Prospective Translational Study Investigating Possible Molecular prEdictors of Resistance to First-Line pazopanIb

Study Overview
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Brief Summary
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This is a prospective, single-arm, monocentric translational study designed to evaluate possible biomarkers of resistance to the first line of therapy with pazopanib in patients with metastatic renal cell carcinoma (mRCC) who have not received systemic therapy in both the adjuvant and metastatic phases.

Detailed Description
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a prospective, single-arm, monocentric translational study

Official Title
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Prospective Translational Study Investigating Possible Molecular prEdictors of Resistance to First-Line pazopanIb in Metastatic reNal Cell Carcinoma

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Pazopanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form Unresectable advanced or metastatic renal cell carcinoma (RCC) with component of clear cell histology and/or component of sarcomatoid histology that has not been previously treated with any systemic agent, including treatment in the adjuvant setting Availability of a representative formalin-fixed paraffin-embedded fractional Fokker-Planck equation (FFPE) tumor specimen collected within 24 months of starting first-line pazopanib that enables the definitive diagnosis of renal cell carcinoma (RCC) (the archival specimen must contain adequate viable tumor tissue to enable candidate biomarkers status; the specimen may consist of a tissue block or at least 15 unstained serial sections; for core needle biopsy specimens at least two cores should be available for evaluation) Measurable disease as defined by RECIST v1.1 Age ≥18 years Hematology Absolute neutrophil count (ANC)≥1.5 X 109/L Hemoglobin ≥9 g/dL (5.6 mmol/L) Platelets ≥100 X 109/L Prothrombin time (PT) or international normalized ratio (INR)b ≤1.5 X upper limit of normal (ULN) Activated partial thromboplastin time (aPTT) ≤1.5 X upper limit of normal (ULN) Hepatic Total bilirubin ≤1.5 X upper limit of normal (ULN) Alanine amino transferase (ALT) and Aspartate aminotransferase (AST)c 2.5 X upper limit of normal (ULN) Patients with documented liver metastases <5 X upper limit of normal (ULN) Renal Serum creatinine 1.5 mg/dL (133 µmol/L) Or, if >1.5 mg/dL: Calculated creatinine clearance (ClCR) (reference appropriate appendix) ≥30 mL/min to ≥ 50 mL/min Urine Protein to Creatinine Ratio (UPC; appropriate appendix)<1 Or, 24-hour urine protein <1g - Eastern Cooperative Oncology Group (ECOG) performance Status 0-1 Exclusion Criteria: Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to: active peptic ulcer disease, known intraluminal metastatic lesion/s with risk of bleeding, inflammatory bowel disease (e.g. ulcerative colitis, Chrohn's disease), or other gastrointestinal conditions with increased risk of perforation, history of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment. History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) - Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 millimetre (s) of mercury (mmHg) or diastolic blood pressure (DBP) of ≥ 90 millimetre (s) of mercury (mmHg)]. Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement. These three values should be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be <140/90 millimetre (s) of mercury (mmHg) (OR 150/90 millimetre (s) of mercury (mm Hg), if this criterion is approved by Safety Review Team) in order for a subject to be eligible for the study - History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible Major surgery or trauma within 28 days prior to first dose of pazopanib and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery). Evidence of active bleeding or bleeding diathesis. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage Note: Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions). Large protruding endobronchial lesions in the main or lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi are allowed. Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in the wall of the bronchi are allowed. Recent hemoptysis (½ teaspoon of red blood within 8 weeks before first dose of study drug). Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures. Treatment with any of the following anti-cancer therapies: chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of Pazopanib

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pazopanib<br>Pazopanib 800 mg (2x400mg ) taken orally daily as per clinical practice | Drug: Pazopanib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A panel of possible predictive candidate biomarkers of resistance to anti-angiogenic targeted tyrosine kinase inhibitor (TKI) | using next-generation sequencing (NGS) methods for future research. This will be done by within-patient comparison of metastatic tissue samples taken on commencement of first-line pazopanib, and secondly on development of TKI resistance | 18 months | 
| The Overall Response Rate (ORR) | evaluate per RECIST v.1.1 criteria in mRCC patients treated with first-line pazopanib in order to either correlate circulating angiogenic factors (CAFs) levels and gene candidate biomarkers status to clinical outcome when resistance develops | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of other protein markers circulating in blood, | To obtain serial blood samples from patients whilst they are being treated with pazopanib | 18 months | 
| compare the frequency of previously defined promising circulating predictive biomarkers for pazopanib treatment | between blood samples taken at commencement of therapy (baseline) and at the time of progressive disease (PD) as per RECIST 1.1 criteria as well as changes of interleukin 8 (IL-8), c-Met and hematopoietic growth factor (HGF) expression between metastatic tumour tissue samples in order to better understand changes in the tumor and in the levels of circulating angiogenic factors as resistance develops. | 18 months | 
| Collect Data | prospective and retrospective demographic, clinical and pathological data on patients who enter the study, enabling current and future correlation of biomarkers to clinical outcomes | 18 months | 
| Perform subgroup analyses | comparing the tissue and blood biomarkers identified in patients who developed secondary resistance with those biomarkers identified in patients who have primary resistance. | 18 months |