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

This is an interventional, prospective, randomized (1:1), controlled, open label, multicenter phase IIb study in patients with advanced metastatic colorectal cancer. The scope of the trial is to evaluate overall survival of either regimen and evaluate safety and tolerability. Patients with advanced metastatic and inoperable, colorectal cancer who have progressed on/after or did not tolerate: fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic therapies (bevacizumab, aflibercept, regorafenib or ramucirumab) and when indicated anti-EGFR (epidermal growth factor receptor) antibodies (cetuximab or panitumumab) will be included in this trial. Patients will be stratified by the duration of previous anti-angiogenic therapy ≥ or \<12 months in total, BRAF V600E mutation status (mutation vs. wildtype), RAS mutation status (mutation vs. wildtype), and randomized 1:1 to receive either ramucirumab/TAS102 (arm A) or TAS102 (arm B). Concurrent use of other chemotherapy is not allowed. Two interim safety analyses will be conducted when 10 and 40 patients are fully documented in arm A after receiving 2 cycles (one 4-week cycle comprises ramucirumab 8mg/kg administered at d1 and d15 and TAS102 35mg/m2 p.o. twice daily administered on d1-5 and d8-12). The analysis will be reviewed by the lead coordinating investigator (Prof. Dr. Kasper) and members of the steering committee and then by the data safety monitoring board. It is not planned to discontinue recruitment for the interim safety analyses. Arm A (ramucirumab/TAS102) Patients randomized to arm A will receive ramucirumab 8 mg/kg iv over 60 min on d1+15, q4w and TAS102 35mg/m2 p.o. twice daily (BID) d1-5 and 8-12, q4w until progression or intolerance or completion of 6 cycles. Arm B (TAS102) Patients randomized to arm B will receive TAS102 35mg/m2 p.o. twice daily (BID) d1-5 and 8-12, q4w until progression, intolerance or completion of 6 cycles. In both arms, tumor assessments (CT or MRI) are performed before enrollment/randomization and then every 8 weeks (every 2nd cycle) during therapy and every 12 weeks during follow-up until progression/relapse, death or end of follow-up. A change from CT into MRI in the follow-up period is possible at any time. During treatment, clinical visits (blood cell counts, detection of toxicity) will be performed prior to every treatment dose of ramucirumab or every two weeks in arm B or if ramucirumab was discontinued in arm A. Safety of TAS102 +/- ramucirumab will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported. Every 4 weeks during therapy Quality of life (QoL) will be assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC-QLQ-C30) and the EuroQol 5 dimensions 5-level version (EQ-5D-5L).