An optimized clinical regimen for the oncolytic virus PV701.
OBJECTIVE
Previous phase 1 trials of i.v.-administered PV701 have shown this virus to be well-tolerated with toxicity primarily associated with the first dose. Our hypothesis, based on preclinical evidence, was that patient tolerability could be improved by slowing the i.v. infusion rate, and that this approach would allow for the safe administration of higher doses. Additionally, this phase 1 trial was the first to measure PV701 clearance.


METHODS
For the first dose, a 3-h infusion was used compared with the 10- and 30-min infusions administered in the two previous trials. Subsequent doses were infused over 1 h. Six doses were given per 3-week cycle. Escalation of the first dose was done separately from the escalation of doses 2 to 6. Viral clearance was determined using whole blood reverse transcription-PCR.


RESULTS
Eighteen patients with advanced chemorefractory cancer were enrolled. The first dose was safely escalated to 24x10(9) plaque-forming units/m2 and doses 2 to 6 were safely escalated to 120x10(9) plaque-forming units/m2. Tolerability was improved compared with the rapid bolus dosing used previously with the elimination of severe flu-like symptoms. Furthermore, infusion reactions were markedly decreased in this trial compared with previous PV701 trials. The presence of neutralizing antibodies did not significantly affect PV701 clearance. Four major and two minor tumor responses were observed.


CONCLUSIONS
Using slow infusion, patient tolerability was improved, while the first dose was safely escalated relative to two previous PV701 trials. Based on improved tolerability and encouraging signs of activity, this slow infusion regimen was selected for further PV701 clinical development.
Hotte
Sébastien J
SJ
Division of Medical Oncology, Juravinski Cancer Centre, Hamilton, Canada.
Lorence
Robert M
RM
Hirte
Hal W
HW
Polawski
Susan R
SR
Bamat
Michael K
MK
O'Neil
James D
JD
Roberts
M Scot
MS
Groene
William S
WS
Major
Pierre P
PP
D000328:Adult; D000906:Antibodies / Q000737:chemistry; D002985:Clinical Protocols; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome
D000906:Antibodies