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Invest New Drugs. 2017 Feb;35(1):68-78. doi: 10.1007/s10637-016-0399-7. Epub 2016 Nov 16.

A phase 1 study combining the HER3 antibody seribantumab (MM-121) and cetuximab with and without irinotecan.

Author information

1
Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA, USA.
2
University of North Carolina, Chapel Hill, NC, USA.
3
Indiana University Simon Cancer Center, Indianapolis, Indiana, USA.
4
Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA.
5
Huntsman Cancer Institute, Salt Lake City, UT, USA.
6
University of California - San Francisco, Box 1705, UCSF, San Francisco, CA, 94143-1705, USA. Michael.Korn@ucsf.edu.

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.

KEYWORDS:

Cetuximab; EGFR; HER3; Seribantumab

PMID:
27853996
DOI:
10.1007/s10637-016-0399-7
[Indexed for MEDLINE]

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