This is an open-label, multicenter dose-escalation phase I study using a 3+3+3 design (i.e., 3 to 9 patients per dose level) in patients with mRCC or others advanced refractory solid tumors. Enrolment will be performed to include approximately ½ of patients with mRCC.

The primary endpoint is the occurrence of limiting toxicities leading to definitive discontinuation of the study drugs during the first 24 weeks in absence of progression of the disease.

Secondary endpoints included the occurrence of Dose Limiting Toxicities (DLTs) evaluated during the first two cycles; overall response rate, 6-months progression-free survival rate and Pharmacokinetic assessments.

The primary endpoint is the occurrence of limiting toxicities leading to definitive discontinuation of the study drugs during the first 24 weeks in absence of progression of the disease.

Secondary endpoints included the occurrence of Dose Limiting Toxicities (DLTs) evaluated during the first two cycles; overall response rate (ORR), 6-months progression-free survival rate and Pharmacokinetic assessments.

The following definitions will be used:

DLT:

The Dose Limiting Toxicities (DLTs) are defined as the occurrence during the first two cycles of any grade 4 toxicity, and of any following events:

• clinical evidence of congestive heart failure,
• any arterial thromboembolic event,
• grade 3 venous thrombosis,
• grade 3 thrombocytopenia >=7 days or associated with bleeding,
• grade 3 hypertension uncontrolled (>=160/90 mmHg) with medications,
• grade 3 elevations in AST/ALT or total bilirubin. Any other grade 3 toxicity >=7 days is also considered as a DLT, with exception of fatigue.

MTD:

The determination of the maximum-tolerated dose (MTD) will be conducted on a 3 + 3 + 3 design. Cohorts of 3 to 9 patients will be sequentially enrolled in 3 steps to receive one of four escalated doses of Pazopanib in combination with Bevacizumab to establish the MTD (step 1: patients 1 to 3; step 2: patients 4 to 6; step 3: patients 7 to 9).

The MTD is considered to be exceeded if DLT is observed during the first 2 cycles (i.e., 56 days) in at least 2 out of 3 or 3 out of 6 patients evaluable for MTD in the two first steps, then in at least 3 out of 9 patients after completion of enrolment (step 3).

When the MTD will be established, patients already involved in the follow-up phase at a dose level above the MTD should decrease to the MTD.

Note: in an exploratory way (i.e., with simulation) the possibility to take into account for the determination of the MTD the occurrence of recurrent grade 2 events or the combination of synergic grade 2-3 toxicities as "1/2 DLT" will be investigated in the study.

Optimal Long Exposure Dose (OLED):

To determine the Optimal Long Exposure Dose (OLED), all patients which will not experience a Dose Limiting Toxicity (DLT) during the first two cycles will continue the treatment and will be followed until week 24, in order to record toxic reactions of lesser severity or mixed toxicities leading to definitive discontinuation of the study drug, in the absence of progression of the disease.

The OLED is defined as the dose level (less than or equal to the MTD) for which the occurrence of sub-acute limiting toxicities leading to definitive discontinuation of the study drug is compatible with further phase II studies.

In practice, if <=2/7-8 patients or <=3/9 patients treated at a dose level <=MTD and followed until week 24 experience sub-acute limiting toxicities, that dose level will be considered as the OLED.

ORR:

The overall response rate (ORR) is defined as the proportion of patients with a complete response (CR) or partial response (PR) - target lesions and tumor response according to RECIST guidelines.

Progression-Free Survival (PFS):

Progression-free survival (PFS) is defined as the time from the date of first study drug administration to the date of the first observation of documented disease progression or death due to any cause. PFS will be determined based on tumor assessment (RECIST criteria) and survival information.

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.