancer, an Eastern

Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate bone marrow,

renal, and hepatic function as well as peripheral neuropathy of grade 1 or less. Patients with

more than three lines of prior chemotherapy for metastatic disease, poorly controlled

hypertension, prolonged QTc interval (≥ 470 msec), heart failure, a history of bleeding within 6

weeks of study entry, current use of warfarin at therapeutic doses, or central nervous system

metastases were excluded. The study protocol was approved by the institutional review board at

each site and was conducted according to the Declaration of Helsinki. All patients gave written

informed consent.

Study Design

This was a phase I, multicenter, open-label, dose-finding study (VEGF105427, clinical

trial registration identifier NCT00388076) with a 3 + 3 design that was expanded at the

maximum tolerated regimen (MTR). Cohorts of patients were treated with paclitaxel in

combination with carboplatin and daily pazopanib (Figure 1A). The MTR was defined as the

maximum dose level at which no more than one of six patients experienced a dose-limiting

toxicity (DLT) during Cycle 1. A DLT was defined as grade 3 or 4 clinically significant non-

hematologic toxicity (excluding alopecia or grade 3 nausea/vomiting in the absence of

supportive therapy), hypertension (grade 3 not adequately controlled with medication),

proteinuria (grade 3 persisting > 3 weeks with no improvement to below grade 2 after

discontinuation of pazopanib), febrile neutropenia, grade 4 thrombocytopenia or

granulocytopenia lasting beyond 5 days with or without fever, and any grade 2 toxicity

considered a DLT in the judgment of the investigator and sponsor. Additionally, the inability to





begin the next course of treatment within 2 weeks of scheduled dosing because of unresolved

toxicity was considered a DLT.

Secondary endpoints included the effect of pazopanib on the pharmacokinetics of

paclitaxel and carboplatin (clearance and maximal concentration [Cmax] for paclitaxel; area under

the curve from 0 to 23 hours [AUC(0-23)] and Cmax for carboplatin) and the clinical activity of the

combination therapy. The pharmacokinetic parameters for pazopanib included Cmax.

Treatment

A phase I trial had previously shown that administration of pazopanib at 800 mg once

daily reduced paclitaxel clearance by approximately 14% (18). Therefore, paclitaxel 175 mg/m2

and carboplatin area under the curve 6 (AUC6) administered intravenously every 21 days and

pazopanib 800 mg once daily were chosen as the starting doses to achieve a predicted

systemic exposure to paclitaxel similar to that following administration of paclitaxel 200 mg/m2

and carboplatin in the absence of pazopanib. Paclitaxel 175 mg/m2 was administered as a 1-

hour infusion, and carboplatin area under the curve 5 (AUC5) or AUC6 was given as a half-hour

infusion on Day 1 of a 21-day cycle. Pazopanib was started on Day 2 of Cycle 1 to permit

assessment of paclitaxel and carboplatin pharmacokinetics individually on Day 1, after which

pazopanib was dosed continuously. Pazopanib was taken at least 1 hour before or 2 hours after

a meal.

Assessments

On Day 1 of each cycle, patients received a physical examination and hematology,

clinical chemistry, and urine protein:creatinine ratio assessments. Hematology and clinical

chemistry were also assessed on Days 8 and 15 of each cycle. An electrocardiogram, ECOG

performance status evaluation, amylase, lipase, and thyroid function tests were obtained on Day

1 of Cycle 2 and all subsequent cycles.





Blood samples for pharmacokinetic analysis of paclitaxel and carboplatin were obtained

on Day 1 of Cycle 1, and blood samples for pharmacokinetic analysis of all three agents were

obtained on Day 1 of Cycle 2. Samples for paclitaxel pharmacokinetics were collected pre-dose

(within 60 minutes before administration) and 0.5, 1 (end of infusion), 1.5, 2, 2.5, 3, 4, 5, 6, 8,

12, and 24 hours after the start of the infusion. Samples for carboplatin pharmacokinetics were

collected pre-dose and 1.5 (end of carboplatin infusion), 4, 8, and 24 hours after the start of the

paclitaxel infusion. Samples for pazopanib pharmacokinetics were collected pre-dose and 1, 2,

3, 4, 6, 8, 12, and 24 hours after administration.

Disease assessments were performed at baseline, after 6 weeks, and then every 9

weeks. Responses were recorded using Response Evaluation Criteria in Solid Tumors (19).

