PMID- 27872953
OWN - NLM
STAT- MEDLINE
DCOM- 20170602
LR  - 20181203
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 79
IP  - 1
DP  - 2017 Jan
TI  - A phase I study of afatinib combined with paclitaxel and bevacizumab in patients 
      with advanced solid tumors.
PG  - 17-27
LID - 10.1007/s00280-016-3189-1 [doi]
AB  - PURPOSE: The combination of afatinib, an irreversible ErbB family blocker, with 
      paclitaxel and bevacizumab was assessed in patients with advanced solid tumors. 
      METHODS: This phase I study used a 3 + 3 design to determine the maximum 
      tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. 
      Safety, pharmacokinetics, and anti-tumor activity were also assessed. The 
      starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel 
      (fixed dose 80 mg/m(2), Days 1, 8, and 15 of a 4-week cycle) and intravenous 
      bevacizumab 5 mg/kg every 2 weeks. RESULTS: Twenty-nine patients were enroled. 
      The afatinib dose was de-escalated to 30 mg and then 20 mg after 2/6 and 2/5 
      evaluable patients developed dose-limiting toxicities at 40 and 30 mg, 
      respectively, when combined with paclitaxel and bevacizumab 5 mg/kg. The 
      bevacizumab dose was subsequently escalated to 10 mg/kg, and MTD was defined as 
      afatinib 20 mg plus paclitaxel 80 mg/m(2) and bevacizumab 10 mg/kg. Frequent (any 
      grade) treatment-related adverse events (AEs) included diarrhea (83%), rash/acne 
      (83%), fatigue (79%), mucosal inflammation (59%), and nausea (59%). Based on 
      overall safety, bevacizumab was amended to 7.5 mg/kg for the recommended phase II 
      dose. Pharmacokinetic analyses suggested no relevant drug-drug interactions. 
      Three (10%) confirmed partial responses were observed; 15 (52%) patients had 
      stable disease. CONCLUSIONS: The recommended phase II dose schedule was afatinib 
      20 mg/day with paclitaxel 80 mg/m(2) (Days 1, 8, and 15 every 4 weeks) and 
      bevacizumab 7.5 mg/kg every 2 weeks. At this dose schedule, AEs were manageable, 
      and anti-tumor activity was observed.
FAU - Spicer, James
AU  - Spicer J
AD  - King's College London, Guy's Hospital, 3rd Floor, Bermondsey Wing, Great Maze 
      Pond, London, SE1 9RT, UK. james.spicer@kcl.ac.uk.
FAU - Irshad, Sheeba
AU  - Irshad S
AD  - King's College London, Guy's Hospital, 3rd Floor, Bermondsey Wing, Great Maze 
      Pond, London, SE1 9RT, UK.
FAU - Ang, Joo Ern
AU  - Ang JE
AD  - Royal Marsden NHS Foundation Trust, Surrey, UK.
FAU - Enting, Deborah
AU  - Enting D
AD  - King's College London, Guy's Hospital, 3rd Floor, Bermondsey Wing, Great Maze 
      Pond, London, SE1 9RT, UK.
FAU - Kristeleit, Rebecca
AU  - Kristeleit R
AD  - Royal Marsden NHS Foundation Trust, Surrey, UK.
AD  - University College London Cancer Institute, London, UK.
FAU - Uttenreuther-Fischer, Martina
AU  - Uttenreuther-Fischer M
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
FAU - Pemberton, Karine
AU  - Pemberton K
AD  - Boehringer Ingelheim Ltd, Bracknell, UK.
FAU - Pelling, Katy
AU  - Pelling K
AD  - Boehringer Ingelheim Ltd, Bracknell, UK.
FAU - Schnell, David
AU  - Schnell D
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
FAU - de Bono, Johann
AU  - de Bono J
AD  - Royal Marsden NHS Foundation Trust, Surrey, UK.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20161121
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Quinazolines)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - 41UD74L59M (Afatinib)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Adult
MH  - Afatinib
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Bevacizumab/administration & dosage/adverse effects
MH  - Female
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Paclitaxel/administration & dosage/adverse effects/pharmacokinetics
MH  - Quinazolines/administration & dosage/adverse effects/pharmacokinetics
PMC - PMC5225194
OTO - NOTNLM
OT  - Afatinib
OT  - Bevacizumab
OT  - Paclitaxel
OT  - Phase I
OT  - Solid tumors
COIS- James Spicer reports consultant/advisory roles from Boehringer Ingelheim Ltd. 
      Sheeba Irshad, Joo Ern Ang, Deborah Enting, and Rebecca Kristeleit have declared 
      no conflict of interest. Martina Uttenreuther-Fischer, Karine Pemberton, Katy 
      Pelling, and David Schnell report employment from Boehringer Ingelheim Ltd. 
      Johann de Bono reports consultant/advisory roles from AstraZeneca, 
      GlaxoSmithKline, Genentech, Astellas, and Sanofi. Ethical standards The study was 
      conducted in accordance with the Declaration of Helsinki and Good Clinical 
      Practice guidelines, and the study protocol was approved by the UK National 
      Research Ethics Review Service. Informed consent Written informed consent was 
      obtained from all study participants.
EDAT- 2016/11/23 06:00
MHDA- 2017/06/03 06:00
PMCR- 2016/11/21
CRDT- 2016/11/23 06:00
PHST- 2016/06/15 00:00 [received]
PHST- 2016/10/31 00:00 [accepted]
PHST- 2016/11/23 06:00 [pubmed]
PHST- 2017/06/03 06:00 [medline]
PHST- 2016/11/23 06:00 [entrez]
PHST- 2016/11/21 00:00 [pmc-release]
AID - 10.1007/s00280-016-3189-1 [pii]
AID - 3189 [pii]
AID - 10.1007/s00280-016-3189-1 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2017 Jan;79(1):17-27. doi: 10.1007/s00280-016-3189-1. 
      Epub 2016 Nov 21.