safety study of the combination of panitumumab, irinotecan and everolimus in the treatment of advanced colorectal cancer

Conditions: Colorectal Cancer; Colorectal Carcinoma; Colorectal Tumors; Neoplasms, Colorectal

Summary: this study will assess the safety of panitumumab, irinotecan and everolimus when given in combination to treat 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

Eligibility criteria:
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.

Keywords: colorectal cancer colorectal carcinoma colorectal tumors neoplasms, colorectal