Statistical Assessments

Pharmacokinetic parameters were calculated by standard noncompartmental analysis

using WinNonlin Pro version 4.1 or higher (Pharsight Corporation, Mountain View, CA). An

analysis of variance (ANOVA) on logarithmic-transformed data was used to assess the

interaction effect of pazopanib on the pharmacokinetics of paclitaxel (Cmax and clearance) and

carboplatin (AUC(0-23) and Cmax). The ANOVA used a mixed-effects model with patient as a

random effect. Fixed-effect terms included dose cohort, treatment, and the dose cohort-

treatment interaction term. The test treatment was defined as pazopanib plus paclitaxel and

carboplatin (Cycle 2, Day 1) and the reference treatment was defined as paclitaxel and

carboplatin (Cycle 1, Day 1). The antilogs of the confidence limits of the 90% confidence

intervals (CI) for the difference in the treatment means of the logarithmic-transformed data were

a 90% CI for the ratio of geometric means between the test and reference treatment for Cmax

and clearance (paclitaxel). Because blood samples for analysis of ultrafilterable platinum were

collected for 23 hours after the start of the carboplatin infusion (24 hours after the start of the

paclitaxel infusion), carboplatin AUC(0-23) was included in the statistical analyses. The geometric





least squares mean ratio and associated 90% CI were provided after transformation of the

results from the logarithmic-transformed analysis back to the original scale. There was no

adjustment for the multiple comparisons of endpoints. The Statistical Analysis Software system

(SAS version 8.2 or higher; SAS Institute, Inc., Cary, NC) was used to analyze the data.





RESULTS

Between November 2006 and March 2009, 34 patients were enrolled (Table 1). All

patients were evaluable for pharmacokinetic analyses and safety, except one patient who was

not evaluable for DLT because of withdrawal from study without a DLT before completion of

Cycle 1 (Day 19). The most common tumor types were breast (29%) and esophageal (12%)

cancers. Less common tumor types (“other” in Table 1) included mesothelioma, NSCLC,

neuroendocrine, prostate cancer, small-cell lung cancer, sarcoma, pleura, and thyroid cancer

(one of each). All but two patients received prior anticancer therapy, which included

chemotherapy (88%), radiotherapy (53%), biologic therapy (29%), and endocrine therapy

(24%). Approximately 85% of patients previously received either antitubulin or platinum therapy.

Maximum Tolerated Regimen

The starting dose level in cohort 1 was paclitaxel 175 mg/m2, carboplatin AUC6, and

pazopanib 800 mg. Three of four patients experienced DLTs during the first cycle, including

grade 4 thrombocytopenia, grade 3 hypertension, and grade 4 neutropenia (Table 2). Given

these events, the dose of pazopanib was decreased to 400 mg in cohort 2. Four of five patients

experienced dose-limiting thrombocytopenia, which in some instances resulted in a delay of

Cycle 2 by more than 2 weeks. In an effort to reduce myelotoxicity in cohort 3, carboplatin was

decreased from AUC6 to AUC5 and pazopanib was decreased from 400 to 200 mg, while

paclitaxel was maintained at 175 mg/m2. The first three patients enrolled did not experience a

DLT. Accordingly, in cohort 4, pazopanib was increased to 400 mg with paclitaxel 175 mg/m2

and carboplatin AUC5, and one of the initial three patients experienced dose-limiting

neutropenia during the first cycle. This cohort was subsequently expanded and two of the next

three patients also experienced dose-limiting neutropenia.





To determine whether maximal doses of chemotherapy could still be administered with

pazopanib, a fifth cohort was treated with paclitaxel 175 mg/m2, carboplatin AUC6, and

pazopanib 200 mg; cohort 3 was also expanded in parallel. In cohort 5, one of the initial three

patients experienced dose-limiting neutropenia during the first cycle. An additional three patients

were enrolled, among whom one patient experienced dose-limiting neutropenia.

Given these findings, the MTR was determined to be paclitaxel 175 mg/m2 and

carboplatin AUC5 every 21 days, with pazopanib 200 mg once daily. Ten additional patients

were enrolled in this cohort for further study, with two patients experiencing DLTs (ie,

neutropenia, hematologic toxicity, and infection resulting in treatment delay). One patient in this

cohort withdrew consent at Day 19 and was therefore excluded for DLT analysis. Overall, two of

the 12 patients evaluable for DLT at this dose level experienced DLTs, confirming the MTR.

