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

This is an open label uncontrolled phase IB/II study to determine the maximum tolerated dose (MTD) and assess the efficacy of everolimus, irinotecan and panitumumab when given in combination for patients with metastatic colorectal cancer and KRAS wild-type (WT). Patients with metastatic colorectal cancer (mCRC) that have failed fluorouracil based first line therapy will be included. It is anticipated that approximately 50 patients will be enrolled over a period of 24 months

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.