PMID- 25140039
OWN - NLM
STAT- MEDLINE
DCOM- 20160318
LR  - 20220318
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 17
IP  - 3
DP  - 2015 Mar
TI  - Phase I/randomized phase II study of afatinib, an irreversible ErbB family 
      blocker, with or without protracted temozolomide in adults with recurrent 
      glioblastoma.
PG  - 430-9
LID - 10.1093/neuonc/nou160 [doi]
AB  - 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.
CI  - (c) The Author(s) 2014. Published by Oxford University Press on behalf of the 
      Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Reardon, David A
AU  - Reardon DA
AD  - 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, Montreal, 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.).
FAU - Nabors, Louis B
AU  - Nabors LB
AD  - 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, Montreal, 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.).
FAU - Mason, Warren P
AU  - Mason WP
AD  - 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, Montreal, 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.).
FAU - Perry, James R
AU  - Perry JR
AD  - 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, Montreal, 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.).
FAU - Shapiro, William
AU  - Shapiro W
AD  - 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, Montreal, 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.).
FAU - Kavan, Petr
AU  - Kavan P
AD  - 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, Montreal, 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.).
FAU - Mathieu, David
AU  - Mathieu D
AD  - 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, Montreal, 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.).
FAU - Phuphanich, Surasak
AU  - Phuphanich S
AD  - 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, Montreal, 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.).
FAU - Cseh, Agnieszka
AU  - Cseh A
AD  - 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, Montreal, 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.).
FAU - Fu, Yali
AU  - Fu Y
AD  - 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, Montreal, 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.).
FAU - Cong, Julie
AU  - Cong J
AD  - 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, Montreal, 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.).
FAU - Wind, Sven
AU  - Wind S
AD  - 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, Montreal, 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.).
FAU - Eisenstat, David D
AU  - Eisenstat DD
AD  - 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, Montreal, 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.).
CN  - BI 1200 36 Trial Group and the Canadian Brain Tumour Consortium
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20140819
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinazolines)
RN  - 41UD74L59M (Afatinib)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Adult
MH  - Afatinib
MH  - Aged
MH  - Antineoplastic Agents/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Brain Neoplasms/*drug therapy/mortality
MH  - Dacarbazine/administration & dosage/*analogs & derivatives/therapeutic use
MH  - Drug Therapy, Combination
MH  - Female
MH  - Glioblastoma/*drug therapy/mortality
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Quinazolines/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Receptor, ErbB-2/antagonists & inhibitors
MH  - Temozolomide
MH  - Treatment Outcome
PMC - PMC4483093
OTO - NOTNLM
OT  - EGFRvIII
OT  - ErbB family
OT  - afatinib
OT  - glioblastoma
OT  - temozolomide
FIR - Reardon, David
IR  - Reardon D
FIR - Wen, Patrick
IR  - Wen P
FIR - Mikkelson, Tom
IR  - Mikkelson T
FIR - Portnow, Jana
IR  - Portnow J
FIR - Giglio, Pierre
IR  - Giglio P
FIR - Lai, Rose
IR  - Lai R
FIR - New, Pamela
IR  - New P
FIR - Shapiro, William
IR  - Shapiro W
FIR - Phuphanich, Surasak
IR  - Phuphanich S
FIR - Nabors, Louis
IR  - Nabors L
FIR - Fink, Karen
IR  - Fink K
FIR - Chowdhary, Sajeel
IR  - Chowdhary S
FIR - Madison, Michael
IR  - Madison M
FIR - Taylor, Lynn
IR  - Taylor L
FIR - Hadjipanayis, Constantinos
IR  - Hadjipanayis C
FIR - Madarnas, Yolanda
IR  - Madarnas Y
FIR - Kavan, Petr
IR  - Kavan P
FIR - Perry, James
IR  - Perry J
FIR - Mason, Warren
IR  - Mason W
FIR - Easaw, Jacob
IR  - Easaw J
FIR - Vallieres, Isabelle
IR  - Vallieres I
FIR - Mathieu, David
IR  - Mathieu D
FIR - Hirte, Hal
IR  - Hirte H
FIR - Whitlock, Pierre
IR  - Whitlock P
FIR - Eisenstat, David
IR  - Eisenstat D
FIR - MacNeil, Mary V
IR  - MacNeil MV
FIR - Bolonna, Anusha
IR  - Bolonna A
FIR - Reardon, David A
IR  - Reardon DA
FIR - Cseh, Agnieszka
IR  - Cseh A
FIR - Fu, Yali
IR  - Fu Y
FIR - Cong, Julie
IR  - Cong J
FIR - Wind, Sven
IR  - Wind S
FIR - Eisenstat, David D
IR  - Eisenstat DD
FIR - Nabors, Louis B
IR  - Nabors LB
FIR - Mason, Warren P
IR  - Mason WP
FIR - Perry, James R
IR  - Perry JR
FIR - Shapiro, William
IR  - Shapiro W
FIR - Kavan, Petr
IR  - Kavan P
FIR - Mathieu, David
IR  - Mathieu D
FIR - Phuphanich, Surasak
IR  - Phuphanich S
EDAT- 2014/08/21 06:00
MHDA- 2016/03/19 06:00
PMCR- 2016/03/01
CRDT- 2014/08/21 06:00
PHST- 2014/04/07 00:00 [received]
PHST- 2014/07/07 00:00 [accepted]
PHST- 2014/08/21 06:00 [entrez]
PHST- 2014/08/21 06:00 [pubmed]
PHST- 2016/03/19 06:00 [medline]
PHST- 2016/03/01 00:00 [pmc-release]
AID - nou160 [pii]
AID - 10.1093/neuonc/nou160 [doi]
PST - ppublish
SO  - Neuro Oncol. 2015 Mar;17(3):430-9. doi: 10.1093/neuonc/nou160. Epub 2014 Aug 19.