Adverse Events

Neutropenia, anemia, fatigue, nausea, thrombocytopenia, vomiting, diarrhea, peripheral

neuropathy, and alopecia were the most commonly reported drug-related adverse events, with

myelotoxicity being the most common grade 3 or 4 event (Table 3).

Hypertension was the most common cardiovascular event reported during the study. In

addition, nine patients experienced hemorrhagic (eg, epistaxis, hemoptysis, melena,

hematochezia, hemorrhoids, ecchymosis/petechiae, vaginal hemorrhage) adverse events

(grade 1 [n = 7] and grade 2 [n = 2]). No cases of proteinuria were reported. Elevations in

hepatobiliary parameters were considered adverse events in seven patients, most of which

were grade 2 (n = 2) or 3 (n = 3); however, one patient experienced grade 4 alanine

aminotransferase increase associated with grade 4 liver abscess and grade 3 bilirubin increase

that was not considered related to study drug.

One patient, treated at the MTR, withdrew during the study because of an adverse event

(grade 4 sepsis) that was considered serious and required hospitalization. Additionally, a patient





with metastatic esophageal cancer, also receiving treatment at the MTR, who remained on

study for more than 57 weeks, died within 4 weeks of the last dose of study drug in the setting of

rapid disease progression, esophageal stricture, and biliary obstruction.

Among all 34 patients who received at least one dose of study drug, 12 (35%)

experienced 37 serious adverse events during the study. There was no clear association

between frequency of serious adverse events and cohort treatment.

A dose interruption of at least one study drug because of adverse events was reported in

30 patients (88%). Most patients (including those at the MTR) experienced interruptions in

pazopanib dosing (79%) or delays in the scheduled administration of paclitaxel (68%) and

carboplatin (62%). The most common toxicities leading to treatment interruption, delay, or dose

reductions were neutropenia and thrombocytopenia. The frequencies of dose reductions were

as follows: pazopanib (26% overall; 0% MTR), paclitaxel (24% overall; 23% MTR), and

carboplatin (35% overall; 38% MTR).

Pharmacokinetics

Concurrent administration of pazopanib 200 mg resulted in an approximately 43%

increase in paclitaxel Cmax (Table 4) and a 54% increase in carboplatin Cmax (AUC5 or AUC6;

Table 5) compared with paclitaxel and carboplatin without pazopanib (Figure 1B, 1C).

Pazopanib 400 mg resulted in similar increases in paclitaxel and carboplatin Cmax (40% and

68%, respectively) as that of pazopanib 200 mg. Pazopanib at 200 mg and 400 mg was found

to decrease paclitaxel clearance by 30% and 17%, respectively. However, because of the wide

variability of individual results, there was no statistically significant difference in paclitaxel

clearance between the pazopanib 200 mg and 400 mg dose.

Median plasma pazopanib Cmax on Cycle 2 Day 1 was 15.8 μg/mL in the cohort receiving

paclitaxel 175 mg/m2, carboplatin AUC5, and pazopanib 200 mg, and median pazopanib Cmax





was 27.5 μg/mL in the cohort receiving paclitaxel 175 mg/m2, carboplatin AUC5, and pazopanib

400 mg.

Efficacy

In this phase I trial, there were two complete responses and four partial responses.

Objective responses were observed at the MTR (paclitaxel 175 mg/m2, carboplatin AUC5, and

pazopanib 200 mg), and included complete responses in two patients with esophageal cancer,

one of whom had prior treatment with combination docetaxel and oxaliplatin, and one who was

chemotherapy-naive, and a partial response in a patient with small-cell lung cancer who had

received one prior line of therapy.

The other three partial responses occurred in previously treated patients with pancreatic

(paclitaxel 175 mg/m2, carboplatin AUC6, and pazopanib 400 mg), gastroesophageal junction,

and breast cancer (both at paclitaxel 175 mg/m2, carboplatin AUC5, and pazopanib 400 mg).

Overall, seven patients (21%) experienced disease stabilization, and the duration of stable

disease ranged from 24 to 77 weeks in a variety of tumor types.





