Lung Cancer, Non-Small Cell, Non-Small Cell Lung Cancer
Conditions
Keywords
pazopanib, I-ELCAP, non-small cell lung cancer, antiangiogenesis, NSCLC, GW786034
Brief summary
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).
Interventions
DRUGPazopanib
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.
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed, written informed consent provided prior to performing any study-specific procedures or assessments. Subject must be willing to comply with treatment and follow-up. * Subjects ≥21 years of age with a life expectancy of ≥12 weeks * The time between initial diagnosis and the scheduled surgery date allows for the subject to receive a minimum of 2 weeks or a maximum of 6 weeks treatment with pazopanib. Note: At least 4 weeks must be available between the diagnostic biopsy and surgery to allow for 1) one-week delay following the diagnostic biopsy prior to first dose of study drug, 2) minimum of 2 weeks on study drug, and 3) minimum of 1 week wash out prior to surgery. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. * Histologically- or cytologically-confirmed Stage IA, IB, IIA, or IIB (to T2) NSCLC according to the International Staging System \[Mountain, 1997\] and must be scheduled for surgical resection. * Disease must consist of only a single lesion and must be measurable according to high-resolution CT scan-assisted volumetric measurement \[Yankelevitz, 2000, Armato, 2004\]. In addition to the measurable single lesion, other small indeterminate nodules may also be present * No approved or investigational anti-cancer therapy concurrently or in the 6 months prior to start of study drug, including surgery, tumor embolization, chemotherapy, radiation therapy, immunotherapy, hormone therapy, biologic therapy, or anti-angiogegneic therapy (e.g., inhibitors of VEGF or VEGFR). * Fresh tumor biopsy for apoptosis and relevant biomarker analyses must be obtained within 30 to 8 days of first dose of study drug and must be available for all subjects prior to start of pazopanib treatment. * System (Laboratory Values) * Hematologic:Absolute neutrophil count (ANC)(≥ 1.5 X 109/L), Hemoglobin (≥9 g/dL), Platelets(≥100 X 109/L) * Hepatic:Albumin (≥ 2.5 g/dL), Serum bilirubin(≤1.5 X upper limit of normal (ULN) unless due to Gilbert's syndrome), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (≤2.0 X ULN) Renal:Serum creatinine(≤1.5 mg/dL) OR Calculated creatinine clearance (≥30 mL/min), Urine Protein (Trace or +1 by dipstick urinalysis or \<1.0 gram determined by 24-hour urine protein analysis.) * Ability to swallow and retain oral medication * A female is eligible to enter and participate in this study if she is of: * Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had: * A hysterectomy * A bilateral oophorectomy (ovariectomy) * A bilateral tubal ligation * Is post-menopausal: * Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value \>40mIU/mL and an estradiol value \<40pg/mL (\<140pmol/L). * Subjects must discontinue HRT prior to study enrollment due to the potential for inhibition of cytochrome P450 enzymes that metabolize estrogens and progestins. For most forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and determination of menopausal status; length of this interval depends on the type and dosage of HRT. If a female subject is determined not to be post-menopausal, they must use adequate contraception, as defined immediately below. * Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. GlaxoSmithKline (GSK)-acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow: * An intrauterine device with a documented failure rate of less than 1% per year * Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female * Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product * Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide) Note: Oral contraceptives are not reliable due to potential drug-drug interactions. * Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 15 days following the last dose of study drug. * A male with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception or abstinence during the study. * Subjects must complete all screening assessments as outlined in the protocol
Exclusion criteria
* Active malignancy or any malignancy in the 6 months prior to first dose of study drug. * Concurrent disease or condition that would make the subject inappropriate for study participation including (1) any unresolved or unstable, serious toxicity from prior administration of another investigational drug, (2) any serious medical disorder that would interfere with the subject's safety, obtaining informed consent, or compliance with all study related procedures. * Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to beginning therapy, or anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedures such as fine needle aspiration or core biopsy within 1 week prior to beginning therapy are also excluded. * History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis. Routine screening with CNS imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) is required only if clinically indicated. * History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C. * History of hemoptysis * Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded * Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal condition increasing the risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to beginning therapy * Active or uncontrolled infection * Concurrent treatment with an investigational agent or participation in another clinical trial. