The mammalian target of rapamycin (mTOR) is a key downstream protein activated via PI3K-AKT pathway, and regulates cell growth, proliferation, and survival. Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This is a phase Ib study to determine the maximum tolerated dose of the combination of everolimus, irinotecan and panitumumab.
Patients and Methods
Patients with KRAS WT mCRC following failure of first line therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout the 14 day cycle. Dose finding used a standard 3+3 design with the MTD being defined as the dose with DLTs in 1/6 or fewer patients. Dose level 1 was irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate days and dose level 2, irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg daily.
12 patients have been enrolled into the study. Five patients were treated at dose level 1. Two patients were not evaluable as treatment was interrupted due to expected irinotecan toxicity leading to a protocol amendment. Three evaluable patients were subsequently enrolled and grade 3 toxicities were; hypomagnesemia, neutropenia, rash, diarrhoea, paronychia. No grade 4 toxicity or DLT. Four patients were enrolled into cohort 2, one withdrew due to unrelated cardiac complications and was non-evaluable. Of 3 evaluable patients there was one DLT due to grade 3 mucositis. The cohort was expanded to 5 evaluable patients but suspended after a further DLT (grade 3 mucositis). Other grade 3 toxicities were anorexia, rash, vomiting, hypersensitivity. There were no grade 4 toxicities.
Dose level 2 exceeded the MTD. Dose level 1 will be expanded by 3 and if no DLT, the phase II component of the study will proceed.
Study supported by an unconditional grant from Amgen/Novartis