DISCUSSION

Taxanes such as paclitaxel in combination with platinum-based agents are the standard

of care as first-line treatment in several solid tumor types (16,17). In the treatment of NSCLC

and ovarian cancer, the standard paclitaxel dose is 175 to 200 mg/m2 every 3 weeks and the

standard carboplatin dose is AUC5 to AUC7.5 (16,17). Previous studies have shown the

feasibility of combining antiangiogenic agents with chemotherapy in patients with colorectal,

NSCLC, and breast cancer (4-8,20). Bevacizumab is approved in combination with paclitaxel

and carboplatin in patients with stage IV, nonsquamous NSCLC, although an increase in the

incidence of treatment-related deaths has been reported with this regimen (6). In patients with

colorectal cancer, the addition of bevacizumab to chemotherapy improved progression-free and

overall survival by 2 to 5 months, but increased the incidence of hypertension and bleeding

(4,20).

Several small studies have evaluated the addition of small-molecule tyrosine kinase

inhibitors such as sorafenib (Nexavar) and cediranib (Recentin) to chemotherapy. In patients

with advanced ovarian cancer, paclitaxel 175 mg/m2 and carboplatin AUC5 with a standard

sorafenib dose of 400 mg twice daily was not feasible because of increased incidence of death

(21). Similar results were reported with paclitaxel 200 mg/m2, carboplatin AUC6, and cediranib

30 mg daily in advanced NSCLC (22). In the present study, the recommended phase II

monotherapy dose of pazopanib, 800 mg once daily, was not feasible with paclitaxel 175 mg/m2

and carboplatin AUC5 or AUC6 every 21 days in patients with advanced solid tumors, because

of myelosuppression.

The safety profile of pazopanib in combination with paclitaxel and carboplatin reflected

established adverse events for each agent. In addition to defining the MTR by reported

toxicities, tolerability was assessed by comparing the actual doses of each agent received

versus the assigned cohort dose. Among the cohorts, more cycles were administered at the





assigned dose for cohorts receiving low daily doses of pazopanib (200 mg) than for cohorts

receiving higher daily doses of pazopanib (400 or 800 mg). These results further support the

identified MTR. In addition, clinical activity was observed at the MTR; two of the four patients

with esophageal carcinomas achieved a complete response, and there were partial responses

and disease stabilization in other tumor types. Although the pazopanib dose in the MTR was

lower than the currently approved dose of 800 mg once daily in renal cell carcinoma, the median

pazopanib concentration achieved was 16 μg/mL, which is within the therapeutic concentration

range (15 - 17.4 μg/mL) (9,23).

In this trial, there was a high incidence of myelosuppression that is likely a consequence

of drug-drug interactions, resulting in increased exposure to the chemotherapy components of

this regimen. Coadministration of pazopanib 200 mg (n = 14) and 400 mg (n = 8) once daily with

paclitaxel 175 mg/m2 and carboplatin every 21 days decreased paclitaxel clearance by 30% and

17%, respectively, and increased paclitaxel Cmax by approximately 40%. Mean paclitaxel

clearance decreased by 14% and mean paclitaxel Cmax increased by 36% after administration of

pazopanib 800 mg once daily and paclitaxel 80 mg/m2 in a weekly regimen (18). These results

indicate that maximal inhibition of paclitaxel clearance is achieved at pazopanib doses at or

below 200 mg. It is known that paclitaxel is a substrate of CYP3A4 and CYP2C8 and that

pazopanib is a weak inhibitor of these cytochrome enzymes, which is likely the basis for the

altered pharmacokinetics of paclitaxel when given with pazopanib. In contrast to the primarily

metabolic elimination of paclitaxel, carboplatin is primarily excreted through the kidneys, and

inhibition of cytochrome enzymes was not expected to alter the pharmacokinetics of carboplatin.

However, coadministration of pazopanib resulted in an increase in carboplatin AUC(0-23) and

Cmax relative to administration of carboplatin and paclitaxel without pazopanib. While the

mechanism of this apparent interaction remains unknown, this is similar to what has been

observed with coadministration of other small-molecule VEGFR tyrosine kinase inhibitors such





as BIBF 1120 (24) and AZD2171 (25), namely, an increase in carboplatin AUC. Interestingly, no

change in the pharmacokinetics of carboplatin was observed when paclitaxel and carboplatin

were administered in the presence of sorafenib dosed intermittently (26). A study with a more

dense blood sampling scheme is required to characterize the pharmacokinetics of carboplatin to

determine more accurately the extent of a pharmacokinetic drug-drug interaction between

pazopanib and carboplatin or other platinum-containing regimens. Administering paclitaxel and

carboplatin at lower doses than in this study may be an alternative, because in combination with

pazopanib the increases in paclitaxel and carboplatin AUC and Cmax would still provide

adequate therapeutic exposure.

In conclusion, pharmacokinetic analysis revealed that exposures to paclitaxel and

carboplatin were higher during concurrent treatment with pazopanib relative to treatment without

pazopanib. This three-drug combination has shown clinical activity at the MTR of paclitaxel

175 mg/m2 and carboplatin AUC5 every 21 days with pazopanib 200 mg daily, and alternative

strategies of administration, such as lower doses of chemotherapy or intermittent dosing of

pazopanib, are being explored to see if a more tolerable side effect profile can be achieved.





ACKNOWLEDGMENTS

We thank the patients and their families, and acknowledge Kristi Beatty and Kathryn

Westlake for their efforts in conducting this study. We also thank Tamalette Loh, PhD, at ProEd

Communications, Inc., for her medical editorial assistance with this manuscript.





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26. Okamoto I, Miyazaki M, Morinaga R, Kaneda H, Ueda S, Hasegawa Y, et al. Phase I

clinical and pharmacokinetic study of sorafenib in combination with carboplatin and

paclitaxel in patients with advanced non-small cell lung cancer. Invest New Drugs

2010;28:844-853.





TABLES

Table 1. Patient Characteristics

Demographics and Disease Characteristics Patients (N = 34)

Age, median years (range) 56 (34 - 78)

Sex, n (%) Male Female

17 (50) 17 (50)

Race, n (%) Caucasian/European African American Asian/East Asian

30 (88)

3 (9) 1 (3)

ECOG performance status, n (%) 0 1

19 (56) 15 (44)

Primary tumor type, n (%) Breast Esophagus Bile duct Bonea Colorectal Endometrial Gastroesophageal Pancreas Other

10 (29) 4 (12) 2 (6) 2 (6) 2 (6) 2 (6) 2 (6) 2 (6)

8 (24)

Prior antitubulin therapy, n (%) 16 (47)

Prior platinum therapy, n (%) 13 (38) a One patient had a primary diagnosis of osteosarcoma and the other had giant cell tumor of the bone. .





Table 2. Dose Levels and Dose-Limiting Toxicities

Cohort Dosing Regimen Patients

Enrolled, n Patients with

DLTs, n Dose-Limiting Toxicities

1 Paclitaxel 175 mg/m2 + Carboplatin AUC6 + Pazopanib 800 mg

4a 3

Grade 4 thrombocytopenia

Grade 3 hypertension

Grade 3 infection with grade 4 neutropenia Grade 4 thrombocytopenia


5a 4

Grade 1 thrombocytopeniab

Grade 1 thrombocytopeniab

Grade 4 thrombocytopenia

Grade 3 thrombocytopeniac


3 0 –


6 3

Grade 3 neutropeniab




6 2 Grade 4 neutropeniab


Expansion cohortd

Paclitaxel 175 mg/m2 + Carboplatin AUC5 + Pazopanib 200 mg

10e 2

Grade 4 neutropenia

Grade 3 oral cavity infectionb Grade 3 thrombocytopeniab


a The study protocol permitted 3 to 6 patients per cohort, and depending on the number screened and the number eligible, some cohorts contained more than 3 patients each. b Start of Cycle 2 delayed by > 2 weeks. c Grade 3 thrombocytopenia was considered to be a DLT by investigator because of grade ≥ 2 toxicity that occurred beyond Day 28. d Cohort 3 was expanded. e Although 10 patients were enrolled, only 9 were evaluable for DLTs and one patient, who did not have a DLT, withdrew before completing Cycle 1.





