1162P - Phase 1 study of everolimus combined with lutetium-177 octreotate radiopeptide therapy of advanced low-grade neuroendocrine tumours
|Date||29 September 2012|
|Event||ESMO Congress 2012|
|Session||Poster presentation I|
|Topics|| Drug Development
P. Claringbold1, J.H. Turner2
Recent clinical trials of mTOR inhibitors have shown benefit from everolimus treatment of advanced low-grade neuroendocrine tumours (NETs). Targeting of NET somatostatin receptors with radiopeptides is another effective therapeutic option. This phase I study investigates the safety of combining everolimus with lutetium-177 octreotate.Methods
Patients with biopsy proven low-grade NETs (Ki 67 index < 5%), positive on gallium 68-octreotate PET scan were studied. All patients received fixed dose 7.8 GBq lutetium-177 octreotate each 8 weeks for 4 cycles, combined with everolimus. Successive cohorts received escalating doses of everolimus in groupings of 5, 7.5 and 10 mg given as a daily oral dose for the 24 weeks of radiopeptide therapy. Dose limiting toxicities were established by standard NCI common toxicity criteria (CTCAE v 4.03).Results
Eleven patients have been treated, 4 patients at the 5 mg everolimus dose level and 3 each at the 7.5 mg and 10 mg levels. Full dose lutetium-177 octreotate for 4 cycles was possible in 6 of 7 patients in cohorts 1 and 2, whilst only 1 of 3 patients completed all cycles at the 10 mg dose level. Patients at 5 mg and 7.5 mg doses of everolimus received 85% of the total planned dosage over 24 weeks. All patients required dose reduction or complete cessation of everolimus at the 10 mg level because of unacceptable toxicities. The commonest reasons for dose reductions in cohorts 1 and 2 were grade 2 or 3 neutropenia and thrombocytopenia. Unexpected reversible grade 2 nephrotoxicity caused significant reductions in creatinine clearance levels of 40-50% baseline in 2 of 3 patients in the 10 mg cohort, not seen in the lower dose levels. Tumour responses have been observed at each dose level.Conclusion
Everolimus can be combined safely with lutetium-177 octreotate to treat low-grade NETs. Toxicities were observed at all dosage levels of everolimus but appear manageable and reversible. The maximum tolerated dose (MTD) of everolimus was 7.5 mg daily in combination with 7.8 GBq lutetium-177 octreotate in a 4 cycle course over 24 weeks.Disclosure
P. Claringbold: Dr Claringbold has acted on an advisory panel and received financial support from Novartis Pharmaceuticals.
J.H. Turner: Dr Turner has acted on an advisory panel and received financial support from Novartis Pharmaceuticals.