TY - JOUR
T1 - A Phase 1 Study of Afatinib in Combination with Postoperative Radiation Therapy with and Without Weekly Docetaxel in Intermediate- and High-Risk Patients with Resected Squamous Cell Carcinoma of the Head and Neck
AU - Margalit, Danielle N.
AU - Haddad, Robert I.
AU - Tishler, R. B.
AU - Chau, Nicole G.
AU - Schoenfeld, Jonathan D.
AU - Bakst, Richard L.
AU - Misiukiewicz, Krzysztof J.
AU - Gupta, Vishal
AU - Posner, Marshall
AU - Hanna, Glenn J.
AU - Mahmood, U.
AU - Rawal, Bhupendra
AU - Catalano, Paul J.
AU - Rath, L.
AU - Bacay, Alyssa
AU - McHugh, Patricia
AU - Rabinowits, Guilherme
N1 - Funding Information:
This work was supported by the National Comprehensive Cancer Network Oncology Research Program grant (to D.N.M.) from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) had no role in the design, analysis, or interpretation of the results in this study; BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances, as well as intellectual property considerations. This work was supported by the National Comprehensive Cancer Network Oncology Research Program grant (to D.N.M.) from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) had no role in the design, analysis, or interpretation of the results in this study; BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances, as well as intellectual property considerations. Disclosures: D.N.M. reports consulting for Galera Therapeutics. R.I.H. reports research support from BMS, Merck, Pfizer, and Genentech; and consulting forBMS, Merck, Celgene, Pfizer, Genenetch, Loxo Oncology, Inc, and Eisai. J.D.S. reports research support from BMS, Merck, and Regeneron; and serving as a consultant/advisory board member for AstraZeneca, BMS, Debiopharm, Nanobiotix, and Tilos. G.J.H. reports research support to institution from BMS and EMD Serono. R.B.T. reports serving on the data safety monitoring board for Intrexon/PSI and on the advisory board for EMD Serono and Regeneron. N.G.C. reports research funding from Merck, Pfizer, and GlaxoSmithKline. G.R. reports consulting for EMD Serono, Pfizer, Merck, Regeneron, Sanofi, and Castle; and owning stocks in Regeneron and Syros pharmaceuticals. We thank the patients and their families who participated in the study. We would like to thank Farzana Masood, clinical research manager at Dana-Farber Cancer Institute, for her contributions to the study. This work was supported by the National Comprehensive Cancer Network Oncology Research Program grant (to D.N.M.) from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) had no role in the design, analysis, or interpretation of the results in this study; BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances, as well as intellectual property considerations. Disclosures: D.N.M. reports consulting for Galera Therapeutics. R.I.H. reports research support from BMS, Merck, Pfizer, and Genentech; and consulting forBMS, Merck, Celgene, Pfizer, Genenetch, Loxo Oncology, Inc, and Eisai. J.D.S. reports research support from BMS, Merck, and Regeneron; and serving as a consultant/advisory board member for AstraZeneca, BMS, Debiopharm, Nanobiotix, and Tilos. G.J.H. reports research support to institution from BMS and EMD Serono. R.B.T. reports serving on the data safety monitoring board for Intrexon/PSI and on the advisory board for EMD Serono and Regeneron. N.G.C. reports research funding from Merck, Pfizer, and GlaxoSmithKline. G.R. reports consulting for EMD Serono, Pfizer, Merck, Regeneron, Sanofi, and Castle; and owning stocks in Regeneron and Syros pharmaceuticals.
Funding Information:
This work was supported by the National Comprehensive Cancer Network Oncology Research Program grant (to D.N.M.) from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) had no role in the design, analysis, or interpretation of the results in this study; BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances, as well as intellectual property considerations. We thank the patients and their families who participated in the study. We would like to thank Farzana Masood, clinical research manager at Dana-Farber Cancer Institute, for her contributions to the study.
