Safety and Efficacy of GW786034 (Pazopanib) In Metastatic Renal Cell Carcinoma
Condition: Carcinoma, Renal Cell
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Pazopanib; placebo
Intervention description: Oral pazopanib tablet 800 mg once daily continuously; matching placebo (800 mg tablet) once daily
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 435.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic; Anti-angiogenesis; GW786034; Pazopanib

Summary:

      To evaluate efficacy and safety of pazopanib compared to placebo in patients with locally
      advanced and/ or metastatic renal cell carcinoma (RCC). Approximately 350-400 eligible
      patients will be stratified and randomized in a 2:1 ratio to receive either 800 mg pazopanib
      once daily or matching placebo. The study treatment will continue until patients experience
      disease progression, unacceptable toxicity or death. Primary objective of the study is to
      evaluate and compare the two treatment arms for progression-free survival. Principal
      secondary objective is to evaluate and compare the two treatment arms with respect to overall
      survival. Other objectives are overall response rate [complete response (CR) + partial
      response (PR)], rate of CR + PR + 6 months stable disease, and the incidence, severity and
      causality of adverse events and serious adverse events. Safety and efficacy assessments will
      be regularly performed on all patients. An Independent Data Monitoring Committee will be
      established to monitor safety during the course of the study and to evaluate interim efficacy
      data on overall survival.
    

Eligibility criteria:

        Inclusion Criteria:

        A patient will be considered for inclusion in this study only if all of the following
        criteria apply:

          -  Signed written informed consent.

          -  Diagnosis of clear cell RCC that is predominantly clear cell histology. Note: cytology
             cannot be the only pathologic criteria to confirm clear cell RCC. Patients with tumor
             types that are interpreted as non-clear cell, e.g. papillary, are excluded.

          -  Locally advanced RCC (defined as disease not amenable to curative surgery or radiation
             therapy) or metastatic RCC (equivalent to Stage IV RCC according to American Joint
             Committee on Cancer (AJCC) staging.

          -  Note: If the metastatic disease is restricted to a solitary lesion, its neoplastic
             nature must be confirmed by histology or cytology. Cytology cannot be the only
             pathologic criteria to confirm clear cell RCC, but can be used in a patient with
             histologically confirmed clear cell RCC to confirm that metastatic disease is
             neoplastic in nature.

          -  Must have measurable disease, i.e. presenting with at least one measurable lesion per
             Response Evaluation Criteria in Solid Tumors (RECIST). A measurable lesion is defined
             as a lesion that can be accurately measured in at least one dimension with the longest
             diameter ≥ 20 mm using conventional techniques, or ≥ 10 mm with spiral CT scan.

          -  Note: Patient should be excluded if all baseline measurable lesions are within
             previously irradiated areas.

          -  Note: A patient must complete all the baseline disease assessments in order to be
             eligible. Baseline head, chest, abdominal and pelvic CT or MRI scans must be performed
             within 2 weeks prior to the first dose of study medication; baseline bone scan must be
             performed within 3 weeks of the first dose of study medication.

          -  Patients who have received only one prior systemic treatment for locally advanced or
             metastatic RCC with documented disease progression or documented treatment
             discontinuation due to unacceptable toxicity. This first-line systemic treatment must
             be cytokine based.

          -  Note: The first-line cytokine-based treatment can be interleukin-2 (IL-2) or
             interferon-α (INFα) monotherapy, IL-2 in combination with INF-α, IL-2 and/or INF-α in
             combination with chemotherapy, hormonal or other therapies excluding agents targeting
             angiogenesis pathways. Agents in a combination regimen can be given sequentially if
             the treatment sequence is pre-determined and the patient does not fail one agent prior
             to starting another.

          -  Note: Prior adjuvant or neo-adjuvant therapies are permitted excluding any agents that
             target vascular endothelial growth factor (VEGF) or VEGF receptors. The
             adjuvant/neo-adjuvant therapies should not be considered as first-line systemic
             treatment for advanced RCC.

        Or,

          -  Patients who have received no prior systemic therapy for advanced/metastatic RCC can
             be enrolled if under any of the following circumstances:

          -  Patients who live in countries or regions where there is no established standard
             first-line therapy for advanced/metastatic RCC or where there are barriers to the
             access of established therapies such as sunitinib, sorafenib, IFNα or IL-2.

          -  Patients who live in countries or regions where IL-2 or INF-α has been approved for
             the treatment of advanced/metastatic RCC, however, these agents are generally not
             recognized by the local clinical community as a standard treatment for
             advanced/metastatic RCC, or where the physician and the patient have determined that
             the available cytokine therapies are not an acceptable therapeutic option.

          -  Patients who have recurred following prior adjuvant or neo-adjuvant cytokine therapy
             for RCC are eligible to participate without receiving a first-line systemic treatment
             for locally advanced or metastatic RCC. These patients should be stratified as the
             first-line population.

