title: Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma.
abstract: BACKGROUND
  This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM).
  
  
  METHODS
  Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m(2)/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m(2) for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression.
  
  
  RESULTS
  Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants.
  
  
  CONCLUSIONS
  Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: Louis B
authors.initials: LB
authors.lastname: Nabors
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: Warren P
authors.initials: WP
authors.lastname: Mason
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: James R
authors.initials: JR
authors.lastname: Perry
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: William
authors.initials: W
authors.lastname: Shapiro
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: Petr
authors.initials: P
authors.lastname: Kavan
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: David
authors.initials: D
authors.lastname: Mathieu
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: Surasak
authors.initials: S
authors.lastname: Phuphanich
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Cseh
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: Yali
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: Julie
authors.initials: J
authors.lastname: Cong
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: Sven
authors.initials: S
authors.lastname: Wind
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts (D.A.R.); University of Alabama, Birmingham, Alabama (L.B.N.); Princess Margaret Hospital, Toronto, Ontario, Canada (W.P.M.); Odette Cancer Centre, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (J.R.P.); Barrow Neurological Institute, Phoenix, Arizona (W.S.); Department of Medical Oncology, McGill University, Montréal, Quebec, Canada (P.K.); Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (D.M.); Johnnie Cochran Brain Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California (S.P., A.C.); Boehringer Ingelheim R.C.V GmbH & Co KG, 1120 Vienna, Austria (A.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (Y.F., J.C.); Boehringer Ingelheim Pharma GmbH & Co. K.G., 88400 Biberach, Germany (S.S.W.); CancerCare Manitoba, Winnipeg, Manitoba, Canada (D.D.E.).
authors.forename: David D
authors.initials: DD
authors.lastname: Eisenstat
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D000077716:Afatinib; D000970:Antineoplastic Agents; D003606:Dacarbazine; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077204:Temozolomide
keywords: EGFRvIII; ErbB family; afatinib; glioblastoma; temozolomide