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

Study Overview
=================
Brief Summary
-----------------
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.

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

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

Intervention / Treatment
-----------------
* Drug: GW786034
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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: 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). 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.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pazopanib<br>All patients receive GW786034. At week 12, some subjects will be randomized based on response (SD) and the others will remain on drug. After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib. | Drug: GW786034<br>* All patients receive GW786034. At week 12, some subjects will be randomized based on response (SD) and the others will remain on drug. After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib.<br>|
| Placebo Comparator: Placebo<br>All patients receive GW786034. At week 12, some subjects will be randomized based on response (SD) and the others will remain on drug. After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib. | Drug: Placebo<br>* All patients receive GW786034. At week 12, some subjects will be randomized based on response (SD) and the others will remain on drug. After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response by RECIST Criteria | The overall response is the number of participants who experience a confirmed complete (CR) or partial response (PR) of the total analysis population. Per the Response Evaluation Criteria In Solid Tumors (RECIST): CR = all detectable tumor has disappeared, PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum, Progressive disease (PD) = a >=20% increase in target lesions, Stable Disease = small changes that do not meet previously given criteria. | Baseline to Response (up to 2.40 years). Assessments occurred at Week 12 and every 8 weeks thereafter. | 
| Stable Disease at 12 Weeks - Interim Analysis of First 60 Participants | The protocol called for an interim analysis of the first 60 participants to determine their status at Week 12, and to determine the number of participants with stable disease, although all categories were reported. Stable disease is defined as a disease that has not grown enough to be called progressive disease and has not shrunk enough to be called partial/complete response. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Using RECIST criteria: date of first confirmed tumor response (CR or PR) to date of tumor progression or to death. Participants who did not progress or die were censored at their last radiologic assessment. Only participants who had a response were analyzed. | First response until progression of disease (up to 2.40 years). Assessments occurred at Week 12 and every 8 weeks thereafter. | 
| Progression-free Survival | Progression-free Survival is defined as the interval between the first day of treatment and the earliest date of disease progression or death due to any cause, whichever occurred first. Progressive disease is defined as a >=20% increase in target lesions. | From the first day of treatment to the earliest date of disease progression or death due to any cause (up to 2.40 years) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Angiogenesis, Renal Cell Carcinoma, Solid tumors, Pazopanib(GW786034)