Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

All Drugs and Chemicals

Amino Acids

Tyrosine Kinase Inhibitors

Tyrosine

Pazopanib is an oral, potent, multi-target receptor tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGFR-alpha and -beta and c-kit. Subjects were to receive 800 mg oral pazopanib daily for a minimum of 2 weeks to a maximum of 6 weeks.

Pazopanib

GSK Clinical Trials

This is a phase 2 open-label, multicenter, non-randomized study to evaluate the safety and efficacy of oral pazopanib as neoadjuvant treatment for patients with stage 1A, 1B, IIA or IIB (to T2) resectable Non-Small Cell Lung Cancer (NSCLC).

Pazopanib As Pre-Surgical Therapy In Treatment-Naive Subjects With Non-Small Cell Lung Cancer

A Phase II Open-Label Multicenter Study to Evaluate the Safety and Efficacy of Pazopanib (GW786034) as Neoadjuvant Therapy in Treatment-Naïve Subjects With Stage IA, IB, IIA or IIB (to T2) Resectable Non-Small Cell Lung Cancer (NSCLC)

Tumor shrinkage was assessed as the change in tumor volume using high-resolution computed tomography scans of the thorax following treatment with pazopanib. Response is defined as the number of participants achieving at least 50% tumor volume reduction following pazopanib treatment. "Responder" is a participant whose tumor volume reduced at least 50% following pazopanib treatment. "Non-responder" is a participant whose tumor volume did not reduce at least 50% following treatment. Tumor assessments were conducted by a central reviewer.

Response is the number of participants achieving either complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR, all detectable tumor has disappeared; PR, a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum; Progressive disease (PD), a \>=20% increase in target lesions; Stable Disease, small changes not meeting previously given criteria. Confirmation requires at least 2 assessments (conducted by a central reviewer) of CR/PR with at least 4 weeks between the assessments.

Response is the number of participants whose tumor demonstrated a 60% or greater reduction in metabolic activity (SUV) as measured by positron emission tomography (PET) or PET/computed tomography (PET/CT) at the end of treatment visit relative to baseline. This analysis was not conducted because insufficient data were collected: only three participants had PET/CT data.

Shifts in hematology values by grade were summarized based on the National Institutes of Health (NIH) Common Terminology Criteria for Adverse Events (Version 3.0 - definitions provided with each parameter below). Shifts to Grade 2 or greater at any point in the study following baseline are reported here.

Shifts in chemistry values by grade were summarized based on the NIH Common Terminology Criteria for Adverse Events (Version 3.0 - definitions provided with each parameter below). Shifts to Grade 2 or greater at any point in the study following baseline are reported here. ULN = upper limit of normal; Gr = grade; mg = milligrams; dL = deciliter; mmol = millimoles.

Increases in systolic or diastolic blood pressure values at any point in the study following baseline were summarized. mmHg = millimeters of mercury. Baseline blood pressure values as well as the change from baseline experienced are given in the category titles.

Tumor cells from pre-treatment and post-operative biopsies were to have been analyzed to determine the number of cells that were exhibiting apoptosis. Due to the limited quantity of tissue in pre- and post-treatment biopsy samples, these assays were not performed.

Gene expression data analysis was performed with GeneSpring GX 7.3.1 (Agilent Technologies). Data were preprocessed using the RMA algorithm. The Benjamini and Hochberg false discovery rate was used for multiple testing corrections. Data below are log-transformed ratios of the post-treatment to pre-treatment expression intensity, indicating the fold increase/decrease in expression of genes. PDGF, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor; c-KIT, a protein tyrosine kinase that is a receptor for stem cell factor or "kit" ligand.

Specific genes (KRAS, MYC, TP53, and others) were to have been analyzed for the presence or absence of amplifications or deletions and for the presence, absence, and sequence of point mutations in pre- or post-treatment tumor biopsies. These analyses were not conducted because the potential results were considered to provide overlapping information with those obtained in the transcriptional and proteomic profiling assays that were conducted. The clinical study report indicates that genetic measures were to have been reported separately.

A pre-treatment tumor biopsy from each participant was to have been analyzed by Western blotting to semi-quantitate levels of various proteins related to angiogenesis and/or to the mechanism of action of pazopanib. These assays were not carried out due to insufficient quantity of tissue present in the pre-treatment biopsy (fine needle aspirate). The clinical study report indicates that results were to have been reported separately.

LDH5 has been shown to be associated with activation of angiogenesis in lung cancer. Circulating levels of LDH5 were to have been measured at each scheduled visit through the post-treatment visit to determine if a correlation with drug effect existed. Levels of LDH5 were measured, but the team determined that greater value was to be derived from transcriptional and plasma biomarker analyses; thus, no analyses were conducted to examine the correlation of LDH5 levels with effects of pazopanib.

Plasma samples were collected from each consenting participant, generally at baseline, to permit evaluation of the presence or absence of genetic variations in select candidate genes in germline DNA. Analyses that could have been done might have examined the relationship between genetic variants and the safety or tolerability or the efficacy of pazopanib. Analyses have not yet been conducted, but a need to do so may yet be identified. The clinical study report indicated that results, if any, would be reported separately.

Analysis not performed as part of study. Appropriate material was not available for analysis.

Baseline and post-therapy plasma samples were obtained from participants. Immunohistochemistry analyses were carried out using a BioPlex 200 machine (Bio-Rad) or by enzyme-linked immunoassays to evaluate levels of angiogenesis-related proteins and other relevant proteins. Post- and pre-treatment changes in cytokines and angiogenic factors in response to pazopanib were analyzed. A negative value indicates that the post-treatment level of the particular target protein was less than the pre-treatment level.

GlaxoSmithKline

Pazopanib 800 milligrams (mg) (tablets) administered orally once a day for a minimum of 2 and a maximum of 6 weeks

Pazopanib 800 mg

Age Continuous

Sex: Female, Male

White

African American/African Heritage

Asian

Race/Ethnicity, Customized

GSK Response Center

Responder

Non-responder

Safety Population: all participants who received at least one dose of pazopanib

Number of Participants Achieving Tumor Shrinkage Based on Change in Tumor Volume

Complete response

Partial response

Stable disease

Progressive disease

Safety population: all participants who received at least one dose of pazopanib

Number of Participants Achieving a Clinical Response Based on RECIST

Number of Participants Achieving a >=60% Reduction in Tumor Metabolic Activity Determined as Standard Uptake Value (SUV)

Lymphocytes, Grade 2 (<0.8-0.5 x 10^9/L)

Lymphocytes, Grade 3 (<0.5-0.2 x 10^9/L)

Neutrophils, Grade 2 (<1.5-1.0 x 10^9/L)

Neutrophils, Grade 3 (<1.0-0.5 x 10^9/L)

White blood cells, Grade 2 (<3.0-2.0 x 10^9/L)

White blood cells, Grade 3 ( <2.0-1.0 x 10^9/L)

Pazopanib 800 mg (tablets) administered orally once a day

Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values

Alkaline phosphatase, Grade 2 (>2.5-5.0 x ULN)

Alanine aminotransferase, Grade 2 (>2.5-5.0 ULN)

Alanine aminotransferase, Gr 3 (>5.0-20.0 x ULN)

Aspartate aminotransferase, Gr 2 (>2.5-5.0 x ULN)

Aspartate aminotransferase, Gr 3 (>5.0-20.0 x ULN)

Total bilirubin, Grade 3 (>3.0-10.0 x ULN)

Hypocalcemia, Grade 4 (<6.0 mg/dL)

Hyperglycemia, Grade 2 (>160-250 mg/dL)

Hyperkalemia, Grade 3 (>6.0-7.0 mmol/L)

Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values

Systolic, BL: 90-139 mmHg; up to 140-169 mmHg

Diastolic, BL: 50-89 mmHg; up to 90-109 mmHg

Number of Participants With the Indicated Change From Baseline in Systolic and Diastolic Blood Pressure

Tissue from Safety Population: all participants who received at least one dose of pazopanib

Number of Cells Exhibiting Apoptosis in Participant Samples

Thrombospondin 1

PDGF-alpha

PDGF-beta

VEGF A

VEGF C

VEGF D

VEGFR-1

VEGFR-2

Angiopoietin 1

Angiopoietin 2

Transforming growth factor 3

Fibroblast growth factor 7

Tumor tissue from Safety Population: all participants who received at least one dose of pazopanib. Only 26 of 35 subjects had sufficient tissue in both pre- and post-treatment samples for analysis.

Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes

Gene Mutations in Pre- or Post-treatment Tumor Biopsies

Intratumoral Levels of Specific Biomarkers

Plasma Levels of Lactate Dehydrogenase-5 (LDH5)

Genetic Variations in Germline DNA

Overall Study Arm

Semiquantitative Levels of Staining in Pre-treatment Tumor Biopsies (e.g. VEGF, VEGFR-1,VEGFR-2).

Vascular endothelial growth factor receptor

Placental growth factor

Interferon inducible cytokine

Cutaneous T-cell attracting chemokine

Stromal cell-derived factor 1

Monokine induced by interferon gamma

Tumor necrosis factor ligand

Interferon alpha 2

Vascular endothelial growth factor

Safety population: all participants who received at least one dose of pazopanib. Only 33 of 35 subjects had plasma samples from both pre- and post-treatment available for analysis.

Spots Global Cancer Trial Database for Pazopanib As Pre-Surgical Therapy In Treatment-Naive Subjects With Non-Small Cell Lung Cancer

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