Inclusion Criteria:
* Advanced, histologically confirmed, metastatic colorectal carcinoma not suitable for resection and chemorefractory or Previously employed chemotherapy regimens and agents should comprise the following: Fluoropyrimidines, oxaliplatin, irinotecan, antiangiogenic agents (bevacizumab, aflibercept or ramucirumab), anti-EFGR-mAbs (in case of all-Ras-wildtype and left-sided primary tumor) and Trifluridin/Tipiracil (TAS102)
* Microsatellite stable subset (MSS) of colorectal cancer
* Prior antineoplastic therapy or radiochemotherapy is allowed up to two weeks prior to start of the study medication. However, for the phase II part of the trial, failure of this strategy must be confirmed. In case of prior radiotherapy/radiochemotherapy the target lesion used for tumor evaluation must not be in the radiation field.
* There must be an oxaliplatin free period of at least 6 months prior to start of the study medication.
* No polyneuropathy of \> grade 1
* Tumor-related ECOG performance status 0-2
* Anticipated life expectancy ≥ 12 weeks
* Creatinine clearance ≥ 30 ml/min
* Serum total bilirubin level ≤ 3 x ULN.
* ALT and AST ≤ 2.5 x ULN or ≤ 5.0 x ULN in the presence of liver metastasis (established after adequate biliary drainage)
* White blood cell count ≥ 3.5 x 106/ml, neutrophil granulocytes count ≥ 1,5 x 106/ml, platelet count ≥ 100 x 106/ml
* Pain that has to be controllable without concomitant use of opioids
* Signed informed consent according to ICH/GCP and national/local regulations (participation in translational research is obligate)
* None of the following concomitant medications: MAO-B-Inhibitors, strong inductors or inhibitors of CYP3A4, antiarrhythmic drugs of class I and III or other drugs that have potential for QT-prolongation
* Age ≥ 18 years
* At least one measurable target lesion according to RECIST 1.1. Pre-irradiated or locally treated lesions must not be used as target lesions.
Exclusion Criteria:
* Microsatellite unstable CRC (MSIhigh)
* Chronic infectious diseases, immune deficiency syndromes
* Polyneuropathy \>grade I according to CTCAE V4.03
* Premalignant hematologic disorders, e.g. myelodysplastic syndrome
* Disability to understand and sign written informed consent document
* Past or current history of malignancies except for the indication under this study and curatively treated:
* Basal and squamous cell carcinoma of the skin
* In-situ carcinoma of the cervix
* Other malignant disease without recurrence after at least 3 years of follow-up
* Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment
* History of or evidence upon physical examination of CNS disease unless adequately treated (e.g. primary brain tumor, seizure not controlled with standard medical therapy or history of stroke).
* Severe non-healing wounds, ulcers or bone fractions
* Evidence of bleeding diathesis or coagulopathy
* Patients not receiving therapeutic anticoagulation must have an INR ≤ 1.4 or PTT ≤ 40 sec within 28 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution)
* Major surgical procedures or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgical procedure during the course of the study.
* Pregnancy or breastfeeding women.
* Use of cannabinoids because of overlapping and /or potentiating of potential side effects
* Concomitant daily use of opioids in the last 3 months including methadone prior start of study medication
* Subjects with known allergies to the study drugs or to any of its excipients.
* Treatment with another investigational drug or participation in another interventional trial (within the 14 days prior randomization or 5 plasma half-lifes of the used investigational drug, whatever is longer)
* Congenital QT-syndrome.
* Alcohol abuse.
* Bronchial asthma.
* Liver cirrhosis \> Child-Pugh classification A.
* Any psychological, familial, sociological or geographical condition potentially compromising compliance with the study protocol and the follow-up schedule; those conditions should be discussed with the patient prior to registration in the trial
