Safety Study of the Combination of Panitumumab, Irinotecan and Everolimus in the Treatment of Advanced Colorectal Cancer

Inclusion Criteria:

* Age \> 18 years
* Histological diagnosis of colorectal cancer that is KRAS wild type
* Metastatic disease not amenable to resection
* Measurable disease as assessed by CT scan using RECIST criteria
* Received and failed fluoropyrimidine therapy
* Radiographically documented disease progression per RECIST criteria
* For phase 1b group only, ECOG PS 0-1
* For phase 2 group only, ECOG PS 0-2
* Adequate bone marrow function with haemoglobin \> 100 g/L, platelets \> 100 X 109/l; neutrophils \> 1.5 X 109/l within 7 days of enrolment
* Adequate renal function, with calculated creatinine clearance \>40 ml/min (Cockcroft and Gault) within 7 days of enrolment
* Adequate hepatic function with serum total bilirubin \< 1.25 X upper limit of normal range and ALT or AST\<2.5xULN (\<5xULN if liver metastases present) within 7 days of enrolment
* Magnesium ≥ lower limit of normal within 7 days of enrolment.
* Fasting serum cholesterol ≤ 7.75mmol/L AND fasting triglycerides ≤ 2.5 x ULN. Note: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
* Life expectancy of at least 12 weeks
* Negative pregnancy test ≤ 72 hours before commencing study treatment (women of childbearing potential only).
* Written informed consent including consent for biomarker studies

Exclusion Criteria:

* Presence of KRAS mutation in tumour sample
* For Phase 1b group only, patients with prior pelvic radiotherapy.
* Systemic chemotherapy, immunotherapy, approved proteins/antibodies or any investigational agent within 4 weeks prior to commencing study treatment
* Radiotherapy within 14 days of commencing study treatment.
* Unresolved toxicities from prior systemic therapy or radiotherapy
* Medical or psychiatric conditions that compromise the patient's ability to give informed consent or to complete the protocol
* Prior treatment with drugs targeting EGFR such as cetuximab, panitumumab or erlotinib
* Prior therapy with mTOR inhibitors (sirolimus, temsirolimus, everolimus)
* Prior therapy with irinotecan
* CYP3A4 enzyme inducing anti-convulsant medication ≤ 14 days prior to study treatment.
* Ketoconazole ≤ 7 days before study treatment.
* Uncontrolled diabetes mellitus defined by fasting glucose \>1.5 x ULN.
* Known cirrhosis, chronic active hepatitis, or chronic persistent hepatitis
* Patients with known interstitial lung disease or severely impaired lung function
* Patients with active bleeding diatheses.
* Any uncontrolled clinically significant cardiac disease, arrhythmias or angina pectoris
* Active inflammatory bowel disease or other bowel disease causing chronic diarrhoea
* Chronic treatment with immunosuppressives
* Patients with a known history of HIV seropositivity
* Patients who have any severe and/or uncontrolled medical conditions or infections
* Untreated or symptomatic CNS metastases
* Patients who have a history of another primary malignant disease
* Pregnancy or lactation.
* Women and partners of women of childbearing potential who are not using effective contraception.