PMID- 26492090
OWN - NLM
STAT- MEDLINE
DCOM- 20160701
LR  - 20181202
IS  - 1423-0232 (Electronic)
IS  - 0030-2414 (Linking)
VI  - 90
IP  - 1
DP  - 2016
TI  - Phase I Dose-Escalation and Pharmacokinetic Study of Intravenous Aflibercept in 
      Combination with Docetaxel, Cisplatin, and 5-Fluorouracil in Patients with 
      Advanced Solid Malignancies.
PG  - 10-20
LID - 10.1159/000440958 [doi]
AB  - PURPOSE: This phase I study (EudraCT No. 2006-001177-25) investigated 
      aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF 
      Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients 
      with advanced solid tumors. PATIENTS AND METHODS: Patients received 2, 4, or 6 
      mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 
      5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or 
      unacceptable toxicity. Primary objectives were to evaluate dose-limiting 
      toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. 
      Pharmacokinetics, tolerability, and antitumor activity were also investigated. 
      RESULTS: Forty-four patients were enrolled and treated (29 patients in a 
      dose-escalation phase and 15 patients in an expansion cohort). Following three 
      cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the 
      protocol was amended to allow earlier granulocyte colony-stimulating factor 
      support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there 
      were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 
      mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. 
      The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), 
      lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade 
      (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), 
      and proteinuria (11.4%). There were 15 partial responses, including 9 in patients 
      with gastroesophageal cancers. Thirteen patients had stable disease. CONCLUSION: 
      Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, 
      cisplatin, and 5- fluorouracil is the recommended dose for further clinical 
      development based on tolerability, pharmacokinetics, and antitumor activity.
CI  - (c) 2015 S. Karger AG, Basel.
FAU - Bahleda, Rastislav
AU  - Bahleda R
AD  - Drug Development Department, Institut Gustave Roussy, Villejuif, France.
FAU - Baker, Jackie
AU  - Baker J
FAU - Massard, Christophe
AU  - Massard C
FAU - Gadgeel, Sirish M
AU  - Gadgeel SM
FAU - Rogers, Jane E
AU  - Rogers JE
FAU - Izzedine, Hassan
AU  - Izzedine H
FAU - Deutsch, Eric
AU  - Deutsch E
FAU - Garris, Jeana L
AU  - Garris JL
FAU - Khan, Akbar
AU  - Khan A
FAU - Boelle, Emmanuelle
AU  - Boelle E
FAU - Assadourian, Sylvie
AU  - Assadourian S
FAU - Soria, Jean-Charles
AU  - Soria JC
FAU - Ajani, Jaffer A
AU  - Ajani JA
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20151023
PL  - Switzerland
TA  - Oncology
JT  - Oncology
JID - 0135054
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Taxoids)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
RN  - 15C2VL427D (aflibercept)
RN  - 15H5577CQD (Docetaxel)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
RN  - Q20Q21Q62J (Cisplatin)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse 
      effects/*pharmacokinetics/pharmacology
MH  - Cisplatin/administration & dosage
MH  - Docetaxel
MH  - Drug Administration Schedule
MH  - Febrile Neutropenia/chemically induced/prevention & control
MH  - Female
MH  - Fluorouracil/administration & dosage
MH  - Granulocyte Colony-Stimulating Factor/*administration & dosage
MH  - Humans
MH  - Hypertension/chemically induced
MH  - Infusions, Intravenous
MH  - Male
MH  - Middle Aged
MH  - Molecular Targeted Therapy
MH  - Neoplasms/*drug therapy/pathology
MH  - Receptors, Vascular Endothelial Growth Factor/*administration & dosage/adverse 
      effects/*pharmacokinetics/pharmacology
MH  - Recombinant Fusion Proteins/*administration & dosage/adverse 
      effects/*pharmacokinetics/pharmacology
MH  - Taxoids/administration & dosage
MH  - Thrombocytopenia/chemically induced
MH  - Treatment Outcome
MH  - Vascular Endothelial Growth Factor A/*antagonists & inhibitors
EDAT- 2015/10/23 06:00
MHDA- 2016/07/02 06:00
CRDT- 2015/10/23 06:00
PHST- 2015/01/18 00:00 [received]
PHST- 2015/09/02 00:00 [accepted]
PHST- 2015/10/23 06:00 [entrez]
PHST- 2015/10/23 06:00 [pubmed]
PHST- 2016/07/02 06:00 [medline]
AID - 000440958 [pii]
AID - 10.1159/000440958 [doi]
PST - ppublish
SO  - Oncology. 2016;90(1):10-20. doi: 10.1159/000440958. Epub 2015 Oct 23.