Multicenter Dose-escalation Study of a Combination of Pazopanib and Bevacizumab in Patients With Metastatic Renal Cell Carcinoma or Others Advanced Solid Tumors

Inclusion Criteria:

* Age \>18 years.
* Dated and signed written informed consent.
* Histologically progressive mRCC or other advanced refractory histologically or cytologically confirmed solid tumors. In mRCC situation, only patients who have received no prior therapy or who have failed only one prior systemic therapy (except tyrosine kinase inhibitors) are allowed; for patients with other advanced refractory solid tumors, no more than three prior systemic therapy regimens (except tyrosine kinase inhibitors) are permitted.
* ECOG performance status of 0 or 1.
* At least one measurable site of disease as defined by RECIST criteria 1.1. based on investigator's assessment.
* Adequate bone marrow function: absolute neutrophil count \>=1.5 x 109/L, platelet count \>= 100 x 109/L, and hemoglobin \>= 9 g/dL.
* Adequate liver function: AST/ALT \<= 2 x upper limit of normal (ULN) and total bilirubin in the normal values.
* Adequate coagulation function: prothrombin time (PT) or international normalized ratio (INR) \<=1.2 x ULN and activated partial thromboplastin time (APTT)\<=1.2x ULN.
* Adequate renal function: serum creatinine ≤ 1.5 mg/dL (133 µmol/L) or, if greater than 1.5 mg/dL: calculated creatinine clearance ≥ 50 mL/min.
* Absence of proteinuria confirmed by urinary dipstick test. If the dipstick test is twice positive, proteinuria will be quantified on a complete 24h urine sample: urine protein value must be \<1 g /L.
* Ability to swallow and retain oral medication.
* Adequate contraception methods.
* Mandatory affiliation with a health insurance company.

Exclusion Criteria:

* Prior Pazopanib treatment.
* Prior Bevacizumab treatment within 6 months prior to begin study treatment. Patients with any grade 3 or grade 4 toxicity during prior BVC therapy are not eligible.
* Prior treatment with any tyrosine kinase inhibitor.
* Concomitant participation to an other clinical study estimating a experimental agent.
* Patients with any haematological, renal, or neurological grade 3-4 toxicity during prior systemic therapy regimens.
* Patients with any liver injury grade 3-4 during prior systemic therapy regimens.
* Patients with squamous non-small cell lung carcinoma.
* Patients with high vascular and nephrologic risks \[uncontrolled hypertension while receiving appropriate medication (SBP ≥ 150 mmHg and DBP ≥ 90 mmHg), significant proteinuria, low creatinine clearance level…\].
* Patients with brain metastases.
* Clinically significant gastrointestinal abnormalities which might interfere with oral dosing:

Active peptic ulcer disease;kown intraluminal metastatic lesion/s with suspected bleeding;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 28 days prior to beginning study treatment; malabsorption syndrome; major resection of the stomach or small bowel.

* History of Gilbert's disease.
* Patients with chronic hepatitis.
* Any unstable or serious concurrent condition (i.e., presence of uncontrolled infection).
* Prolongation of corrected QT interval (QTc) \>480 msecs using Bazett's formula.
* History of any one of more of the following cardiovascular conditions within the past 6 months: Cardiac angioplasty or stenting; myocardial infarction; unstable angina; symptomatic peripheral vascular disease; coronary artery by-pass graft surgery; class III or IV congestive heart failure as defined by the New York Heart Association (NYHA); history of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulant agents (excluding therapeutic warfarin) for at least 6 weeks are eligible.

* Hemoptysis within 6 weeks of first dose of study drug.
* Evidence of active bleeding or bleeding diathesis.
* Anticoagulant treatment with curative intent.
* Known endobronchial lesions or involvement of large pulmonary vessels by tumor.
* 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.
* Radiation therapy, surgery or tumor embolization within 2 weeks prior to the first dose of study drug.
* Chemotherapy, immunotherapy, biological therapy, hormonal therapy or treatment with an investigational agent within 14 days or 5 half-lives, whichever is longer prior to the first dose of study drug.
* Patient unable or unwilling to discontinue predefined prohibited medications listed in the protocol for 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.
* Any ongoing toxicity from prior anti-cancer therapy that is \>Grade 1 and/or that is progressing in severity.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to PZP.
* Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
* Clinically assessed as having inadequate venous access for PK sampling.
* Women who are pregnant or breast feeding.