Table 3. Drug-Related Adverse Events (all grades) Occurring in ≥ 10% of Patients

Patients, n (%)

Pacl 175 mg/m2 + Carbo AUC6 +

Pacl 175 mg/m2 + Carbo AUC5 +

Paz 800 mg (N = 4) Paz 400 mg (N = 5) Paz 200 mg (N = 6) Paz 200 mg (N = 13)a Paz 400 mg (N = 6)

All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4

Hematologic toxicities

Neutropenia 3 (75) 3 (75) 3 (60) 3 (60) 5 (83) 5 (83) 11 (85) 9 (69) 6 (100) 6 (100)

Anemia 1 (25) 1 (25) 2 (40) 0 5 (83) 0 9 (69) 4 (31) 5 (83) 1 (17)

Thrombocytopenia 2 (50) 1 (25) 4 (80) 2 (40) 2 (33) 2 (33) 6 (46) 4 (31) 6 (100) 6 (100)

Leukopenia 1 (25) 0 1 (20) 1 (20) 1 (17) 0 1 (8) 0 2 (33) 0

Non-hematologic toxicities

Fatigue 3 (75) 0 3 (60) 0 2 (33) 0 11 (85) 1 (8) 3 (50) 1 (17)

Nausea 2 (50) 0 3 (60) 0 3 (50) 0 8 (62) 0 4 (67) 0

Vomiting 3 (75) 0 3 (60) 0 2 (33) 0 7 (54) 0 3 (50) 0

Diarrhea 2 (50) 0 2 (40) 0 1 (17) 0 6 (46) 0 3 (50) 0

Peripheral neuropathy 1 (25) 0 2 (40) 0 1 (17) 0 7 (54) 0 3 (50) 0

Alopecia 2 (50) 0 2 (40) 0 1 (17) 0 5 (38) 0 2 (33) 0

Decreased appetite 1 (25) 0 0 0 2 (33) 0 5 (38) 0 1 (17) 0

Dysgeusia 1 (25) 0 1 (20) 0 0 0 2 (15) 0 3 (50) 0

Headache 1 (25) 0 0 0 0 0 3 (23) 0 2 (33) 0

Hypertension 2 (50) 2 (50) 1 (20) 0 1 (17) 1 (17) 1 (8) 1 (8) 0 0

Mucosal inflammation 0 0 1 (20) 0 0 0 2 (15) 0 2 (33) 1 (17)

Dyspepsia 1 (25) 0 1 (20) 0 0 0 0 0 2 (33) 0

Peripheral edema 0 0 0 0 0 0 3 (23) 0 1 (17) 0

Rash 3 (75) 0 0 0 0 0 1 (8) 0 0 0 Abbreviations: Carbo, carboplatin; Pacl, paclitaxel; Paz, pazopanib. a This was the determined to be the maximum tolerated regimen.

.

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Table 4. Statistical Analysis of Paclitaxel Pharmacokinetic Parameters

Geometric Least Squares Mean

Parameter N Cycle 1 Cycle 2 Ratio 90% CI

Pazopanib 200 mg once daily

Clearance, L/h/m2 14 11.6 8.16 0.70 0.61 - 0.80

Cmax, µg/mL 14 26.9 38.5 1.43 1.19 - 1.72


Clearance, L/h/m2 8 11.2 9.23 0.83 0.68 - 1.01

Cmax, µg/mL 8 31.2 43.6 1.40 1.16 - 1.68





Table 5. Statistical Analysis of Ultrafilterable Platinum Pharmacokinetic Parameters Normalized to the Carboplatin AUC6 Dose

Parameter

N

Geometric Least

Squares Mean

Ratio

90% CI Cycle 1 Cycle 2


AUC(0-23), µg*h/mL 11 55.5 78.3 1.41 1.25 - 1.59

Cmax, µg/mL 13 18.2 28.0 1.54 1.12 - 2.10


AUC(0-23), ng*h/mL 6 54.1 70.8 1.31 0.89 - 1.93

Cmax, ng/mL 6 20.8 35.0 1.68 0.91 - 3.10





FIGURE LEGENDS

Figure 1. A: Chemical structures of pazopanib, paclitaxel, and carboplatin. B: Median plasma

paclitaxel concentration-time profile after administration of paclitaxel 175 mg/m2, carboplatin

dosed at area under the curve 5 (AUC5), and pazopanib 200 mg. C: Median ultrafilterable

platinum concentration-time profile after administration of paclitaxel 175 mg/m2, carboplatin

AUC5, and pazopanib 200 mg.




Published OnlineFirst June 7, 2012.Mol Cancer Ther Howard A. Burris III, Afshin Dowlati, Rebecca A Moss, et al. Solid TumorsCarboplatin Given Every 21 Days in Patients with Advanced Phase I Study of Pazopanib in Combination with Paclitaxel and

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