Study of Nintedanib Plus Bevacizumab in Advanced Solid Tumors

Exclusion Criteria

• •1. Previous therapy with Bevacizumab is allowed, but patient who experienced serious dose-limiting toxicities while on prior Bevacizumab therapy are excluded
• •2. Prior treatment with Nintedanib (BIBF1120). Known hypersensitivity to Nintedanib, peanut or soya or any other trial drug, their excipients or to contrast media
• •3. Chemo-, hormone-, radio-(except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug.
• •4. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging
• •5. Persistence of clinically relevant therapy related toxicity from previous chemo and/or radiotherapy
• •6. History of brain involvement with cancer, spinal cord compression, carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with irradiated or resected brain lesions are permitted provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been used for at least 28 days.
• •7. Leptomeningeal disease
• •8. Centrally located tumours with radiographic evidence of local invasion of major blood vessels
• •9. Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial
• •10. Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid \<325mg per day.
• •11. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
• •12. History of clinically significant hemorrhagic or thromboembolic event in the past 6 months.
• •13. Known inherited predisposition to bleeding or thrombosis
• •14. Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 6 months prior to start of study treatment, congestive heart failure \>New York Heart Association II, serious cardiac arrhythmia, pericardial effusion)
• •15. Proteinuria CTCAE grade 2 or greater
• •16. Creatinine \>1.5 ULN or GFR \<45 ml/min
• •17. Hepatic function: total bilirubin outside of normal limits; ALT or AST \>2.5 ULN in pts without liver metastasis. For patients with liver metastasis: total bilirubin outside of normal limits, ALT or AST \>5 x ULN
• •18. Coagulation parameters: International normalized ratio (INR) \>2, prothrombin time (PT) and partial thromboplastin time (PTT) \>50% of deviation of institutional ULN
• •19. Absolute neutrophil count (ANC) \<1500/ml, platelets \<100,000/ml, Hemoglobin \<9.0 g/dl
• •20. Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of the cervix
• •21. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy
• •22. Active or chronic hepatitis C and/or B infection
• •23. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
• •24. Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study.
• •25. Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least three months after end of active therapy.
• •26. Pregnancy or breast feeding. Female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment and must agree with the use of effective contraception during the study and for three months following last dose of Nintedanib.
• •27. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule
• •28. Active alcohol or drug abuse
• •29. Minor surgical procedures such as Mediport placement or core biopsies within 7 days of study treatment
• •30. Stroke, transient ischemic attack, arterial embolism, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG) within the past 6 months
• •31. History of pulmonary hemorrhage or hemoptysis within 6 months of starting study treatment
• •32. Open wounds or unhealed fractures within 28 days of starting study treatment
• •33. Known HIV or AIDS related illness