Dose Of Pazopanib Research Articles

Abstract 2762: Phase I study of pazopanib and ixabepilone in patients with solid tumors

Abstract Background: Pazopanib is a tyrosine kinase inhibitor targeting multiple receptors including vascular endothelial growth factor receptor, platelet derived growth factor receptor, and C-KIT and acts by inhibiting angiogenesis and tumor growth. Ixabepilone is a semi-synthetic analog of epothilone B and promotes microtubule stabilization inducing tumor cell apoptosis. The purpose of this study was to determine the optimal tolerated regimen (OTR) of combination pazopanib and ixabepilone during the first cycle of therapy for the treatment of advanced, previously treated solid tumor malignancies. Methods: Treatment was given until disease progression, unacceptable toxicity, or patient refusal. Ixabepilone was administered intravenously on day 1 of a 21-day cycle. Dose escalation started at 32 mg/m2 and increased to 40mg/m2. Pazopanib was administered orally once daily beginning on day 1 at a starting dose of 400mg and escalating at 200mg increments up to 800mg. Toxicity was assessed by using the Common Terminology Criteria for Adverse Events (version 3.0). Disease assessment was done every 2 cycles. Results: Twenty-eight patients (17 male and 11 female) with ECOG PS of 0 or 1 were enrolled from December 2009 to September 2011.The median age was 58 years (range 30-72). Primary tumor sites included lung (8), colon (9), skin (2), gallbladder (1), cholangiocarcinoma (1), neuroendocrine (1), head and neck (3), esophagus (1), small cell cancer (1), and leimyosarcoma (1). A total of 120 cycles of chemotherapy was administered with a median number of cycles per patient of 4 (range 1-13). Two dose-limiting toxicities (DLT) were seen including grade 4 neutropenia at dose level 2 (ixabepilone 40 mg/m2 and pazopanib 400 mg) and grade 4 thrombocytopenia with proteinuria at dose level 4 (ixabepilone 32 mg/m2 and pazopanib 800 mg). Dose level 2a was added to the study to confirm the safety of the proposed ixabepilone dose (32 mg/m2) before escalating the dose of pazopanib to levels 3 and 4. Dose level 3 was determined to be the optimal tolerated regimen (pazopanib 600 mg and ixabepilone 32 mg/m2). Grade 3-4 hematologic toxicities included neutropenia (14), febrile neutropenia (1), thrombocytopenia (2), and anemia (1). Grade 3-4 non-hematologic toxicities included weakness (1), dehydration (1), transaminitis (1), and fatigue (1). One patient withdrew from the study due to toxicity. Median time to progression during the study period was 3 months. Disease stabilization was seen in 11 patients and partial response in 5 patients. Conclusions: We were able to establish the OTR for combination of pazopanib and ixabepilone. Progression-free survival seen in patients with a variety of previously treated, advanced solid tumors warrants further investigation of this regimen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2762. doi:1538-7445.AM2012-2762

Pazopanib: A Promising New Agent in the Treatment of Soft Tissue Sarcomas

Pazopanib (GW786034) is a novel, small-molecule tyrosine kinase inhibitor. The primary mechanism of action of pazopanib can be described through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of VEGF receptor (VEGFR) and PDGF receptor (PDGFR). It is an orally available angiogenesis inhibitor that targets VEGFR-1, -2 and -3, PDGFR-α and -β, and c-kit. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in that class. Phase I studies defined the recommended monotherapy dose of pazopanib as 800 mg once daily. In 2009, it was approved in the USA for the treatment of advanced and metastatic renal cell carcinoma, and subsequently approved in other countries and demonstrated clinically and statistically significant activity in Phase II and III studies in advanced soft tissue sarcoma patients. This article focuses on its emerging role in the treatment of advanced soft tissue sarcomas.

