Skip to main content

Advertisement

SpringerLink
Log in

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

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345. doi:10.1056/NEJMoa033025

    Article  CAS  PubMed  Google Scholar 

  2. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer H-R, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359(11):1116–1127. doi:10.1056/NEJMoa0802656

    Article  CAS  PubMed  Google Scholar 

  3. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567–578. doi:10.1056/NEJMoa053422

    Article  CAS  PubMed  Google Scholar 

  4. Van Cutsem E, Köhne C-H, Hitre E, Zaluski J, Chang Chien C-R, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14):1408–1417. doi:10.1056/NEJMoa0805019

    Article  CAS  PubMed  Google Scholar 

  5. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon J-L, Van Laethem J-L, Maurel J, Richardson G, Wolf M, Amado RG (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25(13):1658–1664. doi:10.1200/jco.2006.08.1620

    Article  CAS  PubMed  Google Scholar 

  6. Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A (2014) Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov 4(11):1269–1280. doi:10.1158/2159-8290.cd-14-0462

    Article  CAS  PubMed  Google Scholar 

  7. Sacher AG, Jänne PA, Oxnard GR (2014) Management of acquired resistance to epidermal growth factor receptor kinase inhibitors in patients with advanced non-small cell lung cancer. Cancer 120(15):2289–2298. doi:10.1002/cncr.28723

    Article  PubMed  PubMed Central  Google Scholar 

  8. Boeckx C, Baay M, Wouters A, Specenier P, Vermorken JB, Peeters M, Lardon F (2013) Anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: focus on potential molecular mechanisms of Drμg resistance. Oncologist 18(7):850–864. doi:10.1634/theoncologist.2013-0013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW, Hicklin DJ (2002) Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 8(5):994–1003

    CAS  PubMed  Google Scholar 

  10. Ma J, Lyu H, Huang J, Liu B (2014) Targeting of erbB3 receptor to overcome resistance in cancer treatment. Mol Cancer 13(1):105

    Article  PubMed  PubMed Central  Google Scholar 

  11. Gala K, Chandarlapaty S (2014) Molecular pathways: HER3 targeted therapy. Clin Cancer Res 20(6):1410–1416. doi:10.1158/1078-0432.ccr-13-1549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445 (7126):437–441. doi:http://www.nature.com/nature/journal/v445/n7126/suppinfo/nature05474_S1.html

  13. Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, Gondi V, Hsu KT, Harari PM (2008) Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27(28):3944–3956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jain A, Penuel E, Mink S, Schmidt J, Hodge A, Favero K, Tindell C, Agus DB (2010) HER kinase Axis receptor dimer partner switching occurs in response to EGFR tyrosine kinase inhibition despite failure to block cellular proliferation. Cancer Res 70(5):1989–1999. doi:10.1158/0008-5472.can-09-3326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garrido G, Rabasa A, Garrido C, Lopez A, Chao L, Garcia-Lora AM, Garrido F, Fernandez LE, Sanchez B (2014) Preclinical modeling of EGFR-specific antibody resistance: oncogenic and immune-associated escape mechanisms. Oncogene 33(24):3129–3139. doi:10.1038/onc.2013.288

    Article  CAS  PubMed  Google Scholar 

  16. Kawakami H, Okamoto I, Yonesaka K, Okamoto K, Shibata K, Shinkai Y, Sakamoto H, Kitano M, Tamura T, Nishio K, Nakagawa K (2014) The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells. Oncotarget 5(23):11847–11856. doi:10.18632/oncotarget.2663

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jiang N, Wang D, Hu Z, Shin HJC, Qian G, Rahman MA, Zhang H, Amin ARMR, Nannapaneni S, Wang X, Chen Z, Garcia G, MacBeath G, Shin DM, Khuri FR, Ma J, Chen ZG, Saba NF (2014) Combination of anti-HER3 antibody MM-121/SAR256212 and cetuximab inhibits tumor growth in preclinical models of head and neck squamous cell carcinoma. Mol Cancer Ther 13(7):1826–1836. doi:10.1158/1535-7163.mct-13-1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huang S, Li C, Armstrong EA, Peet CR, Saker J, Amler LC, Sliwkowski MX, Harari PM (2013) Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res 73(2):824–833. doi:10.1158/0008-5472.can-12-1611

    Article  CAS  PubMed  Google Scholar 

  19. Iida M, Brand T, Starr M, Huppert E, Luthar N, Bahrar H, Coan J, Pearson H, Salgia R, Wheeler D (2014) Overcoming acquired resistance to cetuximab by dual targeting HER family receptors with antibody-based therapy. Mol Cancer 13(1):242

