Neoadjuvant Pazopanib in Renal Cell Carcinoma

• Recurrence Free Survival (RFS) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  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.
• Altered surgical approach after treatment with pazopanib [ Time Frame: 14 weeks ] [ Designated as safety issue: No ]
  Determine if neoadjuvant treatment with pazopanib alters the planned surgical approach of the urologist, per documented radiographic (CT) response.
• Number of participants with adverse events [ Time Frame: 14 weeks ] [ Designated as safety issue: Yes ]
  Identify any safety issues in subjects treated with pazopanib, neoadjuvantly, followed by nephrectomy.
• Predictive molecular markers in response to treatment with pazopanib [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  To assess the correlation between the expression of biomarkers and CT scan response. Patients are considered as responders when objective response (partial or complete response) is shown on CT scan and measured by RECIST version 1.1

This study will be a single arm phase II clinical trial of 12 weeks of daily, oral neo-adjuvant pazopanib prior to nephrectomy in 40 evaluable patients with histologically confirmed localized renal cell carcinoma (RCC).

The primary objective of this study is to determine the objective response rate Complete Response + Partial Response(CR+PR) associated with neoadjuvant pazopanib at 12 weeks as defined via 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).

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
• ECOG Performance status of 0-1
• Adequate organ function
• Serum calcium, magnesium, potassium within normal limits
• 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 ≥ 90mmHg 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 QTc>480 msec or other clinically significant baseline ECG abnormality