A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors

Because cancer patients may have difficulty swallowing whole tablets, crushing tablets or ingesting an oral suspension is a practical alternative. This open-label, 2-part, randomized crossover, phase I study evaluated the pharmacokinetics and tolerability of pazopanib administered as a crushed tablet or an oral suspension relative to whole tablet in patients with advanced cancer (Part 1). Patients completing Part 1 were eligible for continuous daily pazopanib 800 mg (Part 2). Administration of a single pazopanib 400 mg crushed tablet increased the area under the curve from 0 to 72 h (AUC((0-72)); 46%) and maximum observed plasma concentration (C(max); ~2-fold), and decreased time to achieve maximum plasma concentration (T(max); ~2 h), indicating increased rate and extent of oral absorption relative to whole-tablet administration. Similarly, a single dose of pazopanib 400 mg suspension increased AUC((0-72)) (33%) and C(max) (29%), and decreased T(max) (1 h). These changes in pharmacokinetic parameters were not associated with increases in the magnitude or duration of short-term (ie, up to 72 h) blood pressure elevation compared with whole-tablet administration.

Phase I study of pazopanib in children with relapsed or refractory solid tumors (ADVL0815): A Children’s Oncology Group Phase I Consortium Trial.

9501 Background: Pazopanib, an orally available potent and selective small molecule tyrosine kinase inhibitor, targets VEGFR 1-3, PDGFR α/β, and c-kit. A phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics of pazopanib in children with refractory solid tumors (including CNS) was performed. Methods: Oral pazopanib (tablet formulation) was administered once daily in 28 day cycles, for up to 24 cycles. Cohorts were enrolled at 4 dose levels (275 to 600 mg/m2) using the rolling-six design. Dose determination for subsequent cohorts was based on cycle 1 toxicity (CTC v3) in the prior cohort. Results: 27 subjects were enrolled; 25 were eligible and 23 were evaluable for dose-limiting toxicity (DLT) [13 male, median age 13 yrs (range, 4-21)]. Subjects received a median of 3 cycles (range 1-13). Observed cycle 1 DLTs included: Gr3 lipase elevation (n=1, 275 mg/m2), Gr3 proteinuria and Gr3 hypertension (n=1, 450 mg/m2), Gr3 amylase elevation (n=1, 600 mg/m2) and Gr3 hypertension (n=1, 600 mg/m2). Thus, the MTD was 450 mg/m2. Cycle 1 non-hematologic toxicities observed in >10% of patients included Gr2 hypertension (n=6), left ventricular dysfunction (n=1), fatigue (n=3), rash (n=2), hypothyroidism (n=1), diarrhea (n=1), nausea (n=1) vomiting (n=2), amylase (n=1), lipase (n=2), proteinuria (n=1), abdominal pain (n=2) and headache (n=5); and reversible Gr3 hypophosphatemia (n=1). Prolonged QTc was not observed. Later adverse events requiring treatment discontinuation included: intolerable Gr2 diarrhea; Gr3 myalgia associated with Gr3 microangiopathic hemolytic anemia; Gr3 hand foot syndrome; and recurrent Gr3 neutropenia (each, n=1). PK data will be presented. One subject with hepatoblastoma had a PR by cycle 6, but was removed for neutropenia after cycle 12 (now receiving via compassionate use), and 4 pts had SD > 6 cycles (3 remain on therapy). Plasma VEGF (p=0.006) and PlGF (p<0.001) increased, whereas endoglin (p=0.005) and soluble VEGFR2 (p<0.001) decreased from baseline to d15 (n=22). Conclusions: The MTD of pazopanib in children with solid tumors is 450 mg/m2with toxicities similar to other VEGF blocking agents.