          -  Male or female ≥ 18 years of age.

          -  A woman is eligible to 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 within 2 weeks of the
             first dose of study medication, 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 with a documented failure rate of less than 1% per year.

          -  Vasectomized partner who is sterile prior to the female patient'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).

          -  Oral contraceptives are not reliable due to the potential for drug-drug interactions.

          -  A man with a female partner of childbearing potential is eligible to enter and
             participate in the study if he is abstinent or uses a barrier method of contraception
             during the study.

          -  Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1

          -  Adequate baseline organ function defined as:

          -  Hematologic function:

        Absolute Neutrophil Count (ANC) ≥1 x 10^9/L Hemoglobin ≥ 9 g/dL Platelet ≥75 x 10^9/L

          -  Hepatic function:

        Total bilirubin ≥ 1.5 x Upper Limit of Normal (ULN) Aspartate Aminotransferase (AST) and
        Alanine Aminotransferase (ALT) ≥ 2 x ULN

          -  Renal function:

        Calculated creatinine clearance≥30 mL/min [See Section 14.6 Appendix 6] and

        ≥Urine protein is 0, trace, or +1 determined by dipstick urinalysis, or < 1.0 gram
        determined by 24-hour urine protein analysis.

          -  Note: A patient should first be screened with dipstick urinalysis. If urine protein is
             ≥2+, then a 24-hour urine protein must be assessed and patient will be excluded if
             24-hour urine protein is≥ 1.0 gram.

          -  Corrected serum calcium level within normal range per local clinical laboratory
             standard.

        Note: Patients with hypercalcemia should be treated until the corrected serum calcium level
        reaches the normal range.

          -  At least 4 weeks must have elapsed since the last surgery and 2 weeks must have
             elapsed since radiotherapy or the last systemic cytokine therapy.

          -  Complete recovery from prior surgery, and/or reduction of all AEs to Grade 1 from
             prior systemic therapy or radiotherapy.

          -  Note: In patients with prior radiotherapy, the steroid doses should be stable or
             decreasing for at least 2 weeks.

        Exclusion Criteria:

        A patient will not be eligible for inclusion in this study if any of the following criteria
        apply:

          -  Pregnant or lactating female.

          -  History of another malignancy.

          -  Note: Patients who have had another malignancy and have been disease-free for 5 years,
             or patients with a history of completely resected non-melanomatous skin carcinoma or
             successfully treated in situ carcinoma are eligible.

          -  History or presence of central nervous system (CNS) metastasis or leptomeningeal
             tumors as documented by CT or MRI scan, analysis of cerebrospinal fluid or
             neurological exam.

        Note: A baseline brain CT or MRI scan must be obtained in all patients within 2 weeks of
        the first dose of study medication.

          -  Malabsorption syndrome or disease that significantly affects gastrointestinal
             function, or major resection of the stomach or small bowel that could affect the
             absorption of pazopanib.

          -  Unable to swallow and retain orally administered medication.

          -  Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other
             gastrointestinal conditions with increased risk of perforation; history of abdominal
             fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior
             to beginning study treatment.

          -  History of human immunodeficiency virus infection.

          -  Presence of uncontrolled infection.

          -  Corrected QT interval (QTc) prolongation defined as QTc interval > 470 msecs.

          -  History of Class III or IV congestive heart failure according to New York Heart
             Association (NYHA) classification.

          -  History of any one of the following cardiac conditions within the past 6 months:

          -  Cardiac angioplasty or stenting, or

          -  Myocardial infarction, or

          -  Unstable angina.

          -  History of cerebrovascular accident within the past 6 months.

          -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140mmHg,
             or diastolic blood pressure (DBP) of ≥ 90mmHg].

          -  Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
             study entry. The blood pressure must be re-assessed on two occasions that are
             separated by a minimum of 24 hours. The mean SBP / DBP values from both blood pressure
             assessments must be < 140/90mmHg in order for a patient to be eligible for the study.

          -  History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. a
             calf vein thrombosis that is not treated).

        Note: Patients with recent DVT who are treated with therapeutic anti-coagulating agents
        (excluding therapeutic warfarin) for at least 2 weeks are eligible.

          -  Presence of any non-healing wound, fracture, or ulcer, or presence of symptomatic
             peripheral vascular disease.

          -  Evidence of bleeding diathesis or coagulopathy.

          -  Any serious and/or unstable pre-existing medical, psychiatric, or other conditions
             that could interfere with patient's safety, obtaining informed consent or compliance
             to the study.

          -  Has taken any prohibited medications within 14 days of the first dose of study
             medication.

          -  Current or prior use of an investigational anti-cancer drug within 4 weeks of start of
             study.

          -  Prior use of an investigational or licensed drug that targets VEGF or VEGF receptors
             (eg. bevacizumab, sunitinib, sorafenib, etc).