Investigational New Drugs

, Volume 31, Issue 5, pp 1207–1216 | Cite as

Phase Ib trial of the Toll-like receptor 9 agonist IMO-2055 in combination with 5-fluorouracil, cisplatin, and cetuximab as first-line palliative treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck

  • Jean-Pascal MachielsEmail author
  • Marie-Christine Kaminsky
  • Ulrich Keller
  • Tim H. Brümmendorf
  • Thomas Goddemeier
  • Ulf Forssmann
  • Jean-Pierre Delord


Background This Phase Ib trial assessed the maximum tolerated dose (MTD) and safety of the Toll-like receptor 9 agonist IMO-2055 combined with 5-fluorouracil, cisplatin, and cetuximab (PFE) as first-line palliative treatment in patients with relapsed and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Methods A standard 3 + 3 study design was used. Patients were sequentially enrolled to be treated with IMO-2055 (0.16, 0.32, or 0.48 mg/kg/day; days 1, 8, 15), 5-fluorouracil (1,000 mg/m2/day; days 1–4), cisplatin (100 mg/m2/day; day 1) and cetuximab (400 mg/m2/day first dose; then 250 mg/m2/day; days 1, 8, 15) every 3 weeks. Results Thirteen patients received IMO-2055. Dose-limiting toxicities (DLTs; ie, any Grade [G]3/4 treatment-related adverse events [TEAEs] in cycle 1) occurred in 2/4 patients treated with IMO-2055 0.32 mg/kg (G4 hypokalemia and hypomagnesemia [n = 1]; G4 septicemia, hyperthermia, febrile neutropenia, and G3 hypotension [n = 1]). In the IMO-2055 0.16-mg/kg expansion cohort, 1 patient experienced DLTs of G3 sepsis, bacteremia, and hyperthermia. The most common G ≥ 3 TEAEs were neutropenia (n = 9; not including febrile neutropenia [n = 1]), hypokalemia (n = 5), and hypomagnesemia (n = 4). Serious adverse events (SAEs) occurred in 8 patients, including 4 with SAEs considered IMO-2055 related; 1 of these patients died. Best response achieved overall was partial response in 3 patients and stable disease in 9 patients. The overall safety profile led to early trial termination; the safety monitoring committee did not confirm the MTD (formally IMO-2055 0.16 mg/kg). Conclusions Regimens combining IMO-2055 and PFE cannot be recommended for further development in R/M SCCHN patients.


Squamous cell carcinoma of the head and neck (SCCHN) IMO-2055 (EMD 1201081) Toll-like receptor 9 (TLR9) agonist, cetuximab, Phase I 



The authors would like to thank patients, investigators, co-investigators, and the study teams at each of the participating centers and at Merck KGaA, Darmstadt, Germany, and Merck Serono SA – Geneva, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany). Editorial and medical writing support in the preparation of this manuscript was provided by Marianne Eyholzer, PhD, TRM Oncology, The Hague, The Netherlands, funded by Merck KGaA, Darmstadt, Germany. The clinical trial was sponsored by Merck KGaA, Darmstadt, Germany.

Ethical Standards

This clinical trial was conducted in compliance with the clinical trial protocol, the Declaration of Helsinki, the International Conference on Harmonization guidelines for Good Clinical Practice (ICH Topic E6, 1996), and applicable regulatory requirements. Informed consent was obtained from all patients prior to their inclusion into the trial.

Conflict of interest

JP Machiels, MC Kaminsky, and JP Delord declare that they have no conflict of interest. U Keller and TH Brümmendorf are members of the advisory board and speakers for Merck KGaA, Darmstadt, Germany. T Goddemeier is an employee of Merck KGaA, Darmstadt, Germany. U Forssmann is an employee of Merck Serono SA – Geneva, Switzerland (a branch of Merck Serono SA, Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany).


  1. 1.
    Westra WH (2009) The changing face of head and neck cancer in the 21st century: the impact of HPV on the epidemiology and pathology of oral cancer. Head Neck Pathol 3:78–81CrossRefGoogle Scholar
  2. 2.
    Worsham MJ (2011) Identifying the risk factors for late-stage head and neck cancer. Expert Rev Anticancer Ther 11:1321–1325CrossRefGoogle Scholar
  3. 3.
    Langer CJ (2008) Targeted therapy in head and neck cancer: state of the art 2007 and review of clinical applications. Cancer 112:2635–2645CrossRefGoogle Scholar
  4. 4.
    Gibson MK, Li Y, Murphy B et al (2005) Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 23:3562–3567CrossRefGoogle Scholar
  5. 5.
    Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127CrossRefGoogle Scholar
  6. 6.
    Grégoire V, Lefebvre J-L, Licitra L, Felip E (2010) Squamous cell carcinoma of the head and neck: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(suppl 5):v184–v186CrossRefGoogle Scholar
  7. 7.
    Damiano V, Caputo R, Bianco R et al (2006) Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors. Clin Cancer Res 12:577–583CrossRefGoogle Scholar
  8. 8.
    Damiano V, Caputo R, Garofalo S et al (2007) TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts. Proc Natl Acad Sci USA 104:12468–12473CrossRefGoogle Scholar
  9. 9.
    Rosa R, Melisi D, Damiano V et al (2011) Toll-like receptor 9 agonist IMO cooperates with cetuximab in K-ras mutant colorectal and pancreatic cancers. Clin Cancer Res 17:6531–6541CrossRefGoogle Scholar
  10. 10.
    Vicari AP, Luu R, Zhang N et al (2009) Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse. Cancer Immunol Immunother 58:615–628CrossRefGoogle Scholar
  11. 11.
    Zent CS, Smith BJ, Ballas ZK et al (2012) Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. Leuk Lymphoma 53:211–217CrossRefGoogle Scholar
  12. 12.
    Kim YH, Girardi M, Duvic M et al (2010) Phase I trial of a Toll-like receptor 9 agonist, PF-3512676 (CPG 7909), in patients with treatment-refractory, cutaneous T-cell lymphoma. J Am Acad Dermatol 63:975–983CrossRefGoogle Scholar
  13. 13.
    Thompson JA, Kuzel T, Drucker BJ, Urba WJ, Bukowski RM (2009) Safety and efficacy of PF-3512676 for the treatment of stage IV renal cell carcinoma: an open-label, multicenter phase I/II study. Clin Genitourin Cancer 7:E58–E65CrossRefGoogle Scholar
  14. 14.
    Kuzel T, Dutcher J, Ebbinghaus S et al (2009) A phase 2 multicenter, randomized, open-label study of two dose levels of IMO-2055 in patients with metastatic or recurrent renal cell carcinoma. Presented at the 8th International Kidney Cancer Symposium (Sept 25–26):
  15. 15.
    Hofmann MA, Kors C, Audring H, Walden P, Sterry W, Trefzer U (2008) Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma. J Immunother 31:520–527CrossRefGoogle Scholar
  16. 16.
    Smith DA, Conkling P, Richards DA et al (2012) Efficacy and safety of IMO-2055, a novel TLR9 agonist, in combination with erlotinib (E) and bevacizumab (bev) in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed following prior chemotherapy. J Clin Oncol 30(suppl; abstract e18047)Google Scholar
  17. 17.
    Manegold C, van Zandwijk N, Szczesna A et al (2012) A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol 23:72–77CrossRefGoogle Scholar
  18. 18.
    Hirsh V, Paz-Ares L, Boyer M et al (2011) Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 29:2667–2674CrossRefGoogle Scholar
  19. 19.
    Malik S, Hwang J, Cotarla I et al (2007) Initial phase 1 results of gemcitabine, carboplatin and IMO-2055, a toll like receptor 9 (TLR9) agonist, in patients (pts) with advanced solid tumors: P3-112. J Thorac Oncol 2:S726–S727CrossRefGoogle Scholar
  20. 20.
    Storer BE (1989) Design and analysis of phase I clinical trials. Biometrics 45:925–937CrossRefGoogle Scholar
  21. 21.
    Yao X, Panichpisal K, Kurtzman N, Nugent K (2007) Cisplatin nephrotoxicity: a review. Am J Med Sci 334:115–124CrossRefGoogle Scholar
  22. 22.
    Sánchez-González PD, López-Hernández FJ, López-Novoa JM, Morales AI (2011) An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity. Crit Rev Toxicol 41:803–821CrossRefGoogle Scholar
  23. 23.
    Stoehlmacher-Williams J, Villanueva C, Foa P et al (2012) Safety and efficacy of panitumumab (pmab) in HPV-positive (+) and HPV-negative (−) recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Analysis of the global phase III SPECTRUM trial. J Clin Oncol 30 (suppl; abstract 5504)Google Scholar
  24. 24.
    Vermorken JB, Stöhlmacher J, Davidenko I et al (2009) An analysis of safety in patients (pts) with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) receiving chemotherapy (CT) with or without panitumumab (pmab) in a phase III clinical trial (SPECTRUM). J Clin Oncol 27:15 s(suppl; abstract 6050)CrossRefGoogle Scholar
  25. 25.
    Vermorken JB, Guigay J, Mesia R et al (2011) Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part. Br J Cancer 104:1691–1696CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jean-Pascal Machiels
    • 1
    • 8
    Email author
  • Marie-Christine Kaminsky
    • 2
  • Ulrich Keller
    • 3
  • Tim H. Brümmendorf
    • 4
  • Thomas Goddemeier
    • 5
  • Ulf Forssmann
    • 6
  • Jean-Pierre Delord
    • 7
  1. 1.Service d’Oncologie Médicale, Centre du Cancer, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (IREC, MIRO)Université Catholique de LouvainBruxellesBelgium
  2. 2.Département d’Oncologie MédicaleCentre Alexis VautrinVandoeuvre-lès-NancyFrance
  3. 3.III. Medizinische Klinik, Klinikum Rechts der IsarTechnische Universität MünchenMunichGermany
  4. 4.Klinik für Onkologie und HämatologieUniversitätsklinikum der Rheinisch-Wesfählischen Technischen Hochschule (RWTH) AachenAachenGermany
  5. 5.Merck KGgADarmstadtGermany
  6. 6.Merck Serono SA - GenevaGenevaSwitzerland
  7. 7.Clinical Research Unit and Pharmacology LabInstitut Claudius RegaudToulouseFrance
  8. 8.Université Catholique de LouvainBruxellesBelgium

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