Funding Information:
This work was supported by the National Comprehensive Cancer Network Oncology Research Program grant (to D.N.M.) from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) had no role in the design, analysis, or interpretation of the results in this study; BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances, as well as intellectual property considerations.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Purpose: To determine the maximum tolerated dose and tolerability of (1) afatinib in combination with postoperative radiation therapy (PORT) for patients with intermediate-risk squamous cell carcinoma of the head and neck (SCCHN) and (2) afatinib in combination with PORT and weekly docetaxel for high-risk SCCHN. Methods and Materials: An open-label, multicenter, 2-cohort, phase 1 dose-escalation trial was conducted using a 3 + 3 design. Eligible patients had definitive surgery for SCCHN, including the oral cavity, oropharynx, larynx, or hypopharynx and had intermediate- or high-risk pathologic features. Afatinib was given for a 1-week lead in before PORT and daily during 6 to 6.5 weeks of PORT with or without weekly docetaxel. The starting dose was 30 mg and could be escalated to 40 mg or de-escalated to 20 mg. The primary objective was to determine the maximum tolerated dose of afatinib with PORT or PORT + docetaxel. Results: Between April 2013 and November 2017, 27 patients were enrolled and started study treatment, including 16 intermediate-risk patients and 11 high-risk patients, all with Eastern Cooperative Oncology Group performance status of 0 to 1. Most patients (n = 25) had oral cavity cancer and were treated to a median total dose of 60 Gy in the intermediate-risk arm and 65 Gy in the high-risk arm. There was 1 grade 4 event, but no deaths. The maximum tolerated dose was not established owing to dose-limiting toxicities (DLTs) in both arms. In the high-risk arm, DLTs were grade 3 mucositis (n = 3) and grade 3 diarrhea/hypokalemia (n = 1). In the intermediate-risk arm, DLTs were grade 3 mucositis (n = 4) and grade 3 diarrhea (n = 2). Conclusions: Afatinib in combination with PORT for mucosal SCCHN was difficult to tolerate because of grade 3 toxicity, mostly mucositis, in a cohort of patients requiring high-dose PORT to the oral cavity. This regimen may be better tolerated for a non-oral cavity site or if given in a different schedule.
AB - Purpose: To determine the maximum tolerated dose and tolerability of (1) afatinib in combination with postoperative radiation therapy (PORT) for patients with intermediate-risk squamous cell carcinoma of the head and neck (SCCHN) and (2) afatinib in combination with PORT and weekly docetaxel for high-risk SCCHN. Methods and Materials: An open-label, multicenter, 2-cohort, phase 1 dose-escalation trial was conducted using a 3 + 3 design. Eligible patients had definitive surgery for SCCHN, including the oral cavity, oropharynx, larynx, or hypopharynx and had intermediate- or high-risk pathologic features. Afatinib was given for a 1-week lead in before PORT and daily during 6 to 6.5 weeks of PORT with or without weekly docetaxel. The starting dose was 30 mg and could be escalated to 40 mg or de-escalated to 20 mg. The primary objective was to determine the maximum tolerated dose of afatinib with PORT or PORT + docetaxel. Results: Between April 2013 and November 2017, 27 patients were enrolled and started study treatment, including 16 intermediate-risk patients and 11 high-risk patients, all with Eastern Cooperative Oncology Group performance status of 0 to 1. Most patients (n = 25) had oral cavity cancer and were treated to a median total dose of 60 Gy in the intermediate-risk arm and 65 Gy in the high-risk arm. There was 1 grade 4 event, but no deaths. The maximum tolerated dose was not established owing to dose-limiting toxicities (DLTs) in both arms. In the high-risk arm, DLTs were grade 3 mucositis (n = 3) and grade 3 diarrhea/hypokalemia (n = 1). In the intermediate-risk arm, DLTs were grade 3 mucositis (n = 4) and grade 3 diarrhea (n = 2). Conclusions: Afatinib in combination with PORT for mucosal SCCHN was difficult to tolerate because of grade 3 toxicity, mostly mucositis, in a cohort of patients requiring high-dose PORT to the oral cavity. This regimen may be better tolerated for a non-oral cavity site or if given in a different schedule.
UR - http://www.scopus.com/inward/record.url?scp=85067034164&partnerID=8YFLogxK
U2 - 10.1016/j.ijrobp.2019.04.034
DO - 10.1016/j.ijrobp.2019.04.034
M3 - Article
C2 - 31082494
AN - SCOPUS:85067034164
SN - 0360-3016
VL - 105
SP - 132
EP - 139
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 1
ER -