    Article  PubMed  PubMed Central  Google Scholar 

  20. Schoeberl B, Faber AC, Li D, Liang M-C, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, Fulgham A, Song Y, Nielsen UB, Engelman JA, Wong K-K (2010) An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res 70(6):2485–2494. doi:10.1158/0008-5472.can-09-3145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Denlinger CS, Keedy VL, Cleary JM, Kubasek W, Onsum M, Moulis S, Garcia G, Schoeberl B, MacBeath G, Nering R, Murray J, Moyo V, Wong K-K, Shapiro G (2011) Abstract LB-410: Phase I dose escalation study of MM-121, a fully human monoclonal antibody to ErbB3, in patients with advanced solid tumors. Cancer Res 71(8 Supplement):LB–410. doi:10.1158/1538-7445.am2011-lb-410

    Article  Google Scholar 

  22. Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Jänne PA, Lynch T, Johnson BE, Miller VA (2010) Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non–small-cell lung cancer. J Clin Oncol 28(2):357–360. doi:10.1200/jco.2009.24.7049

    Article  CAS  PubMed  Google Scholar 

  23. Huang J, Wang S, Lyu H, Cai B, Yang X, Wang J, Liu B (2013) The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells. Mol Cancer 12:134

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yu HA, Riely GJ, Lovly CM (2014) Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. Clin Cancer Res 20(23):5898–5907. doi:10.1158/1078-0432.ccr-13-2437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Corà D, Di Nicolantonio F, Buscarino M, Petti C, Ribero D, Russolillo N, Muratore A, Massucco P, Pisacane A, Molinaro L, Valtorta E, Sartore-Bianchi A, Risio M, Capussotti L, Gambacorta M, Siena S, Medico E, Sapino A, Marsoni S, Comoglio PM, Bardelli A, Trusolino L (2011) A molecularly annotated platform of patient-derived xenografts (“Xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 1(6):508–523. doi:10.1158/2159-8290.cd-11-0109

    Article  CAS  PubMed  Google Scholar 

  26. Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Jänne PA (2011) Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab. Sci Transl Med 3(99):99ra86. doi:10.1126/scitranslmed.3002442

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong S-M, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SKN, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih l-M, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang T-L, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA (2014) Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies. Sci Transl Med 6(224):224ra224. doi:10.1126/scitranslmed.3007094

    Article  Google Scholar 

  28. Misale S, Arena S, Lamba S, Siravegna G, Lallo A, Hobor S, Russo M, Buscarino M, Lazzari L, Sartore-Bianchi A, Bencardino K, Amatu A, Lauricella C, Valtorta E, Siena S, Di Nicolantonio F, Bardelli A (2014) Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer. Sci Transl Med 6(224):224ra226. doi:10.1126/scitranslmed.3007947

    Article  Google Scholar 

  29. Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A, Conner EA, Gillen MC, Roskams T, Roberts LR, Factor VM, Thorgeirsson SS (2012) Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors. Gastroenterology 142(4):1021–1031 . doi:10.1053/j.gastro.2011.12.005e1015

    Article  CAS  PubMed  Google Scholar 

  30. Ross JS, Wang K, Gay L, Al-Rohil R, Rand JV, Jones DM, Lee HJ, Sheehan CE, Otto GA, Palmer G, Yelensky R, Lipson D, Morosini D, Hawryluk M, Catenacci DVT, Miller VA, Churi C, Ali S, Stephens PJ (2014) New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 19(3):235–242. doi:10.1634/theoncologist.2013-0352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang X, Wang W, Wang C, Wang L, Yang M, Qi M, Su H, Sun X, Liu Z, Zhang J, Qin X, Han B (2014) Characterization of EGFR family gene aberrations in cholangiocarcinoma. Oncol Rep 32(2):700–708. doi:10.3892/or.2014.3261

    PubMed  Google Scholar 

  32. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T (2015) Genomic spectra of biliary tract cancer. Nat Genet 47(9):1003–1010. doi:10.1038/ng.3375 http://www.nature.com/ng/journal/v47/n9/abs/ng.3375.html#supplementary-information

    Article  CAS  PubMed  Google Scholar 

  33. Chong DQ, Zhu AX (2016) The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets 2016

  34. Lubner SJ, Mahoney MR, Kolesar JL, LoConte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong W-P, Horvath L, Van Hazel G, Erlichman CE, Holen KD (2010) Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with Unresectable biliary cancer: a phase II consortium study. J Clin Oncol 28(21):3491–3497. doi:10.1200/jco.2010.28.4075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Borbath I, Ceratti A, Verslype C, Demols A, Delaunoit T, Laurent S, Deleporte A, Vergauwe P, Van Maanen A, Sempoux C, Van Cutsem E, Van Laethem JL (2013) Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology. Ann Oncol 24(11):2824–2829. doi:10.1093/annonc/mdt337

    Article  CAS  PubMed  Google Scholar 

Download references

Role of the sponsor

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

Author information

Authors and 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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Autumn J. McRee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geoffrey I. Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara M. Tolaney
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bert H. O’Neil
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeffrey D. Kearns
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sara Mathews
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rachel Nering
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gavin MacBeath
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akos Czibere
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sunil Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. W. Michael Korn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W. Michael Korn.

Ethics declarations

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.

Funding source

Merrimack Pharmaceuticals, Inc.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-016-0399-7

Keywords

Search

Navigation