Abstract P2-14-02: A Pilot Study of Vascular Endothelial Growth Factor Inhibition with Pazopanib in Patients (pts) with Lymphedema Following Breast Cancer Treatment

Abstract Purpose: Lymphedema is a significant long-term complication of primary therapy for breast cancer. VEGF has a major impact on vascular permeability and lymphangiogenesis. In a prior case control study, we found a significant increase in serum VEGF-C (median 6895 vs. 5349 pg/mL, p=0.0016) in women with lymphedema compared to women without lymphedema suggesting inhibition of VEGF-C as a potential therapeutic strategy. Methods: Pts with significant unilateral lymphedema were treated with pazopanib 800 mg/day continuously. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C,-D, and R3. IFP was measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R3 are assessed every 4 weeks. Results: Ten pts were enrolled. Median duration of lymphedema was 3.5 years (0.7-8.2) Median time since surgery was 5.1 years (1.0-14.2); median time since radiation (n=9) was 4.7 years (0.4-8.8). Complete IFP data are available in 7 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (mean 5.73 vs. -1.78 mmHg; p=0.0005). Mean IFP in the affected arm decreased an average of 76% 24 hours after initiation of pazopanib (5.73 vs. 1.56 mmHg; p=0.0061). Toxicity was greater than anticipated with grade 3 fatigue (n=3), arthralgia (n=2), and anorexia (n=1); three pts discontinued therapy prior to the first post-treatment assessment. Five pts met the definition of response with a ≥25% reduction in excess arm volume four weeks after initiating treatment. ECF significantly (p=0.014) decreased as well though the mean difference in excess arm volume did not significantly change (p=0.06). Conclusions: Preliminary data supports the hypothesis that VEGF plays a role in the development and/or persistence of lymphedema after local therapy for breast cancer. Pazopanib acutely decreases IFP, leading to a decrease in ECF and modest improvement in arm volume but results in significant toxicity at the dose used on this study. Subsequent studies will explore a lower dose of pazopanib in this population. This study was supported by the Breast Cancer Research Foundation with pazopanib supplied by GSK. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-02.

A Phase I Study of the Pharmacokinetic and Safety Profiles of Oral Pazopanib With a High-Fat or Low-Fat Meal in Patients With Advanced Solid Tumors

Pazopanib is an oral angiogenesis inhibitor of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and cytokine receptor. This open-label, randomized, crossover, phase I study evaluated the effect of low- and high-fat meals on the pharmacokinetics (PK) of pazopanib in patients with advanced solid tumors. Patients participated in either the lead-in cohort or randomized food-effect cohort. Patients in the lead-in cohort were administered a single dose of pazopanib 400 mg with a high-fat meal. Patients in the food-effect cohort were randomized to receive single doses of pazopanib 800 mg in fed condition (high- or low-fat meal) or fasting condition, in random sequence 14 days apart. After completion of the study, patients were given the opportunity to continue treatment with daily pazopanib 800 mg. Administration of pazopanib with both low- and high-fat meals increased maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) by approximately twofold as compared with the corresponding values when administered to patients in the fasted condition. Therefore, pazopanib should be administered to patients in the fasted state so as to minimize within- and between-day variability in the systemic exposure to pazopanib in patients with cancer.

Effect of pazopanib on hair and skin hypopigmentation: A series of three patients.

e13602 Background: Pazopanib, an inhibitor of multiple kinases including VEGF-R, PDGF-R, and c-KIT, is the latest of a series of tyrosine kinase inhibitors (TKIs) to be FDA approved for the treatment of human cancers. Hair and skin hypopigmentation have been occasionally reported in response to therapy with c-Kit inhibitors, such as imatinib, but not with other TKIs. Methods: We report our experience with severe skin and hair hypopigmentation in 3 representative patients treated with pazopanib (800 mg daily continuously, 28 day cycles) for advanced and progressive thyroid cancers enrolled in an ongoing IRB and NCI/CTEP-approved phase II clinical trial. Results: More than 50% of patient's enrolled in our ongoing phase II trial, who have remained on study for >6 months, have experienced hair and skin hypopigmentation. The 3 patients presented here (1 African American, 2 Caucasians - Hürthle cell, medullary, follicular histology respectively) all responded to therapy - with maximal reduction of target lesions by 59%, 19%, and 35%, respectively, and reduction in respective tumor markers by 71%, 76%, and 51%. All 3 patients are still receiving pazopanib after 14 to 17 cycles of therapy. Hypopigmentation was first noted after 1 or 2 cycles, with maximal hypopigmentation noted after 6 to 10 cycles. Our African American patient experienced severe sunburn for the first time in her life, presumably due to profound hypopigmentation. She has now started to regain skin pigmentation in response to pazopanib dose reduction. The 2 Caucasian patients are hypopigmented to a degree otherwise expected only in albinism. One of the Caucasian patients is slowly regaining pigmentation while on pazopanib in the absence of a dose reduction. Conclusions: The precise incidence of pazopanib induced hypopigmentation is not yet known. However, severe hypopigmentation of the hair and skin has been commonly observed in our thyroid cancer trial. We postulate that dual potent inhibition of c-Kit and PDGF-R may be responsible. Whether pazopanib-induced hypopigmentation may represent a biomarker of response remains uncertain. Patients and physicians should be aware of this complication, and of its potential reversibility. Supported in part by NCI-CA15083 and NO1-CM62205. No significant financial relationships to disclose.

