Neoadjuvant Pazopanib in Renal Cell Carcinoma

Study Overview
=================
Brief Summary
-----------------
This study will be a single arm phase II clinical trial of 8 weeks of daily, oral neo-adjuvant pazopanib prior to nephrectomy in 39 evaluable patients with histologically confirmed localized renal cell carcinoma (RCC).

Detailed Description
-----------------
The primary objective of this study is to determine the objective response rate Complete Response + Partial Response(CR+PR) associated with neoadjuvant pazopanib at 8 weeks as defined via Response Evaluation Criteria in Solid Tumors (RECIST1.1). The investigators will also estimate the recurrence free survival (RFS), specifically the 1 and 2 year rates, with recurrence defined via RECIST1.1, and characterize the safety issues. Finally, this study also includes a number of exploratory analyses designed to evaluate potential correlations between RFS and; serum levels of cytokine and angiogenesis factor (CAF).

Official Title
-----------------
Neoadjuvant Pazopanib: A Phase II Study to Evaluate the Effect on Disease Response and Recurrence and to Establish Predictive Biomarkers of Drug Activity in Renal Cell Carcinoma

Conditions
-----------------
Renal Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: Pazopanib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years with radiographic evidence of nonmetastatic renal cell carcinoma Histological verification of clear cell renal cell carcinoma (-Clinical stage 2 (7 cm) or greater with localized disease No evidence of extranodal metastatic disease Appropriate candidate for surgery The Eastern Cooperative Oncology Group (ECOG) Performance status of 0-1 Adequate organ function Serum calcium, magnesium, potassium within normal limits, or if outside of normal limits, must be deemed clinically insignificant by the Investigator. No known coagulopathy Ability to read and follow instructions Women of childbearing potential must have a negative serum pregnancy test performed within 14 days prior to the start of pazopanib treatment and both men and women must be willing to use adequate contraception. Able to provide written, informed consent Blood and urine samples must be provided from all subjects for biomarker analysis before and during treatment with pazopanib Exclusion Criteria Known or suspected allergy to pazopanib Inability to swallow or retain oral medication Prior malignancy Exception: Subjects who have had another malignancy and have been disease-free for three years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. Unable or unwilling to discontinue use of prohibited medications at least 7 days prior to the first dose of study drug and for the duration of the study. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. History of any one or more cardiovascular conditions within the past 6 months Hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg OR diastolic blood pressure (DBP) of ≥ 90 mmHg in spite of optimal medical management. Evidence of active bleeding or bleeding diathesis. Any serious and/or unstable pre-existing medical (especially hepatic disease), psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures. Prior 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). Pregnant or breastfeeding; breastfeeding may not resume for 14 days after the last dose of pazopanib Prior treatment with any of the following anti-cancer therapies for treatment of their RCC: radiation therapy, surgery or tumor embolization chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy Baseline Corrected QT Interval (QTc) >480 msec or other clinically significant baseline ECG abnormality

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single Arm Neoadjuvant Pazopanib<br>Pazopanib 800 mg PO once daily for 8 weeks | Drug: Pazopanib<br>* 800 mg orally once daily for 8 weeks, prior to nephrectomy<br>* Other names: Votrient;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Determine the objective response rate (CR+PR) using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 at 8 weeks after neoadjuvant treatment with pazopanib in patients with locally advanced renal cell carcinoma. Evaluation of Target Lesions using RECIST 1.1 Criteria: Complete response (CR)-Disappearance of all target lesions. Any pathological lymph node (LN) target or no must have decreased in short axis to <10mm. Partial response (PR)-At least a 30% decrease in the sum of the longest diameter (LD) of the target lesions taking as reference the baseline sum LD. | 8 weeks after neoadjuvant treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence Free Survival (RFS) | Estimate recurrence free survival (RFS) following neoadjuvant treatment with pazopanib followed by nephrectomy, specifically reporting the 1 year and 2 year rate estimates with their 95% confidence intervals. | 2 years | 
| Number of Participants Who Needed an Altered Surgical Approach After Treatment With Pazopanib | Determine if neoadjuvant treatment with pazopanib alters the planned surgical approach of the urologist, per documented radiographic (CT) response. | 14 weeks | 
| Number of Participants With Adverse Events Related to Treatment. | Identify any safety issues in subjects treated with pazopanib, neoadjuvantly, followed by nephrectomy. Number of patients that had adverse events reported that had an attribution of; possible, probable, or definite that are graded a 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event. | 9 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RCC, Renal Cell Carcinoma, Votrient, Pazopanib, Nephrectomy, Neoadjuvant, Phase II, LCCC 1028, Lineberger Comprehensive Cancer Center