RAMucirumab in Combination Wth TAS102 vs. TAS102 Alone in Chemotherapy Refractory Metastatic Colorectal Cancer Patients

Inclusion Criteria: 1. Metastatic and inoperable, colorectal cancer who has progressed on/after, or did not tolerate, refuse or have contraindications to: fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic therapies (bevacizumab, aflibercept, regorafenib or ramucirumab) and if indicated anti-EGFR antibodies (cetuximab or panitumumab). Intolerance is defined as a permanent discontinuation of the respective treatment resulting from toxicity 2. Signed informed consent before start of specific protocol procedure 3. Histologically or cytologically documented diagnosis of adenocarcinoma of the colon or rectum 4. Presence of at least one measurable site of disease following RECIST 1.1 criteria 5. ECOG (Eastern Cooperative Oncology Group) performance 0-1 6. Known RAS and BRAF V600E mutational status 7. Life expectancy of at least 3 months 8. Adequate hematological, hepatic and renal function parameters: 1. Leukocytes ≥3000/mm³, platelets ≥100,000/mm³, neutrophil count (ANC) ≥1500/μL, hemoglobin ≥9 g/dL (5.58 mmol/L) 2. Adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5, and a partial thromboplastin time (PTT) ≤5 seconds above the ULN (upper limit of normal) (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocoumon must be switched to low molecular weight heparin and have achieved a stable coagulation profile prior to first dose of protocol therapy 3. Serum creatinine ≤1.5 x upper limit of normal or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is \>1.5 times the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed) 4. Urinary protein ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate \<1000 mg of protein in 24 hours to allow participation in this protocol) 5. Bilirubin ≤1.5 x upper limit of normal, AST and ALT ≤3.0 x upper limit of normal, ≤5xULN if liver metastasis present, alkaline phosphatase ≤6 x upper limit of normal 9. Patient able and willing to provide written informed consent and to comply with the study protocol 10. Female and male patients ≥18. Patients in reproductive age must be willing to use adequate contraception during the study and for 7 months after the end of ramucirumab treatment (appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy) or hormonal contraception (implantable, patch, oral). Women who use a hormonal contraception method should use an additional barrier method like IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start (There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.) Exclusion Criteria: 1. Known hypersensitivity against ramucirumab or TAS102 2. Other known contraindications against ramucirumab, TAS102, or other anti-angiogenic therapies 3. Prior therapy with TAS102 4. Drug-related severe adverse events upon pretreatment with antiangiogenic drugs that would require permanent discontinuation and not allow re-challenge with the same class of drug (i.e. ramucirumab) such as noncontrollable severe hypertension or thromboembolic events 5. Any antineoplastic treatment including irradiation within 14 days (42 days for mitomycin c) prior to start of therapy. 6. Major surgery within 4 weeks of starting therapy within this study, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial. 7. Symptomatic brain metastasis 8. Clinically significant cardiovascular disease * NYHA\>II°, myocardial infarction within 6 months prior study entry * Known clinically significant valvular defect * Uncontrolled or poorly-controlled hypertension (\>160 mmHg systolic or \>100 mmHg diastolic for \>4 weeks) despite standard medical management * Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy * History of deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy 9. Active clinically serious infections (\> grade 2 NCI-CTC version 4.0) 10. Chronic inflammatory bowel disease 11. History of uncontrolled HIV infection or chronic hepatitis B or C 12. Patients with evidence of bleeding diathesis 13. Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy 14. Receiving chronic antiplatelet therapy, including aspirin (once daily aspirin use (maximum dose 325 mg/day) is permitted), nonsteroidal anti-inflammatory drugs (including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents 15. History of gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation 16. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy 17. Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix or bladder, or low/intermediate risk prostate cancer (Gleason score ≤7) with normal PSA levels 18. Any condition that could jeopardize the safety of the patient and their compliance of the study 19. Medical, psychological or social conditions that may interfere with the participation in the study 20. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis 21. On-treatment participation in another clinical study or received investigational drug therapy in the period 30 days prior to inclusion and during the study 22. Subject pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment 23. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4) 24. Any other concurrent antineoplastic treatment including irradiation