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib * Has taken/received prohibited medications within specified timeframes. * Corrected QT interval (QTc) prolongation defined as QTc interval \>480 msecs * History of any one of the following cardiac conditions within the past 6 months: cardia angioplasty or stenting, myocardial infarction,or unstable angina * History of cerebrovascular accident within the past 6 months * Has Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system. * Poorly controlled hypertension (mean systolic blood pressure (SBP) of ≥140mmHg, or mean diastolic blood pressure (DBP) of ≥ 90mmHg. Note: Initiation or adjustment of anti-hypertensive medication(s) is permitted prior to study entry. The blood pressure (BP) must be re-assessed on two occasions that are separated by a minimum of 5 minutes. The mean SBP/DBP values from both BP assessments must be \< 140/90mmHg in order for a subject to be eligible for the study. * History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. calf vein thrombosis). * Presence of any non-healing wound, fracture, or ulcer, or the presence of symptomatic peripheral vascular disease. * Receiving therapeutic warfarin or heparin as a concurrent medication. Note: prophylactic low-dose warfarin (less than or equal to 2 mg daily) is permitted. * Evidence of bleeding diathesis or coagulopathy * Pregnant or lactating female
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Tumor Shrinkage Based on Change in Tumor Volume | Baseline to at least two weeks or at most six weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving a >=60% Reduction in Tumor Metabolic Activity Determined as Standard Uptake Value (SUV) | Baseline to at least two weeks or at most six weeks | 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. |
| Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values | Baseline to at least three weeks and at most 8 weeks | 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. |
| Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Baseline to at least three weeks and at most 8 weeks | 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. |
| Number of Participants With the Indicated Change From Baseline in Systolic and Diastolic Blood Pressure | Baseline to at least three weeks and at most 8 weeks | 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. |
| Number of Cells Exhibiting Apoptosis in Participant Samples | Baseline to at least three weeks and at most 8 weeks (surgery date) | 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. |
| Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | Baseline to at least three weeks and at most 8 weeks (surgery date) | 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. |
| Number of Participants Achieving a Clinical Response Based on RECIST | Baseline to at least two weeks or at most six weeks | 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. |
| Intratumoral Levels of Specific Biomarkers | Baseline tumor biopsy | 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. |
| Plasma Levels of Lactate Dehydrogenase-5 (LDH5) | Baseline to at least three weeks and at most 8 weeks | 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. |
| Genetic Variations in Germline DNA | Baseline | 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. |
| Semiquantitative Levels of Staining in Pre-treatment Tumor Biopsies (e.g. VEGF, VEGFR-1,VEGFR-2). | Entire study interval | Analysis not performed as part of study. Appropriate material was not available for analysis. |
| Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Baseline to at least two weeks and at most 6 weeks | 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. |
| Gene Mutations in Pre- or Post-treatment Tumor Biopsies | Baseline to at least three weeks and at most 8 weeks (surgery date) | 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. |
Countries
Israel, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib 800 mg Pazopanib 800 milligrams (mg) (tablets) administered orally once a day for a minimum of 2 and a maximum of 6 weeks | 35 |
| Total | 35 |
Baseline characteristics
| Characteristic | Pazopanib 800 mg |
|---|---|
| Age Continuous | 63.7 years STANDARD_DEVIATION 8.84 |
| Race/Ethnicity, Customized African American/African Heritage | 3 participants |
| Race/Ethnicity, Customized Asian | 4 participants |
| Race/Ethnicity, Customized White | 28 participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 35 |
| serious Total, serious adverse events | 7 / 35 |
Outcome results
Primary
Number of Participants Achieving Tumor Shrinkage Based on Change in Tumor Volume
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.
