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

This is an interventional treatment trial for Colorectal Cancer focused on measuring Colorectal Cancer, Colorectal Carcinoma, Colorectal Tumors, Neoplasms, Colorectal Read More

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.