PMID- 18219445
OWN - NLM
STAT- MEDLINE
DCOM- 20080717
LR  - 20211020
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 26
IP  - 2
DP  - 2008 Apr
TI  - Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in 
      patients with solid tumors.
PG  - 159-67
LID - 10.1007/s10637-008-9112-9 [doi]
AB  - BACKGROUND: ZD6126 is a novel vascular-targeting agent that disrupts the 
      endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature 
      and extensive tumor necrosis. This Phase I clinical study was conducted to 
      evaluate the dose and administration schedule of ZD6126. METHODS: Adult patients 
      with solid tumors refractory to existing treatments received a 10-min, 
      single-dose intravenous infusion of ZD6126 every 14 or 21 days. Subsequent dose 
      escalation was performed, based on the incidence of adverse events (AEs) within 
      the first cycle of drug administration. Blood samples were obtained for 
      pharmacokinetic analysis, and the effects of ZD6126 on tumor vasculature were 
      visualized using DCE-MRI technology. RESULTS: Forty-four patients received ZD6126 
      (5-112 mg/m2 in the 21-day schedule, n=35; 40-80 mg/m2 in the 14-day schedule, 
      n=9). Common AEs were similar in both groups and included abdominal pain, nausea 
      and vomiting, which appeared to be dose related. The incidence of abdominal pain 
      at 112 mg/m2 in the 21-day study prevented further dose escalation. 
      Pharmacokinetic studies confirmed that ZD6126 is rapidly hydrolyzed to ZD6126 
      phenol. There was no difference in the pharmacokinetics of ZD6126 phenol upon 
      repeat administration or between the two dosing regimens. DCE-MRI evaluation has 
      demonstrated the antivascular effects of ZD6126. CONCLUSIONS: This study 
      identified that ZD6126 administered every 2 or 3 weeks at 80 mg/m2 was well 
      tolerated, with mild but manageable gastrointestinal AEs. In approximately 11% (5 
      out of 44) of patients, ZD6126 was associated with cardiac events categorized as 
      dose limiting toxicities (one patient with asymptomatic decreased left 
      ventricular ejection fraction (LVEF), two with increased troponin concentrations, 
      one with myocardial ischemia, and one with ECG signs of myocardial ischemia).
FAU - LoRusso, Patricia M
AU  - LoRusso PM
AD  - Karmanos Cancer Institute, Wayne State University, 4100 John R, Mail Code: 
      HW04HO, Detroit, MI 48201, USA. lorussop@karmanos.org
FAU - Gadgeel, Shirish M
AU  - Gadgeel SM
FAU - Wozniak, Antoinette
AU  - Wozniak A
FAU - Barge, Alan J
AU  - Barge AJ
FAU - Jones, Helen K
AU  - Jones HK
FAU - DelProposto, Zachary S
AU  - DelProposto ZS
FAU - DeLuca, Pamela A
AU  - DeLuca PA
FAU - Evelhoch, Jeffrey L
AU  - Evelhoch JL
FAU - Boerner, Scott A
AU  - Boerner SA
FAU - Wheeler, Catherine
AU  - Wheeler C
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20080125
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents)
RN  - 0 (N-acetylcochinol-O-phosphate)
RN  - 0 (Organophosphorus Compounds)
RN  - 0 (Tubulin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Endothelium, Vascular/drug effects
MH  - Female
MH  - Humans
MH  - Infusions, Intravenous
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Organophosphorus Compounds/*administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Tubulin/drug effects
EDAT- 2008/01/26 09:00
MHDA- 2008/07/18 09:00
CRDT- 2008/01/26 09:00
PHST- 2007/03/07 00:00 [received]
PHST- 2008/01/07 00:00 [accepted]
PHST- 2008/01/26 09:00 [pubmed]
PHST- 2008/07/18 09:00 [medline]
PHST- 2008/01/26 09:00 [entrez]
AID - 10.1007/s10637-008-9112-9 [doi]
PST - ppublish
SO  - Invest New Drugs. 2008 Apr;26(2):159-67. doi: 10.1007/s10637-008-9112-9. Epub 
      2008 Jan 25.