Time frame: Baseline to at least two weeks or at most six weeks
Population: Safety Population: all participants who received at least one dose of pazopanib
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg | Number of Participants Achieving Tumor Shrinkage Based on Change in Tumor Volume | Responder | 2 participants |
| Pazopanib 800 mg | Number of Participants Achieving Tumor Shrinkage Based on Change in Tumor Volume | Non-responder | 33 participants |
95% CI: [0.7, 19.2]
Secondary
Gene Mutations in Pre- or Post-treatment Tumor Biopsies
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.
Time frame: Baseline to at least three weeks and at most 8 weeks (surgery date)
Population: Safety Population: all participants who received at least one dose of pazopanib
Secondary
Genetic Variations in Germline DNA
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.
Time frame: Baseline
Population: Safety Population: all participants who received at least one dose of pazopanib
Secondary
Intratumoral Levels of Specific Biomarkers
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.
Time frame: Baseline tumor biopsy
Population: Safety Population: all participants who received at least one dose of pazopanib
Secondary
Number of Cells Exhibiting Apoptosis in Participant Samples
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.
Time frame: Baseline to at least three weeks and at most 8 weeks (surgery date)
Population: Tissue from Safety Population: all participants who received at least one dose of pazopanib
Secondary
Number of Participants Achieving a >=60% Reduction in Tumor Metabolic Activity Determined as Standard Uptake Value (SUV)
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.
Time frame: Baseline to at least two weeks or at most six weeks
Population: Safety Population: all participants who received at least one dose of pazopanib
Secondary
Number of Participants Achieving a Clinical Response Based on RECIST
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.
Time frame: Baseline to at least two weeks or at most six weeks
Population: Safety population: all participants who received at least one dose of pazopanib
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg | Number of Participants Achieving a Clinical Response Based on RECIST | Progressive disease | 1 participants |
| Pazopanib 800 mg | Number of Participants Achieving a Clinical Response Based on RECIST | Complete response | 0 participants |
| Pazopanib 800 mg | Number of Participants Achieving a Clinical Response Based on RECIST | Partial response | 3 participants |
| Pazopanib 800 mg | Number of Participants Achieving a Clinical Response Based on RECIST | Stable disease | 31 participants |
95% CI: [1.8, 23.1]
Secondary
Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values
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.
Time frame: Baseline to at least three weeks and at most 8 weeks
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Alanine aminotransferase, Grade 2 (>2.5-5.0 ULN) | 6 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Alanine aminotransferase, Gr 3 (>5.0-20.0 x ULN) | 2 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Hyperglycemia, Grade 2 (>160-250 mg/dL) | 4 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Alkaline phosphatase, Grade 2 (>2.5-5.0 x ULN) | 2 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Aspartate aminotransferase, Gr 2 (>2.5-5.0 x ULN) | 3 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Aspartate aminotransferase, Gr 3 (>5.0-20.0 x ULN) | 1 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Total bilirubin, Grade 3 (>3.0-10.0 x ULN) | 1 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Hypocalcemia, Grade 4 (<6.0 mg/dL) | 1 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values | Hyperkalemia, Grade 3 (>6.0-7.0 mmol/L) | 1 participants |
Secondary
Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values
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.
Time frame: Baseline to at least three weeks and at most 8 weeks
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values | White blood cells, Grade 3 ( <2.0-1.0 x 10^9/L) | 0 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values | Lymphocytes, Grade 2 (<0.8-0.5 x 10^9/L) | 5 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values | Lymphocytes, Grade 3 (<0.5-0.2 x 10^9/L) | 1 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values | Neutrophils, Grade 2 (<1.5-1.0 x 10^9/L) | 4 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values | Neutrophils, Grade 3 (<1.0-0.5 x 10^9/L) | 1 participants |
| Pazopanib 800 mg | Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values | White blood cells, Grade 2 (<3.0-2.0 x 10^9/L) | 3 participants |
Secondary
Number of Participants With the Indicated Change From Baseline in Systolic and Diastolic Blood Pressure
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.
