Summary
Background The phosphatidylinositol-3 kinase pathway is often altered in head and neck squamous cell carcinoma (HNSCC), and is involved in the resistance to EGFR inhibitors. Objective We investigated the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetics, and preliminary efficacy of the combination of copanlisib, an intravenous, pan-class I PI3K inhibitor, with the anti-EGFR monoclonal antibody cetuximab in recurrent and/or metastatic HNSCC patients in a phase I dose-escalation trial. Patients and methods Copanlisib was given intravenously on days 1, 8, and 15 of 28-day cycles at the dose of 45 mg and 30 mg, in combination with standard doses of weekly cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 on days 8, 15, and 22, and weekly thereafter). Results Three patients received copanlisib 45 mg, of whom two experienced grade 3 hyperglycemia during Cycle 1 that met the DLT criteria. Eight patients were then treated with copanlisib at the dose of 30 mg. Because of the occurrence of hyperglycemia, a premedication with metformine was introduced on the day of the injections. No DLTs were reported at this dose level. The trial was stopped early because of the unfavourable toxicity profile of the combination. Among eight evaluable patients for response, four patients (50%) had disease stabilization according to RECIST1.1 as best response. Conclusion Copanlisib combined with cetuximab demonstrated unfavorable toxicity and limited efficacy in heavily pretreated recurrent and/or metastatic HNSCC patients.
Trial registration NCT02822482, Date of registration: June 2016.
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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank the participating patients, the UNICANCER Head and Neck research team, Marta Jimenez, Celia Dupain, and Linda Larbi Cherif.
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The study was funded by Bayer.
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CLT, MA, KR, JG, and MC wrote the protocol. CLT, NI, ESB, FR, EB, MA, and DV contributed to the recruitment and treatment of patients in the trial. All authors contributed to the acquisition of data, the analysis, and the interpretation of data. CLT and GM designed the figures and wrote the first draft of the manuscript. All authors reviewed the manuscript before submission.
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All procedures performed in studies involving 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.
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CLT participated in advisory boards from MSD, BMS, Merck Serono, Astra Zeneca, Celgene, Seattle Genetics, Roche, Novartis, Rakuten, Nanobiotix, and GSK. JG participated in advisory boards from Astra Zeneca, BMS, Innate Pharma, Merck Serono, Roche, and as invited speaker for Merck SD and Merck Serono. All other authors have no conflict of interest to disclose.
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Marret, G., Isambert, N., Rezai, K. et al. Phase I trial of copanlisib, a selective PI3K inhibitor, in combination with cetuximab in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Invest New Drugs 39, 1641–1648 (2021). https://doi.org/10.1007/s10637-021-01152-z
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DOI: https://doi.org/10.1007/s10637-021-01152-z