A phase 1b study of cetuximab and BYL719 (alpelisib) concurrent with intensity modulated radiation therapy in stage III-IVB head and neck squamous cell carcinoma Journal Article
| Authors: | Dunn, L. A.; Riaz, N.; Fury, M. G.; McBride, S. M.; Michel, L.; Lee, N. Y.; Sherman, E. J.; Baxi, S. S.; Haque, S. S.; Katabi, N.; Wong, R. J.; Xiao, H.; Ho, A. L.; Pfister, D. G. |
| Article Title: | A phase 1b study of cetuximab and BYL719 (alpelisib) concurrent with intensity modulated radiation therapy in stage III-IVB head and neck squamous cell carcinoma |
| Abstract: | Purpose: Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration–approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. Methods and Materials: This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. Results: Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. Conclusions: The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted. © 2019 Elsevier Inc. |
| Keywords: | adult; clinical article; treatment response; aged; fatigue; intensity modulated radiation therapy; advanced cancer; diarrhea; drug dose reduction; drug withdrawal; recommended drug dose; side effect; cancer patient; cancer staging; nuclear magnetic resonance imaging; magnetic resonance imaging; anorexia; low drug dose; phase 2 clinical trial; anemia; nausea; vomiting; radiotherapy; food and drug administration; mutational analysis; cetuximab; alanine aminotransferase blood level; aspartate aminotransferase blood level; dizziness; drug dose escalation; fever; hyperglycemia; loading drug dose; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; dysphagia; maculopapular rash; xerostomia; alkaline phosphatase blood level; headache; maximum tolerated dose; phase 1 clinical trial; toxicity; dyspepsia; hand foot syndrome; dry skin; intensity-modulated radiation therapy; lymphocyte count; radiation dermatitis; oral mucositis; mouth pain; dysgeusia; sore throat; chemical activation; cell signaling; head and neck squamous cell carcinoma; dose limiting toxicity; drug products; body weight loss; head-and-neck squamous cell carcinoma; methods and materials; human; male; female; priority journal; article; alpelisib; american joint committee on cancers; presyncope |
| Journal Title: | International Journal of Radiation Oncology, Biology, Physics |
| Volume: | 106 |
| Issue: | 3 |
| ISSN: | 0360-3016 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2020-03-01 |
| Start Page: | 564 |
| End Page: | 570 |
| Language: | English |
| DOI: | 10.1016/j.ijrobp.2019.09.050 |
| PUBMED: | 31678634 |
| PROVIDER: | scopus |
| PMCID: | PMC9478566 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 March 2020 -- Source: Scopus |