Abstract A6: Pazopanib combination with paclitaxel and carboplatin in patients with advanced solid tumors and gynecological cancers: Results of two phase I studies

Abstract Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit with w/ a recommended dose of 800 mg/day as monotherapy. Preclinical activity supports combining PAZ with paclitaxel (P) and carboplatin (C). Safety, PK, and and clinical activity of PAZ with P and and C were evaluated in two Phase I studies. Methods: Two Phase I studies were conducted using a once daily QD regimen of PAZ (200–800 mg), and once every Q21 days of C (AUC 4–6 mg·min/mL) and P (175 mg/m2) to determine the optimally tolerated regimen (OTR) MTD defined as a dose limiting toxicity (DLT) frequency of &amp;lt;33% in Cycle 1. Study 1 (S1) was a 3 + 3 design expanded at the OTR in patients (pts) with w/ metastatic disease treated with w/ no more than 3 prior lines of therapy. Study 2 (S2) enrolled subjects with w/ gynecological cancer in 2 cohorts of 6 pts each as first-1st line treatment. Results: In Study 1S1, 34 pts (mean age 54; M/F: 17/17; ECOG 0/1: 19/15) were enrolled. Breast (29%) and esophagus (12%) were the most common primary tumor sites. In Study 2S2, 12 pts (mean age 53.754, M/F: 0/12; ECOG 0/1: 8/4) were enrolled. Ovary (50%) and endometrium/uterus (25%) were the most common primary tumor sites. The frequency of adverse events (AEs), regardless of causality, in the 2 studies (1 vs 2), were similar for neutropenia (82% vs 75%) and fatigue (68% vs 75%) and different for nausea (71% vs 50%), thrombocytopenia (68% vs 33%), anemia (65% vs 25%), and abdominal pain (24% vs 50%). The OTR MTD in Study 1S1 was P 175, C AUC 5, and PAZ 200; an OTR MTD was not determined for Study 2S2 due to poor tolerability. In Study 1S1, in the presence of PAZ 200 mg and 400, mg, the AUC (0–23) of C increased by 41 and 31%, respectively and while the Cmax for P increased by 43 and 40%, respectively. Best response in Study 1S1 at the OTRMTD (n=13) was CR [2 pts (15%); 406 and 446 days] and PR [3 pts (23%); 42–208 days]. Conclusions: Full doses of PAZ and C were not tolerated in combination with w/ P due predominantly to hematologicale toxicities in Study 1S1 and to non-hemeatological toxicities in Study 2S2. A drug interaction between PAZ and P and C along with more extensive prior therapy may explain increased myelotoxicity with this triplet in Study 1S1. Based on this PK interaction, lower doses of P and C may still provide adequate therapeutic exposure and better safety profile when combined with a higher dose of PAZ relative to the OTR MTD in study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A6.

