title: A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma.
abstract: BACKGROUND
  Afatinib is an ErbB family receptor inhibitor with efficacy in head and neck squamous cell carcinoma (HNSCC). A phase I trial was conducted to determine the maximally tolerated dose (MTD) of afatinib in combination with carboplatin and paclitaxel as induction chemotherapy (IC).
  
  
  METHODS
  Patients with newly diagnosed, locally advanced HPV-negative or HPV-positive HNSCC with a significant smoking history were enrolled. Afatinib alone was given daily for two weeks as lead-in and subsequently given with carboplatin AUC 6mg/mlmin and paclitaxel 175mg/m(2) every 21days as IC. Afatinib was started at a dose of 20mg daily and dose escalated using a modified Fibonacci design. After completion of IC, afatinib was discontinued and patients received concurrent cisplatin 40mg/m(2) weekly and standard radiation. Toxicity was assessed using CTCAE version 4.0.
  
  
  RESULTS
  Seven of nine patients completed afatinib lead-in and IC. Five patients had partial response and two patients had stable disease after IC. Dose level 1 (afatinib 20mg) was well tolerated with one grade 3 (ALT elevation) and one grade 4 (neutropenia) toxicities. However, dose level 2 (afatinib 30mg) was not well tolerated with nine grade 3 (pneumonia, abdominal pain, diarrhea, pancytopenia, and UTI), two grade 4 (sepsis) and one grade 5 (death) toxicities.
  
  
  CONCLUSIONS
  The MTD of afatinib given with carboplatin AUC 6mg/mlmin and paclitaxel 175mg/m(2) is 20mg daily. Combination of afatinib at doses higher than 20mg with carboplatin and paclitaxel should be administered with caution due to the toxicities.
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States; Moffitt Cancer Center & Research Institute, Tampa, FL, United States. Electronic address: christine.chung@moffitt.org.
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: mrudek2@jhmi.edu.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: hkang30@jhmi.edu.
authors.forename: Hyunseok
authors.initials: H
authors.lastname: Kang
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: smarur1@jhmi.edu.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Marur
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: pjohn5@jhmi.edu.
authors.forename: Pritish
authors.initials: P
authors.lastname: John
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: tsottna@jhmi.edu.
authors.forename: Nancy
authors.initials: N
authors.lastname: Tsottles
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: sboneri1@jhmi.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bonerigo
authors.affiliation: Gentris, A CGI Company, Morrisville, NC, United States. Electronic address: Andy.Veasey@cgix.com.
authors.forename: Andy
authors.initials: A
authors.lastname: Veasey
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: akiess1@jhmi.edu.
authors.forename: Ana
authors.initials: A
authors.lastname: Kiess
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: hquon2@jhmi.edu.
authors.forename: Harry
authors.initials: H
authors.lastname: Quon
authors.affiliation: Vanderbilt University, Nashville, TN, United States. Electronic address: anthony.cmelak@vanderbilt.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cmelak
authors.affiliation: Vanderbilt University, Nashville, TN, United States. Electronic address: barbara.murphy@vanderbilt.edu.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Murphy
authors.affiliation: Vanderbilt University, Nashville, TN, United States. Electronic address: jill.gilbert@vanderbilt.edu.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilbert
mesh_terms: D000077716:Afatinib; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods; D004334:Drug Administration Schedule; D005260:Female; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077716:Afatinib; D016190:Carboplatin; D017239:Paclitaxel
keywords: ABCB1; Afatinib; Carboplatin; Efficacy; Head and neck squamous cell carcinoma; Paclitaxel; Phase I trial; Toxicity