Phase I, pharmacokinetic, and pharmacodynamic study of intravenously administered Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene, in patients with advanced cancer.
OBJECTIVE
The purpose of this study was to assess the feasibility of administering Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene to patients with advanced malignancies, characterize the pertinent pharmacokinetic parameters, identify evidence of viral uptake in both normal and tumor tissue, and seek evidence of antitumor activity.


METHODS
Patients were treated with escalating doses of Ad5CMV-p53 intravenously over 30 minutes on days 1, 2, and 3, every 28 days. The clearance of circulating Ad5CMV-p53 (INGN 201) DNA was characterized in the plasma and paired tumor and skin biopsies were performed in patients treated at the two highest dose levels to assess vector uptake into tissues.


RESULTS
Seventeen patients received 36 courses of Ad5CMV-p53 at doses ranging from 3 x 10(10) to 3 x 10(12) virus particles (vp). Fatigue, nausea, vomiting, and fever were common, but rarely severe. Abnormalities of coagulation parameters, including decreases in fibrinogen and increases in fibrin degradation products at 3 x 10(12)vp, precluded additional dose escalation. Ad5CMV-p53 DNA could be detected in the plasma by polymerase chain reaction assay in the majority of patients at 14 days and 28 days at doses of 3 x 10(10) and higher. Six patients treated at 1 x 10(12)vp and 3 x 10(12)vp dose levels had Ad5CMV-p53 DNA detected within paired tumor tissue collected day 4.


CONCLUSIONS
Ad5CMV-p53 can be safely and repetitively administered up to 1 x 10(12)vp intravenously daily for 3 consecutive days. The absence of severe toxicities, the presence of circulating adenovirus 24 hours after administration, and detectable p53 transgene within tumor tissue distant from the site of administration demonstrates that systemic therapy with this adenoviral vector containing p53 is feasible.
Tolcher
Anthony W
AW
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. atolcher@idd.org
Hao
Desiree
D
de Bono
Johann
J
Miller
Alex
A
Patnaik
Amita
A
Hammond
Lisa A
LA
Smetzer
Leslie
L
Van Wart Hood
Jill
J
Merritt
James
J
Rowinsky
Eric K
EK
Takimoto
Chris
C
Von Hoff
Dan
D
Eckhardt
S Gail
SG
D000260:Adenoviruses, Human / Q000235:genetics*; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D003587:Cytomegalovirus / Q000235:genetics*; D004247:DNA / Q000032:analysis / Q000097:blood; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000628:therapy*; D010314:Partial Thromboplastin Time; D011401:Promoter Regions, Genetic
D000914:Antibodies, Viral; D004247:DNA