Abstract A10: Antiangiogenic therapy (VEGF-R1–3 and PDGFR inhibitor) increases tumor hemoglobin saturation and decreases interstitial pressure, and microvessel density

Abstract Methods: We evaluate the effects of pazopanib, a novel multi-targeted tyrosine kinase inhibitor, by examining its effects on tumor oxygenation, interstitial pressure (IFP), and vascularity as compared to an untreated control group. Nude mice (n=35) were injected with A-549 NSCLC tumor cells. Tumors reached an average volume of 650 mm3 before treatment with pazobanib 100mg/kg/day, Pazobanib 30mg/kg/day. or Vehicle (Control). Animals were treated daily for 14 days. Spectroscopic Measurements: A novel Skinskan spectrofluorometer was used to obtain non-invasive measurements of hemoglobin saturation (Hbsat) and total Hb for each tumor. Measurements were performed every other day, starting the day of treatment. These values were analyzed by a custom MATLAB program. IFP Measurements: IFP was measured on the last day of treatment(day 14), prior to sacrifice. Immunohistochemical staining: The number of vessels, determined by positive CD31 staining, was averaged over 6–8 image fields to obtain microvessel density (MVD). Results: Optical Spectroscopy: A significant increase in Hbsat was observed at day 8 for the low and high pazopanib dose groups, compared to control (p=0.0109, p=0.0290, respectively). After the 8th treatment day, Hbsat trended downward toward baseline. Tumor IFP: Tumor IFP for animals treated with pazopanib 100mg/kg was significantly reduced, compared to control (p=0.0026). Treatment with pazopanib 30mg/kg also demonstrated a strong trend towards IFP reduction, compared to control (p=0.0645). MVD: MVD was significantly reduced in mice treated with low and high dose pazopanib, compared to control (p=0.0271, p=0.0107, respectively). Conclusions: Treatment with pazopanib lead to a significant reduction in IFP, MVD, and increase in tumor Hb sat. This result demonstrates that pazopanib enhances efficiency of tumor perfusion which could lead to better drug distribution into the tumor, and increased of tumor Hb saturation would correlate with better oxygenation and predicts better response to radiotherapy. Work supported by a grant from GlaxoSmithKline. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A10.

A phase I study of pazopanib in patients with advanced hepatocellular carcinoma

3561 Background: Patients (pts) with advanced hepatocellular carcinoma (HCC) have a poor prognosis. HCC is a highly vascular tumor with increased levels of angiogenic factors including VEGF and VEGFR. Pazopanib (GW786034) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit. A Phase I study was conducted to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics and efficacy of pazopanib in patients with locally unresectable and/or advanced HCC. Methods: Eligibility criteria included unresectable and/or metastatic HCC with at least 1 target lesion, recovery from prior systemic regimens, ECOG PS 0 or 1, Child-Pugh A, and adequate organ function. Doses of pazopanib were escalated from 200 mg once daily (QD) to 800 mg QD in a 3 + 3 design. DCE- MRI was performed to assess changes in tumor permeability. Results: 27 Asian pts have been enrolled at QD doses of 200 (4 pts), 400 (10), 600 (8), 800 (5): median (range) age = 61 (38–76); M/F = 85%/15%; ECOG 0/1 = 59%/41%; 81% with metastatic disease; 67% with Stage IV; 22% with prior systemic therapy, 26% with prior TACE. Most common AEs were: diarrhea (59%; 4% Gr 3); hypertension (44%; 26% Gr 3), cough (19%); fatigue (19%; 4% Gr 3); and hair depigmentation (15%). Hepatobiliary lab abnormalities were: AST elevation (63%; 15% Gr 3), hyperbilirubinemia (63%; 4% Gr 3), ALT elevation (41%; 7% Gr 3), and Alk phos (37%; 4% Gr 3). DLTs were Gr 3 malaise (1 pt) and Gr 3 AST/ALT elevation (1 pt) at 800 mg. MTD was determined to be 600 mg QD. Median (range) days on study was 85 (4–663) overall; 106 days (4–274) at the MTD. Best response was PR in 2 pts (7%; 1 at 800mg, 1 at 600 mg) and SD &gt; 4 mos in 11 pts (41%). Median TTP at the MTD was 137.5 days (4–280 days). Median % change in tumor permeability (Ktrans) following 3 weeks of pazopanib administration at the MTD (5 pts) was 45%. Predose and maximum plasma pazopanib concentrations at 800 mg QD were similar to values observed previously at the same dose. Conclusions: Pazopanib has a manageable safety profile in HCC at the MTD of 600mg QD. Preliminary evidence of antitumor activity was observed. Changes in tumor DCE-MRI parameters were seen following repeated dose pazopanib administration. [Table: see text]

