GW786034 In Subjects With Locally Recurrent Or Metastatic Clear Cell Renal Cell Carcinoma

A Phase II Study of GW786034 Using a Randomised Discontinuation Design in Subjects With Locally Recurrent or Metastatic Clear-Cell Renal Cell Carcinoma

Phase II, multi-center, two-stage study utilising a randomised discontinuation design to evaluate the safety and efficacy of GW786034 (pazopanib) in adult subjects with locally recurrent or metastatic clear-cell Renal Cell Carcinoma (RCC). After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib.

Inclusion criteria:

• Histologically or cytologically confirmed diagnosis of Renal Cell Carcinoma of predominantly clear-cell histology (excluding chromophobe, papillary, collecting duct, and undifferentiated tumors) which is metastatic or locally recurrent
• Either no prior systemic therapy or failed only 1 prior cytokine-based or bevacizumab-based therapy
• Evidence of documented measurable disease by RECIST criteria
• Male or female at least 21 years of age

A woman is eligible to enter and participate in the study if she is of:

1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who:

   • Has had a hysterectomy,
   • Has had a bilateral oophorectomy (ovariectomy),
   • Has had a bilateral tubal ligation,
   • Is post-menopausal (total cessation of menses for >= 1 year).

2. Childbearing potential, has a negative serum pregnancy test at Screening Period and serum or urine pregnancy test at Day1, and agrees to use adequate contraception. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:

   • An intrauterine device (IUD) 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 investigation product, through the clinical trial, 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).

A man with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception (e.g. condom) or abstinence during the study and for 28 days following the last dose of investigational drug.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
• Adequate bone marrow function.
• Adequate hepatic function.
• Adequate renal function.
• Adequate PT/PTT or INR/aPTT.
• Able to swallow and retain oral medications.
• Written informed consent.

Exclusion criteria:

• Received prior non-cytokine or non-bevacizumab therapies .
• Received chemotherapy for renal cell carcinoma.
• Have had any major surgery, radiotherapy, or immunotherapy within the last 28 days and/or not recovered from prior therapy.
• History of hypercalcemia within two months of start of therapy.
• Patients who are pregnant or lactating.
• Poorly controlled hypertension.
• QTc prolongation defined as a QTc interval ≥ 480 msecs or other significant ECG abnormalities.
• Has Class II, III or IV heart failure as defined by the New York Heart Association functional classification system. A subject who has a history of Class II heart failure and is asymptomatic on treatment may be considered eligible.
• Any history of cerebrovascular accident [CVA].
• History of myocardial infarction, admission for unstable angina, cardiac angioplasty or stenting within the last 12 weeks.
• History of venous thrombosis in last 12 weeks.
• Current use of therapeutic warfarin.
• Use of antiplatelet agents other than aspirin (≤ 325 mg/day).
• Leptomeningeal or brain metastases.
• Prior history of malignancies other than renal cell carcinoma (except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or the subject has been free of any other malignancies for > 5 years).
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with subject safety or obtaining informed consent.
• History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism or excretion of study drugs. Has any unresolved bowel obstruction or diarrhea.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
• Is on any specifically prohibited medication or requires any of these medications during treatment with GW786034.