title: A phase 1 study combining the HER3 antibody seribantumab (MM-121) and cetuximab with and without irinotecan.
abstract: Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with EGFR-dependent cancers. In Part I, escalating doses of seribantumab and cetuximab were administered. In Part II of the trial, escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks. Results 34 patients were enrolled in Part I (seribantumab/cetuximab) and 14 patients were enrolled in Part II (seribantumab/cetuximab/irinotecan). Common toxicities of seribantumab/cetuximab included acneiform rash, diarrhea, stomatitis, and paronychia. The MTD of Part I was seribantumab 40 mg/kg bolus, then 20 mg/kg weekly combined with cetuximab 400 mg/m2 bolus, then 250 mg/m2 IV weekly. Common toxicities reported in the seribantumab/cetuximab/irinotecan combination were similar to the Part I portion. However, toxicities were more frequent and severe with the triplet combination. There was one treatment-related death in Part II secondary to Grade 4 neutropenia and grade 3 diarrhea. Other dose-limiting toxicities in Part II were Grade 3 mucositis and Grade 3 diarrhea. A cholangiocarcinoma patient, previously untreated with EGFR-directed therapy, had a confirmed partial response (PR). One colorectal cancer patient, previously treated with EGFR-directed therapy, had an unconfirmed PR. Conclusions Seribantumab/cetuximab was well tolerated and patients experienced toxicities typical to EGFR inhibition. Unlike the seribantumab/cetuximab doublet, seribantumab/cetuximab/irinotecan was difficult to tolerate in this heavily pretreated population. There was limited efficacy of the combination therapy.
authors.affiliation: Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.affiliation: University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Autumn J
authors.initials: AJ
authors.lastname: McRee
authors.affiliation: Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Tolaney
authors.affiliation: University of North Carolina, Chapel Hill, NC, USA.|Indiana University Simon Cancer Center, Indianapolis, Indiana, USA.
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.affiliation: Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kearns
authors.affiliation: Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Mathews
authors.affiliation: Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nering
authors.affiliation: Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
authors.affiliation: Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Akos
authors.initials: A
authors.lastname: Czibere
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: University of California - San Francisco, Box 1705, UCSF, San Francisco, CA, 94143-1705, USA. Michael.Korn@ucsf.edu.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Korn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068818:Cetuximab / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020893:Receptor, ErbB-3 / Q000276:immunology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000589319:seribantumab; D000077146:Irinotecan; C512478:EGFR protein, human; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D000068818:Cetuximab; D002166:Camptothecin
keywords: Cetuximab; EGFR; HER3; Seribantumab