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Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer
Author(s) -
Ciunci Christine A.,
Perini Rodolfo F.,
Avadhani Anjali N.,
Kang Hyunseon C.,
Sun Weijing,
Redlinger Maryann,
Harlacker Kathleen,
Flaherty Keith T.,
Giantonio Bruce J.,
Rosen Mark A.,
Divgi Chaitanya R.,
Song Hee Kwon,
Englander Sarah,
Troxel Andrea,
Schnall Mitchell,
O'Dwyer Peter J.
Publication year - 2013
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.28294
Subject(s) - everolimus , cetuximab , medicine , mucositis , pharmacodynamics , clinical endpoint , toxicity , response evaluation criteria in solid tumors , sirolimus , pharmacology , phases of clinical research , oncology , pharmacokinetics , cancer , urology , clinical trial , colorectal cancer
BACKGROUND Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. METHODS A total of 29 patients were randomized to a run‐in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m 2 loading, 250 mg/m 2 maintenance) weekly, followed by the combination in this dose‐escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [ 18 F]Fluorodeoxyglucose positron emission tomography (FDG‐PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. RESULTS Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose‐limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUV max ) for those treated initially with everolimus was −24% (2% to −54%), and with cetuximab was −5% (−23 to 36%). The K trans measured by DCE‐MRI did not decrease, regardless of run‐in drug. CONCLUSIONS Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population. Cancer 2014;120:77–85 . © 2013 American Cancer Society .