Time frame: Baseline to at least three weeks and at most 8 weeks
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg | Number of Participants With the Indicated Change From Baseline in Systolic and Diastolic Blood Pressure | Systolic, BL: 90-139 mmHg; up to 140-169 mmHg | 12 participants |
| Pazopanib 800 mg | Number of Participants With the Indicated Change From Baseline in Systolic and Diastolic Blood Pressure | Diastolic, BL: 50-89 mmHg; up to 90-109 mmHg | 4 participants |
Secondary
Plasma Levels of Lactate Dehydrogenase-5 (LDH5)
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.
Time frame: Baseline to at least three weeks and at most 8 weeks
Population: Safety Population: all participants who received at least one dose of pazopanib
Secondary
Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes
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.
Time frame: Baseline to at least three weeks and at most 8 weeks (surgery date)
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | PDGF-beta | 4.075 ratio | Standard Deviation 1.504 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | KIT | 1.394 ratio | Standard Deviation 1.621 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | Fibroblast growth factor 7 | 3.679 ratio | Standard Deviation 1.31 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | Thrombospondin 1 | 3.234 ratio | Standard Deviation 1.56 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | PDGF-alpha | 10.350 ratio | Standard Deviation 2.433 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | VEGF A | -1.129 ratio | Standard Deviation 0.852 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | VEGF C | 3.232 ratio | Standard Deviation 1.547 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | VEGF D | 3.569 ratio | Standard Deviation 2.537 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | VEGFR-1 | 4.258 ratio | Standard Deviation 1.792 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | VEGFR-2 | 1.943 ratio | Standard Deviation 1.572 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | Angiopoietin 1 | 4.901 ratio | Standard Deviation 2.066 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | Angiopoietin 2 | 4.207 ratio | Standard Deviation 1.587 |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes | Transforming growth factor 3 | 3.054 ratio | Standard Deviation 1.28 |
p-value: 0.0028t-test, 2 sided
p-value: 0.0324t-test, 2 sided
p-value: 0.0082t-test, 2 sided
p-value: 0.0082t-test, 2 sided
Secondary
Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins
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.
Time frame: Baseline to at least two weeks and at most 6 weeks
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Vascular endothelial growth factor receptor | -1.35 ratio |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Placental growth factor | 18.04 ratio |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Interferon inducible cytokine | 1.60 ratio |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Cutaneous T-cell attracting chemokine | 1.12 ratio |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Stromal cell-derived factor 1 | 1.08 ratio |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Monokine induced by interferon gamma | 1.33 ratio |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Tumor necrosis factor ligand | 1.05 ratio |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Interferon alpha 2 | 1.04 ratio |
| Pazopanib 800 mg | Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins | Vascular endothelial growth factor | -1.01 ratio |
p-value: <0.01Wilcoxon (Mann-Whitney)
p-value: <0.01Wilcoxon (Mann-Whitney)
p-value: 0.00024Wilcoxon (Mann-Whitney)
p-value: 0.0029Wilcoxon (Mann-Whitney)
p-value: 0.0062Wilcoxon (Mann-Whitney)
p-value: 0.0069Wilcoxon (Mann-Whitney)
p-value: 0.0093Wilcoxon (Mann-Whitney)
p-value: 0.021Wilcoxon (Mann-Whitney)
p-value: 0.326Wilcoxon (Mann-Whitney)
Secondary
Semiquantitative Levels of Staining in Pre-treatment Tumor Biopsies (e.g. VEGF, VEGFR-1,VEGFR-2).
Analysis not performed as part of study. Appropriate material was not available for analysis.
Time frame: Entire study interval
Population: Safety Population: all participants who received at least one dose of pazopanib