Phase I study of the safety, tolerability, and pharmacokinetics (PK) of weekly paclitaxel administered in combination with pazopanib (GW786034)

3552 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit with demonstrated activity in renal cell cancer, sarcoma, and ovarian cancer when administered at 800 mg daily. Improved efficacy of weekly paclitaxel with the anti-VEGF agent bevacizumab in metastatic breast cancer provides a rationale for combining an angiogenesis inhibitor with a taxane. Methods: Patients (pts) with advanced cancer (ECOG PS 0–1) were eligible. Dose escalations of paclitaxel (15–80 mg/m2) on days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) daily were evaluated for safety, PK, and clinical response. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK; the optimally tolerated regimen (OTR) consisted of ≤ 1/6 pts experiencing a DLT; 9 additional pts were enrolled to confirm the OTR. Results: 25 pts received paclitaxel/pazopanib at doses of 15/400 (3), 15/800 (3), 50/800 (3) and 80/800 (16) mg. Median age was 58 y; M: 48%; 92% Caucasian. Most common tumor types were breast (5), CRC (3), esophageal (3), and NSCLC (3). Most frequent adverse events (AEs) (mostly Gr 1/2) were nausea (68%), fatigue (56%), diarrhea (52%), vomiting (48%), rash (44%), anorexia (32%), visual disturbance (24%), alopecia (24%), and constipation (24%). Hepatic enzyme elevations: ALT (48%), AST (44%), alkaline phosphatase (24%), and bilirubin (12%) were mainly Gr 1/2. The OTR was defined as 80 mg/m2 paclitaxel and 800 mg pazopanib (median 2.5 cycles [range 1–8]; median no. of 2 prior regimens [range 1–5]); 1 DLT (Gr 3 groin abscess) was observed at this dose. 12/16 pts at the OTR required dose modifications; 3 of these were withdrawn due to an AE. For pazopanib, 7 pts required interruptions and 3 pts required dose reductions. For paclitaxel, 11 pts required interruptions/delays and 5 pts required dose reductions. Liver enzyme elevation was the most common reason for dose modification. Pazopanib increased mean paclitaxel AUC (45%) and Cmax (40%). Clinical activity at the OTR: PR in 5/16 (31%) pts and SD > 8 wks in 10/16 (63%) pts. Conclusions: Therapeutic doses of daily pazopanib and weekly paclitaxel can be combined with a manageable toxicity profile and evidence of clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline Eli Lilly, Genentech™ BioOncology Aventis, Celgene, GlaxoSmithKline, OSI Oncology

Analyses of plasma cytokine/angiogenic factors (C/AFs) profile during preoperative treatment with pazopanib (GW786034) in early-stage non-small cell lung cancer

