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

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Non-Small Cell Lung Cancer, Lung Cancer, Non-Small Cell

Intervention / Treatment
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* Drug: Pazopanib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>800 mg pazopanib oral daily | Drug: Pazopanib<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to at least two weeks or at most six weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to at least two weeks or at most six weeks | 
| 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. | Baseline to at least two weeks or at most six weeks | 
| 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. | Baseline to at least three weeks and at most 8 weeks | 
| 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. | Baseline to at least three weeks and at most 8 weeks | 
| 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. | Baseline to at least three weeks and at most 8 weeks | 
| 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. | Baseline to at least three weeks and at most 8 weeks (surgery date) | 
| 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. | Baseline to at least three weeks and at most 8 weeks (surgery date) | 
| 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. | Baseline to at least three weeks and at most 8 weeks (surgery date) | 
| 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. | Baseline tumor biopsy | 
| 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. | Baseline to at least three weeks and at most 8 weeks | 
| 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. | Baseline | 
| 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. | Entire study interval | 
| 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. | Baseline to at least two weeks and at most 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pazopanib, I-ELCAP, non-small cell lung cancer, antiangiogenesis, NSCLC, GW786034