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

Prior treatment

• Other known contraindications against ramucirumab, TAS102, or other anti-angiogenic therapies
• Prior therapy with TAS102
• Any antineoplastic treatment including irradiation within 14 days (42 days for mitomycin c) prior to start of therapy.
• 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.
• 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
• Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
• 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
• Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
• On-treatment participation in another clinical study or received investigational drug therapy in the period 30 days prior to inclusion and during the study
• Any other concurrent antineoplastic treatment including irradiation

Other illness

• Known hypersensitivity against ramucirumab or TAS102
• 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
• Active clinically serious infections (\> grade 2 NCI-CTC version 4.0)
• Chronic inflammatory bowel disease
• History of uncontrolled HIV infection or chronic hepatitis B or C
• Patients with evidence of bleeding diathesis
• History of gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation
• 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
• Any condition that could jeopardize the safety of the patient and their compliance of the study
• Medical, psychological or social conditions that may interfere with the participation in the study
• 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

Other

• Symptomatic brain metastasis
• Subject pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment
• Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)

• 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
• Signed informed consent before start of specific protocol procedure
• Histologically or cytologically documented diagnosis of adenocarcinoma of the colon or rectum
• Presence of at least one measurable site of disease following RECIST 1.1 criteria
• ECOG (Eastern Cooperative Oncology Group) performance 0-1
• Known RAS and BRAF V600E mutational status
• Life expectancy of at least 3 months
• Adequate hematological, hepatic and renal function parameters:
  • Leukocytes ≥3000/mm³, platelets ≥100,000/mm³, neutrophil count (ANC) ≥1500/μL, hemoglobin ≥9 g/dL (5.58 mmol/L)
  • 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
  • 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)
  • 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)
  • 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
• Patient able and willing to provide written informed consent and to comply with the study protocol
• 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.)