7568 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit. In a single-arm phase II trial (NCT00367679; VEG105290), patients received pazopanib 800 mg QD for 2–6 weeks before scheduled surgery. Tumor volume measurements were performed using high resolution CT images before and after treatment. An exploratory analysis was planned to describe the modulation of C/AFs during pazopanib treatment and identify potential predictive plasma markers. Methods: Plasma samples were collected pre- treatment and on the last day of pazopanib dosing. Levels of 52 C/AFs were measured by suspension bead multiplex assays (BioRad) or ELISA. Results were correlated with change in tumor volume. Statistical analyses included Wilcoxon tests and Pearson correlation tests. Results: 19 paired samples have been analyzed. Pazopanib treatment was associated with a significant modulation of 13 C/AFs, including a decrease in soluble VEGFR-2 (p<0.001) and increases in PlGF, IFN-α2 and HGF; chemokines/monokines: SDF1-α, CTACK, CXCL-10, CXCL-9, RANTES; and further factors: IL-12; M-CSF and TRAIL (all with p<0.05). PlGF showed the highest up-regulation during treatment with an average 15.9 fold increase, whereas changes compared to baseline for the remaining factors varied between 5 and 60%. The exploratory correlation of C/AF changes with tumor changes indicated an association with 6 factors (sVEGFR-2 (r = 0.77), VEGF (r = - 0.68), IL-16, IL-1RA, MCP-3, and IL-4; all with p<0.05). A significant correlation between baseline levels of C/AFs and tumor reduction was observed for 8 factors (PlGF, IL-2R, IL-12, IL-16, TRAIL, SCF, IL-3 and CTACK). Conclusions: Pazopanib treatment was associated with decreases in sVEGFR2 and increases in an additional 12 C/Afs, with PlGF demonstrating a particularly striking increase. The exploratory analysis identifies that baseline levels of several C/Afs may have predictive value for pazopanib treatment. Moreover a strong correlation between sVEGFR-2 changes during pazopanib treatment and tumor shrinkage was observed making this factor a potentially attractive marker of response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Pneum Rx, General Electric GlaxoSmithKline, Pneum Rx GlaxoSmithKline GlaxoSmithKline

Phase I study of the safety and pharmacokinetics (PK) of paclitaxel or paclitaxel with carboplatin administered in combination with pazopanib (GW786034)

14118 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit. Pazopanib also is a moderate inhibitor of CYP2C8 and CYP3A4 in vitro. Paclitaxel (T), a substrate for CYP2C8 and CYP3A4, administered alone and in combination with carboplatin (Cb) is highly active in breast, NSCLC, and ovarian cancers. The additive benefit of the anti-VEGF agent bevacizumab with T or T-Cb in breast and NSCLC provides strong rationale for use of a multi-targeted TKI with T or T-Cb. Methods: Pts with advanced cancer (ECOG PS 0–1) were eligible. Dose escalation was split into Part 1 [T (15–80 mg/m2) days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) QD starting on day 2 of cycle 1] and Part 2 [T (80- 225 mg/m2) plus Cb AUC 6 q 21 days plus pazopanib 800 mg QD starting on day 2 of cycle 1]. Safety, PK, and clinical response were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK. Results: 12 pts in Part 1 received the following pazopanib/T doses (n = pts): 400 mg/15 mg/m2 (3), 800 mg/15 mg/m2 (3), 800mg /50 mg/m2 (3), 800mg /80 mg/m2 (3). Preliminary data were available from 9 pts in Part 1. Selected mean PK results for T are shown. 4 pts in Part 2 received 800mg /175 mg/m2/AUC 6 of pazopanib/T/Cb (data not yet available). Most common AEs (&gt;20%) in Part 1 were Gr 1/2 and consisted of fatigue, diarrhea, anorexia, nausea, vomiting, dysgeusia, AST elevation, rash, hypertension, and cough; Gr 3 diarrhea was reported in 1 pt. The 800mg pazopanib/80 mg/m2 T cohort in Part 1 is being expanded to 6 pts due to a DLT (dose delay of &gt; 2 wks due to an abscess). Best response (n=6 pts) in Part 1 was SD (83%) (range 1–5 cycles). Conclusions: Concomitant administration of pazopanib increased paclitaxel mean Cmax and AUC(0–8) approximately 20–35%. Determination of the MTR in Parts 1 and 2 is ongoing. These findings warrant further studies at therapeutic doses of pazopanib, paclitaxel, and carboplatin. [Table: see text] No significant financial relationships to disclose.