A randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy and safety of pazopanib as adjuvant therapy for subjects with localized or locally advanced RCC following nephrectomy

Study Objective

Primary Objective

The primary objective of the study is to evaluate disease-free survival (DFS) with pazopanib as compared to placebo as adjuvant therapy for subjects with localized/locally advanced RCC following nephrectomy.

Secondary Objective(s)

Efficacy

The secondary efficacy objectives include:

• To evaluate OS in subjects treated with pazopanib compared to those treated with placebo
• To evaluate DFS rates at yearly time points (eg 1 year, 2 years, etc) in subjects treated with pazopanib as compared to those treated with placebo.

Safety

The safety objective is to evaluate safety and tolerability in subjects treated with pazopanib compared to those treated with placebo.

Health Outcomes

The health outcome objective is to evaluate health-related quality of life (HRQoL) in subjects treated with pazopanib compared to those treated with placebo. The HRQoL assessments will be to determine if patient’s overall HRQoL/functional status is maintained during treatment with pazopanib versus placebo. Additionally, the extent of worsening from baseline and time to worsening in HRQoL/RCC symptoms and EuroQoL EQ-5D (EQ-5D) utilities for pazopanib compared with placebo will be determined for recurrence period.

Participation conditions

Inclusion Criteria

Subjects eligible for enrolment in the study must meet all of the following criteria:

• Signed written informed consent
• Diagnosis of RCC with clear-cell or predominant clear-cell histology.
• Subjects with non-metastatic disease (M0) fulfilling any of the following combinations of pathologic staging based on AJCC TNM staging version 2010 and Fuhrman nuclear grading
  • pT2, G3 or G4, N0; or,
  • pT3, Gany, N0; or, pT4, Gany, N0; or,
  • pTany, Gany, N1

In order to properly stratify subjects, it is required that the investigator designate the nodal status as either N0 or N1 according to the following criteria which will be captured in the eCRF:

N0 requires that a subject have no abnormal regional lymph nodes on preoperative scans or visualized at surgery, OR have regional lymph nodes biopsied with negative (no tumor present) result.
N1 requires that a subject have regional lymph nodes biopsied with positive (tumor present) result.

• Fulfill all of the following criteria of disease-free status at baseline:
  • Had complete gross surgical resection of all RCC via radical or partial nephrectomy using either open or laparoscopic technique.
  • Baseline imaging of chest, abdomen and pelvis shows no metastasis or residual tumor lesions as confirmed centrally by an independent radiologist.

• Received no prior adjuvant or neo-adjuvant treatment for RCC.
• Recovered from nephrectomy: any surgery related toxicities should be reduced to ≤ grade 1 per NCI CTCAE
• Karnofsky performance scale (KPS) of ≥ 80.
• Adequate organ system function
• Male or female, age ≥ 18 years

Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled in the study:

• History of another malignancy.
  Exception: Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
   
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
  • Active peptic ulcer disease
  • Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’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
     
• Active diarrhea of any grade
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
  • Malabsorption syndrome
  • Major resection of the stomach or small bowel
     
• History of human immunodeficiency virus (HIV) infection
• History of active hepatitis
• Presence of uncontrolled infection.
• 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
     
• History of Class III or IV congestive heart failure
• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months
• Corrected QT interval (QTc) > 480 milliseconds (msec)
• Poorly controlled hypertension, defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg.
• Evidence of active bleeding or bleeding diathesis
• 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
• Unable or unwilling to discontinue use of prohibited medications for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study treatment and for the duration of the study.
• Concurrent therapy given to treat cancer including treatment with an investigational agent or concurrent participation in another clinical trial involving anti-cancer investigational drug.
• Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or excipients that in the opinion of the investigator contraindicates their participation.
• Prior or current use of systemic anti-VEGF inhibitors, cytokines

Centre Hospitalier de Luxembourg