title: A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer.
abstract: mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC. Treatment consisted of cetuximab 500 mg/m(2) i.v. every two weeks with lenalidomide given orally days 1-21 on a 28-day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcγRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. Twenty-two patients were enrolled (19 colorectal cancer, 3 HNSCC). Fatigue was the only dose-limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m(2) with lenalidomide 25 mg daily, days 1-21. Correlative studies demonstrated a dose-dependent increase in natural killer cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of antitumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted. Mol Cancer Ther; 15(9); 2244-50. ©2016 AACR.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio. erin.bertino@osumc.edu.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Bertino
authors.affiliation: Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: McMichael
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Melanie
authors.initials: M
authors.lastname: Davis
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Paul
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Michael
authors.initials: M
authors.lastname: Grever
authors.affiliation: Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Otterson
mesh_terms: D000328:Adult; D000368:Aged; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab / Q000008:administration & dosage / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D019233:Retreatment; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D013792:Thalidomide; D000077269:Lenalidomide; D000068818:Cetuximab