Temsirolimus and Irinotecan for Treatment Resistant Patients With Metastatic Colorectal Cancer and KRAS Mutations

Inclusion Criteria:

* Histologically verified colorectal adenocarcinomas
* Age \> 18 years and \< 70
* Metastatic colorectal cancer refractory 5-FU, oxaliplatin and irinotecan containing treatment regimes
* KRAS mutation detected by DxS kit in primary tumor or metastatic lesion.
* Measurable disease according to RECIST
* ECOG performance status 0, 1 or 2
* Adequate renal, hepatic and haematological function
* Normal serum cholesterol and triglycerides
* Blood samples and available paraffin embedded tumor material for translational research studies
* Fertile males and females (\< 2 years after last period for women) must use effective birth control
* Signed Informed consent

Exclusion Criteria:

* Clinically significant heart disease, active severe infections or other concurrent disease
* Other malignant diseases within 5 years of inclusion in the study, except basal cell squamous cell carcinoma of the skin and cervical carcinoma-in-situ
* Prior radiotherapy within 30 days of treatment start
* Other experimental therapy within 30 days of treatment initiation
* Patients who are breast feeding, childbearing or of childbearing potential without using dual effective contraception
* Clinical or radiological evidence of CNS metastasis
* Completed any major surgery, excision biopsy or significant traumatic lesion ≥ 4 weeks from start of treatment and completed any minor surgery ≥ 1 week prior to start of treatment

  * Insertion of a vascular access device is not considered major or minor surgery from the viewpoint of protocol eligibility
  * Patients must have fully recovered from the procedure and have a fully healed incision
* Planned radiation therapy against target-lesions
* Patients with significant non-healing wounds or ulcers
* History or evidence of thrombotic or hemorrhagic disorders

  * Significant haemorrhage (\> 30 ml/bleeding episode in previous 3 months)
  * Haemoptysis (\> 5 ml fresh blood in previous 4 weeks)
* Patients on full-dose anticoagulation (e.g., warfarin) are eligible provided that both of the following criteria are met:

  * The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or is on a stable dose of low molecular weight heparin
  * The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
* Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoid Hemorrhage (SAH) within 12 months prior to randomization
* No known or history of HIV seropositivity
* The use of ACE inhibitors is not permitted during the study
* Known allergy to temsirolimus, sirolimus, polysorbate 80 or included agents.
* Agents with strong CYP3A4-inhibitory potential