Sequential Therapy in Metastatic Renal Cell Carinoma

Exclusion Criteria

• •Any investigational drug within the 30 days before inclusion.
• •Known or suspected allergy or hypersensitivity reaction to any of the components of study treatments or their excipients.
• •Pregnancy (absence to be confirmed by beta-hCG test) or lactation period.
• •Men or women of child-bearing potential who are sexually active and unwilling to use a highly effective method of contraception (Pearl index \< 1%) during the trial. Oral contraceptives are acceptable if a barrier method is applied in conjunction.
• •Clinically symptomatic brain or meningeal metastasis (known or suspected), unless completion of local therapy for at least 3 months with discontinuation of steroids prior to start of treatment.
• •Cardiac arrhythmias requiring anti-arrhythmics (excluding beta blockers, digoxin or digitoxin).
• •History of any of the following cardiac events within the past 6 months:
• •1. myocardial infarction (including severe/unstable angina),
• •2. coronary/peripheral artery bypass graft,
• •3. congestive heart failure (CHF) (NYHA Class III, or IV),
• •4. cerebrovascular accident,
• •5. transient ischemic attack,
• •6. pulmonary embolism, abdominal or tracheo-oesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess
• •Hemorrhage ≥ grade 3 or clinically significant hemoptysis within the past 4 weeks
• •Uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 90 mm Hg despite the use of ≥ 3 anti-hypertensive drugs).
• •History of relevant pulmonary hypertension or interstitial lung disease or severely impaired lung function.
• •Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease or chronic diarrhea.
• •Previous malignancy (other than renal cell cancer) in the last 3 years, except basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a prostate carcinoma or superficial bladder tumor \[Ta, Tis and T1\].
• •History of organ allograft.
• •Significant disease which, in the investigator's opinion would exclude the patient from the study.
• •Medication that is known to interfere with any of the agents applied in the trial.
• •Patients with a serious non-healing wound, ulcer or bone fracture.
• •Patients with a history of seizure(s) not controlled with standard medical therapy.
• •Patients receiving chronic systemic treatment with corticosteroids (dose of \> 20 mg/day methylprednisone equivalent) or another immune-suppressive agent. Inhaled and topical steroids are acceptable.
• •Legal incapacity or limited legal capacity.
• •Medical or psychological conditions that would not permit the patient to complete the study or sign informed consent.
• •Significant vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic peripheral vascular disease.
• •Evidence or history of recurrent thromboembolism (\>1 episode of deep venous thrombosis/peripheral embolism ≥ CTCAE Grade 3) during the past 2 years, bleeding diathesis or coagulopathy.
• •Poorly controlled diabetes as defined by fasting serum glucose \> 2.0 x ULN.
• •Active (acute or chronic) or uncontrolled infection of bacterial, mycotic or viral genesis.
• •Liver disease such as chronic active hepatitis or chronic persistent hepatitis.
• •Patients with a known history of HIV seropositivity.
• •QT prolongation (QTc \> 450 msec).