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

Investigational New Drugs volume 35, pages 68–78 (2017)Cite this article

Summary

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.

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Role of the sponsor

Merrimack Pharmaceuticals was involved in the study design, data collection, data analysis, and preparation of the manuscript.

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Affiliations

  1. Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA, USA

    James M. Cleary, Geoffrey I. Shapiro & Sara M. Tolaney

  2. University of North Carolina, Chapel Hill, NC, USA

    Autumn J. McRee & Bert H. O’Neil

  3. Indiana University Simon Cancer Center, Indianapolis, Indiana, USA

    Bert H. O’Neil

  4. Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA

    Jeffrey D. Kearns, Sara Mathews, Rachel Nering, Gavin MacBeath & Akos Czibere

  5. Huntsman Cancer Institute, Salt Lake City, UT, USA

    Sunil Sharma

  6. University of California – San Francisco, Box 1705, UCSF, San Francisco, CA, 94143-1705, USA

    W. Michael Korn

Authors
  1. James M. Cleary
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  2. Autumn J. McRee
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  3. Geoffrey I. Shapiro
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Correspondence to W. Michael Korn.

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Conflicts of interest

JC reports research funding to his institution from Merrimack Pharmaceuticals, Taiho Oncology, Merck, Roche, Abbvie, Precision Biologics, and Bristol Myers Squib. He was a paid consultant with Agios Pharmaceuticals. GI was a paid consultant for Lilly, GI Therapeutics, EMD Serono, Chugai, and Millennium. He has also received research funding from Pfizer. ST reports research funding to her institution from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, and Novartis. SM, RN, GM, JK and AC are all employees of Merrimack Pharmaceuticals. WMK is a paid consultant for Merrimack Pharmaceuticals. AM, BO, and SS report no conflicts of interest.

Funding support

This study was sponsored by Merrimack Pharmaceuticals.

Statement of human rights

All procedures performed in human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all individual participants included in the study.

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Merrimack Pharmaceuticals, Inc.

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Cleary, J.M., McRee, A.J., Shapiro, G.I. et al. A phase 1 study combining the HER3 antibody seribantumab (MM-121) and cetuximab with and without irinotecan. Invest New Drugs 35, 68–78 (2017). https://doi.org/10.1007/s10637-016-0399-7

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Keywords

  • Seribantumab
  • Cetuximab
  • HER3
  • EGFR