Christine H Chung1, Michelle A Rudek2, Hyunseok Kang3, Shanthi Marur4, Pritish John5, Nancy Tsottles6, Sarah Bonerigo7, Andy Veasey8, Ana Kiess9, Harry Quon10, Anthony Cmelak11, Barbara A Murphy12, Jill Gilbert13. 1. Johns Hopkins Medical Institutions, Baltimore, MD, United States; Moffitt Cancer Center & Research Institute, Tampa, FL, United States. Electronic address: christine.chung@moffitt.org. 2. Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: mrudek2@jhmi.edu. 3. Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: hkang30@jhmi.edu. 4. Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: smarur1@jhmi.edu. 5. Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: pjohn5@jhmi.edu. 6. Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: tsottna@jhmi.edu. 7. Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: sboneri1@jhmi.edu. 8. Gentris, A CGI Company, Morrisville, NC, United States. Electronic address: Andy.Veasey@cgix.com. 9. Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: akiess1@jhmi.edu. 10. Johns Hopkins Medical Institutions, Baltimore, MD, United States. Electronic address: hquon2@jhmi.edu. 11. Vanderbilt University, Nashville, TN, United States. Electronic address: anthony.cmelak@vanderbilt.edu. 12. Vanderbilt University, Nashville, TN, United States. Electronic address: barbara.murphy@vanderbilt.edu. 13. Vanderbilt University, Nashville, TN, United States. Electronic address: jill.gilbert@vanderbilt.edu.
Abstract
INTRODUCTION: 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). MATERIAL AND 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.
INTRODUCTION: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). MATERIAL AND 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: K Kian Ang; Jonathan Harris; Richard Wheeler; Randal Weber; David I Rosenthal; Phuc Felix Nguyen-Tân; William H Westra; Christine H Chung; Richard C Jordan; Charles Lu; Harold Kim; Rita Axelrod; C Craig Silverman; Kevin P Redmond; Maura L Gillison Journal: N Engl J Med Date: 2010-06-07 Impact factor: 91.245
Authors: Christine H Chung; Kim Ely; Loris McGavran; Marileila Varella-Garcia; Joel Parker; Natalie Parker; Carolyn Jarrett; Jesse Carter; Barbara A Murphy; James Netterville; Brian B Burkey; Robert Sinard; Anthony Cmelak; Shawn Levy; Wendell G Yarbrough; Robbert J C Slebos; Fred R Hirsch Journal: J Clin Oncol Date: 2006-09-01 Impact factor: 44.544
Authors: Tristan M Sissung; Klaus Mross; Seth M Steinberg; Dirk Behringer; William D Figg; Alex Sparreboom; Stephan Mielke Journal: Eur J Cancer Date: 2006-09-06 Impact factor: 9.162
Authors: Gypsyamber D'Souza; Aimee R Kreimer; Raphael Viscidi; Michael Pawlita; Carole Fakhry; Wayne M Koch; William H Westra; Maura L Gillison Journal: N Engl J Med Date: 2007-05-10 Impact factor: 91.245
Authors: Carole Fakhry; William H Westra; Sigui Li; Anthony Cmelak; John A Ridge; Harlan Pinto; Arlene Forastiere; Maura L Gillison Journal: J Natl Cancer Inst Date: 2008-02-12 Impact factor: 13.506
Authors: Marshall R Posner; Diane M Hershock; Cesar R Blajman; Elizabeth Mickiewicz; Eric Winquist; Vera Gorbounova; Sergei Tjulandin; Dong M Shin; Kevin Cullen; Thomas J Ervin; Barbara A Murphy; Luis E Raez; Roger B Cohen; Monica Spaulding; Roy B Tishler; Berta Roth; Rosana del Carmen Viroglio; Varagur Venkatesan; Ilya Romanov; Sanjiv Agarwala; K William Harter; Matthew Dugan; Anthony Cmelak; Arnold M Markoe; Paul W Read; Lynn Steinbrenner; A Dimitrios Colevas; Charles M Norris; Robert I Haddad Journal: N Engl J Med Date: 2007-10-25 Impact factor: 91.245
Authors: Christine H Chung; Beloo Mirakhur; Emily Chan; Quynh-Thu Le; Jordan Berlin; Michael Morse; Barbara A Murphy; Shama M Satinover; Jacob Hosen; David Mauro; Robbert J Slebos; Qinwei Zhou; Diane Gold; Tina Hatley; Daniel J Hicklin; Thomas A E Platts-Mills Journal: N Engl J Med Date: 2008-03-13 Impact factor: 91.245
Authors: Merrill S Kies; Floyd Christopher Holsinger; J Jack Lee; William N William; Bonnie S Glisson; Heather Y Lin; Jan S Lewin; Lawrence E Ginsberg; Katharine A Gillaspy; Erminia Massarelli; Lauren Byers; Scott M Lippman; Waun K Hong; Adel K El-Naggar; Adam S Garden; Vassiliki Papadimitrakopoulou Journal: J Clin Oncol Date: 2009-11-16 Impact factor: 44.544
Authors: Sharon Marsh; Howard McLeod; Eileen Dolan; Sunita J Shukla; Cara A Rabik; Li Gong; Tina Hernandez-Boussard; Xing Jian Lou; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2009-07 Impact factor: 2.089
Authors: Pei San Yee; Nur Syafinaz Zainal; Chai Phei Gan; Bernard K B Lee; Kein Seong Mun; Mannil Thomas Abraham; Siti Mazlipah Ismail; Zainal Ariff Abdul Rahman; Vyomesh Patel; Sok Ching Cheong Journal: Target Oncol Date: 2019-04 Impact factor: 4.493
Authors: Ines De Pauw; Filip Lardon; Jolien Van den Bossche; Hasan Baysal; Erik Fransen; Vanessa Deschoolmeester; Patrick Pauwels; Marc Peeters; Jan Baptist Vermorken; An Wouters Journal: Mol Oncol Date: 2018-05-01 Impact factor: 6.603