A Phase I trial of TNFerade biologic in patients with soft tissue sarcoma in the extremities.
OBJECTIVE
TNFerade is a second-generation replication-deficient adenovector carrying a transgene encoding human tumor necrosis factor alpha under control of a radiation- induced promoter. The objective of this study was to assess the tolerance of combining TNFerade and radiation therapy in patients with soft tissue sarcomas of the extremity.


METHODS
TNFerade was administered in combination with single-daily fractionated radiation therapy in 14 patients with soft tissue sarcoma of the extremities. Three escalating dose levels of TNFerade (4 x 10(9) -4 x 10(11) particle units) were planned, given in 1 log increments by intratumoral injections, twice weekly during week 1 and once weekly during weeks 2-5 of radiation therapy.


RESULTS
TNFerade was well tolerated with no dose-limiting toxicities noted. Grade 1-2 chills (50.0%), fever (43.0%), fatigue (36.0%), and flu-like symptoms (21.0%) were the most common side effects. Serum-tumor necrosis factor alpha levels were low in all of the patients (<15 pg/mL). No patients had virus-detected blood, sputum, or urine cultures. Of the 13 evaluable patients, 11 received TNFerade preoperatively, and 2 received the treatment for palliation. Eleven patients (85%) showed objective or pathological tumor responses (2 complete and 9 partial), and 1 had stable disease. Partial responses were achieved despite some of these tumors being very large (up to 675 cm(2)). Of the 11 patients who underwent surgery, 10 (91%) showed a pathological complete response/partial response.


CONCLUSIONS
TNFerade + radiation therapy was well tolerated in the treatment of patients with soft-tissue sarcoma of the extremity. The high number of objective responses observed warrants additional studies of this approach in a larger controlled prospective trial.
Mundt
Arno J
AJ
University of Chicago Medical Center, Chicago, Illinois, USA. amundt@radonc.uchicago.edu
Vijayakumar
Srinivasan
S
Nemunaitis
John
J
Sandler
Alan
A
Schwartz
Herbert
H
Hanna
Nader
N
Peabody
Terrence
T
Senzer
Neil
N
Chu
Karen
K
Rasmussen
Camilla S
CS
Kessler
Paul D
PD
Rasmussen
Henrik S
HS
Warso
Michael
M
Kufe
Donald W
DW
Gupta
Tapas Das
TD
Weichselbaum
Ralph R
RR
D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005121:Extremities; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha