pazopanib_NCRCC,Ph2 STUDY

• Progression-free survival [ Time Frame: 2years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: 2years ] [ Designated as safety issue: No ]
• Number of Adverse Events [ Time Frame: 2years ] [ Designated as safety issue: Yes ]
• Exploratory analysis [ Time Frame: 2years ] [ Designated as safety issue: No ]
  c-kit protein expression,the relationship between efficacy and tumoral fibroblast growth factor receptor 1 gene amplification (FISH), the relationship between efficacy and MET mutation in papillary carcinoma, the relationship between efficacy and microvessel density and/or VEGF-R2 expression in tumor by immunohistochemistry

• Progression-free survival [ Time Frame: 2years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: 2years ] [ Designated as safety issue: No ]
• safety [ Time Frame: 2years ] [ Designated as safety issue: Yes ]
• Exploratory analysis [ Time Frame: 2years ] [ Designated as safety issue: No ]
  c-kit protein expression,the relationship between efficacy and tumoral fibroblast growth factor receptor 1 gene amplification (FISH), the relationship between efficacy and MET mutation in papillary carcinoma, the relationship between efficacy and microvessel density and/or VEGF-R2 expression in tumor by immunohistochemistry

Recent advances in understanding the biology and genetics of renal cell carcinoma (RCC) have led to major therapeutic implications. Von Hippel-Lindau (VHL) gene inactivation, present in the majority of sporadic forms of RCC, leads to a defective VHL protein, followed by an active transcription of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), c-kit, and others. However, the concept of VHL inactivation in RCC and the subsequent malignant phenotype is almost exclusively seen in patients with clear cell histology.

The data about efficacy of VEGF receptor inhibitors for non-clear cell RCC (NCRCC) is rare until now. Recently, however, sunitinib and sorafenib showed its worth for NCRCC in extended access programs.1-3 Although it is not certain, the underlying mechanism of their action might lie in that papillary, chromophobe, and sarcomatoid type overexpress c-kit, which is also a target of both drugs and could therefore provide a therapeutic target for non-clear cell subtypes.4-7 Pazopanib is also a potent and selective, orally available, small molecule inhibitor of VEGFR-1,-2, and -3, PDGF-α, PDGF-β, and c-kit tyrosine kinases. It has been validated and licensed for advanced clear cell RCC (CCRCC).8 However, there is very few data about its efficacy for NCRCC.

In this study, we try to evaluate the efficacy of pazopanib in metastatic NCRCC.

Inclusion Criteria:

1. Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow up. Procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol.
2. Age ≥ 18 years or legal age of consent if greater than 18 years
3. Histologically or cytologically confirmed confirmation of renal cell carcinoma with less than 50% of a clear cell histologic component, e.g., papillary type, chromophobe type, collecting duct, or unclassified cell types should be major component (≥ 50%) (including sarcomatoid type without any component of clear cell carcinoma)
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 -1
5. At least one measurable lesion by RECIST 1.1, which has not been affected previously with radiotherapy
6. Locally advanced or metastatic (stage IV) disease not amenable to surgery, radiotherapy, or combined modality therapy with curative intent
7. Received no prior systemic therapy including VEGFR tyrosine kinase therapy (sunitinib, sorafenib, bevacizumab or other VEGF TKI), MET inhibitor, or c-kit inhibitor for advanced RCC

8. Adequate organ system function as defined in the Table Definitions for Adequate Organ Function System Laboratory Values Hematology

   -Absolute neutrophil count (ANC):1.5 X 109/L

   • Hemoglobina:9 g/dL (5.6 mmol/L)
   • Platelets:100 X 109/L
   • Prothrombin time (PT) or international normalized ratio (INR):1.2 X ULN
   • Activated partial thromboplastin time (aPTT):1.2 X ULN
   • Total bilirubin:1.5 X ULN
   • Alanine amino transferase (ALT) and Aspartate aminotransferase (AST):2.5 X ULN
   • Serum creatinine:1.5 mg/dL (133 µmol/L) Or, if >1.5 mg/dL: Calculated creatinine clearance (ClCR):50 mL/min
   • Urine Protein to Creatinine Ratio :<1

9. A female is eligible to enter and participate in this study if she is of:

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

      • A hysterectomy

      • A bilateral oophorectomy (ovariectomy)
      • A bilateral tubal ligation
      • Is post-menopausal Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).

      Subjects using HRT must have experienced total cessation of menses for >= 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT

   2. Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, 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 follow:

      • Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product

      • Oral contraceptive, either combined or progestogen alone

      • Injectable progestogen
      • Implants of levonorgestrel
      • Estrogenic vaginal ring
      • Percutaneous contraceptive patches
      • Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year
      • Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject
      • Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository) Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

      Exclusion Criteria:

      • 1. Patients who have 50% or more for component of clear cell type renal cell carcinoma 2. Prior malignancy cannot be included excepting for these cases: Subjects who have had another malignancy and have been disease-free for 2 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma and follicular or papillary thyroid cancer are eligible.

        3. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic for 4 weeks, and have had no requirement for steroids or anti-seizure medication for 2 weeks prior to first dose of study drug. Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases.

        4. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:

        • Active peptic ulcer disease

        • Known intraluminal metastatic lesion/s with risk of bleeding

        • 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.

        5. 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. 6. Presence of uncontrolled infection. 7. Corrected QT interval (QTc) > 480 msecs using Bazett's formula 8. 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 9. Class II, III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) 10. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of =140 mmHg or diastolic blood pressure (DBP) of = 90mmHg].

      Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement. These three values should be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be <140/90 mmHg (OR 150/90 mm Hg, if this criterion is approved by Safety Review Team) in order for a subject to be eligible for the study.

      11. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 2 months.

      Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 2 weeks are eligible 12. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major) (RFA or cryoablation is not major surgery).

      13. Evidence of active bleeding or bleeding diathesis. 14. Hemoptysis in excess of 2.5 mL per cough (or one half teaspoon) within 8 weeks of first dose of study drug (small amount of blood tinged sputum can be acceptable).

      15. 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.

      16. Unable or unwilling to discontinue use of prohibited medications listed in Appendix C Section XX for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study (Appendix C) (Section XX).

      17. Treatment with any of the following anti-cancer therapies:

      • radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib / RFA or cryoablation within 14 days prior to the first dose of pazopanib OR

      • Prior treatment history with angiogenesis inhibitors such as sunitinib, sorafenib, bevacizumab is not permitted (prior MET inhibitor or c-kit inhibitor are also not permitted)

      • Prior immunotherapy (last dose should complete 6 weeks before enrollment)) or mTOR inhibitor (last dose should complete 3 weeks before enrollment), such as interferon, interleukin-2, everolimus, or temsirolimus, is acceptable for the enrollment.

      • Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia.

      18. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage.