title: 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.
abstract: 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/m(2)/day; days 1-4), cisplatin (100 mg/m(2)/day; day 1) and cetuximab (400 mg/m(2)/day first dose; then 250 mg/m(2)/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.
authors: Service d'Oncologie Médicale, Centre du Cancer, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (IREC, MIRO), Université Catholique de Louvain, Bruxelles, Belgium, Jean-Pascal.Machiels@uclouvain.be.
authors: Jean-Pascal
authors: JP
authors: Machiels
authors: Marie-Christine
authors: MC
authors: Kaminsky
authors: Ulrich
authors: U
authors: Keller
authors: Tim H
authors: TH
authors: Brümmendorf
authors: Thomas
authors: T
authors: Goddemeier
authors: Ulf
authors: U
authors: Forssmann
authors: Jean-Pierre
authors: JP
authors: Delord
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009841:Oligonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D051217:Toll-Like Receptor 9 / Q000819:agonists; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C587694:IMO-2055; D009841:Oligonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil
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