Clinical trial NCT02835833 (phase 1, status: completed)
Conditions: renal cell carcinoma, colorectal adenocarcinoma, non-squamous non-small cell lung cancer, platinum-refractory ovarian carcinoma, cervical carcinoma
ICD codes: C22.0, C4A.9, C7B.1, C4A.0, C4A.31, C4A.51, C4A.8, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31, C78.00, C78.01, C78.02, D14.30, D14.31, D14.32, C34.2, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31
Drugs: nintedanib, bevacizumab
SMILES: COC(=O)C1=CC=C2C(NC(=O)\C2=C(/NC2=CC=C(C=C2)N(C)C(=O)CN2CCN(C)CC2)C2=CC=CC=C2)=C1, [H][N]1([H])[C@@H]2CCCC[C@H]2[N]([H])([H])[Pt]11OC(=O)C(=O)O1
Eligibility criteria:

        Inclusion Criteria:

          1. Age >18

          2. Histologically proven advanced or metastatic solid cancer for which Bevacizumab has an
             indication: renal cell carcinoma, colorectal adenocarcinoma, non-squamous non-small
             cell lung cancer, platinum- refractory ovarian carcinoma, cervical carcinoma.

          3. Life expectancy at least 3 months

          4. ECOG performance status score 0-1

          5. Progression after at least first-line systemic therapy for metastatic disease

          6. At least one measurable lesion according to RECIST criteria or any other baseline
             prerequisite for the assessment of the principal judgement criteria.

          7. Signed and dated written informed consent prior to admission to the study

          8. Resolution of all acute adverse events resulting from prior cancer therapies to NCI
             CTCAE grade less than/equal to 1 or baseline (except alopecia)

          9. Adequate organ function as defined by the following criteria

               -  AST/ALT ≤ 2.5x upper limit of normal (ULN) in the case of liver metastases or
                  AST/ALT ≤ 1.5 x ULN in patients without liver metastases

               -  total serum bilirubin within normal limits regardless of liver metastases

               -  absolute neutrophil count (ANC) > 1500

               -  Platelets > 100k without transfusion support in the past 28 days

               -  Hemoglobin > 9.0 without transfusion support in the past 28 days

               -  Serum creatinine < 1.5x ULN

               -  Prothrombin time/INR and partial thromboplastin time within normal limits

               -  Urinalysis ≤ 1+ protein

         10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
             tests, and other study procedures

        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