PMID- 22805331
OWN - NLM
STAT- MEDLINE
DCOM- 20121019
LR  - 20211021
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 107
IP  - 4
DP  - 2012 Aug 7
TI  - A phase I dose-escalation study of aflibercept administered in combination with 
      pemetrexed and cisplatin in patients with advanced solid tumours.
PG  - 604-11
LID - 10.1038/bjc.2012.319 [doi]
AB  - BACKGROUND: To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics 
      of aflibercept, and to identify the recommended phase II dose (RP2D) of 
      aflibercept in combination with pemetrexed and cisplatin. METHODS: Aflibercept 
      was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with 
      fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 
      weeks. Blood samples were collected for PK analyses. Serum antiaflibercept 
      antibodies were quantified to assess their impact on systemic aflibercept 
      concentrations. RESULTS: Eighteen patients were enrolled. One patient dosed at 4 
      mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), 
      which prompted a cohort expansion. No further DLTs were observed in the 4 mg 
      kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of 
      all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia 
      (78), and neutropenia (72). Grade >/= 3 AEs consistent with anti-vascular 
      endothelial growth factor therapy included (%): hypertension (22), pulmonary 
      embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild 
      neurocognitive disturbance. No episodes of reversible posterior 
      leukoencephalopathy syndrome (RPLS) were noted. CONCLUSION: The results of this 
      phase I study allowed further evaluation of the combination of aflibercept with 
      pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg 
      kg(-1), to be administered intravenously every 3 weeks in combination with 
      pemetrexed and cisplatin.
FAU - Diaz-Padilla, I
AU  - Diaz-Padilla I
AD  - Division of Medical Oncology and Hematology, Department of Medicine, Princess 
      Margaret Hospital, University Health Network, University of Toronto, 610 
      University Avenue, 5-700, Toronto, Ontario M5G 2M9, Canada. ivan.padilla@uhn.ca
FAU - Siu, L L
AU  - Siu LL
FAU - San Pedro-Salcedo, M
AU  - San Pedro-Salcedo M
FAU - Razak, A R A
AU  - Razak AR
FAU - Colevas, A D
AU  - Colevas AD
FAU - Shepherd, F A
AU  - Shepherd FA
FAU - Leighl, N B
AU  - Leighl NB
FAU - Neal, J W
AU  - Neal JW
FAU - Thibault, A
AU  - Thibault A
FAU - Liu, L
AU  - Liu L
FAU - Lisano, J
AU  - Lisano J
FAU - Gao, B
AU  - Gao B
FAU - Lawson, E B
AU  - Lawson EB
FAU - Wakelee, H A
AU  - Wakelee HA
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20120717
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Glutamates)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 15C2VL427D (aflibercept)
RN  - 5Z93L87A1R (Guanine)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
MH  - Cisplatin/*administration & dosage
MH  - Drug Administration Schedule
MH  - Fatigue/chemically induced
MH  - Female
MH  - Glutamates/*administration & dosage
MH  - Guanine/administration & dosage/*analogs & derivatives
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Nausea/chemically induced
MH  - Neoplasms/*drug therapy
MH  - Pemetrexed
MH  - Receptors, Vascular Endothelial Growth Factor
MH  - Recombinant Fusion Proteins/*administration & dosage/blood
PMC - PMC3419963
COIS- LLS and HAW receive research funding from Regeneron Pharmaceuticals. FAS has 
      received honoraria from Regeneron Pharmaceuticals. AT, LL, JL, BG, and EBL are 
      employees of Regeneron Pharmaceuticals. All remaining authors declare no conflict 
      of interest.
EDAT- 2012/07/19 06:00
MHDA- 2012/10/20 06:00
PMCR- 2013/08/07
CRDT- 2012/07/19 06:00
PHST- 2012/07/19 06:00 [entrez]
PHST- 2012/07/19 06:00 [pubmed]
PHST- 2012/10/20 06:00 [medline]
PHST- 2013/08/07 00:00 [pmc-release]
AID - bjc2012319 [pii]
AID - 10.1038/bjc.2012.319 [doi]
PST - ppublish
SO  - Br J Cancer. 2012 Aug 7;107(4):604-11. doi: 10.1038/bjc.2012.319. Epub 2012 Jul 
      17.