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.

Abstract

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.

• Authors: Grégoire Marret, Nicolas Isambert, Keyvan Rezai, Jocelyn Gal, Esma Saada-Bouzid, Frédéric Rolland, Maggy Chausson, Edith Borcoman, Marie Alt, Jerzy Klijanienko, Damien Vansteene, Joël Guigay, Maud Kamal, Ivan Bièche, Christophe Le Tourneau, UNICANCER Head, Neck Group
• Journal: Investigational new drugs (Invest New Drugs) Vol. 39 Issue 6 Pg. 1641-1648 (12 2021) ISSN: 1573-0646 [Electronic] United States
• PMID: 34322775 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Antineoplastic Agents
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Quinazolines
• Cetuximab
• copanlisib

Topics

• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Area Under Curve
• Cetuximab (therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Head and Neck Neoplasms (drug therapy)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Phosphoinositide-3 Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Quinazolines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Squamous Cell Carcinoma of Head and Neck (drug therapy)