A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer.
OBJECTIVE
17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with antiproliferative activity in several mouse xenograft models, including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer.


METHODS
Patients with at least one prior systemic therapy and a rising prostate-specific antigen (PSA) were eligible. Patients received 17-AAG at a dose of 300 mg/m2 i.v. weekly for 3 of 4 weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, and to measure interleukin-6, interleukin-8, and maspin levels and quality of life.


RESULTS
Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of two cycles. Severe adverse events included grade 3 fatigue (four patients), grade 3 lymphopenia (two patients), and grade 3 back pain (two patients). The median PSA progression-free survival was 1.8 months (95% confidence interval, 1.3-3.4 months). The 6-month overall survival was 71% (95% confidence interval, 52-100%).


CONCLUSIONS
17-AAG did not show any activity with regard to PSA response. Due to insufficient PSA response, enrollment was stopped at the end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 i.v. weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted.
Heath
Elisabeth I
EI
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA. heathe@karmanos.org
Hillman
David W
DW
Vaishampayan
Ulka
U
Sheng
Shijie
S
Sarkar
Fazlul
F
Harper
Felicity
F
Gaskins
Melvin
M
Pitot
Henry C
HC
Tan
Winston
W
Ivy
S Percy
SP
Pili
Roberto
R
Carducci
Michael A
MA
Erlichman
Charles
C
Liu
Glenn
G
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016227:Benzoquinones / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007118:Immunoassay; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood / Q000187:drug effects; D053208:Kaplan-Meier Estimate; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011788:Quality of Life; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000096:biosynthesis / Q000187:drug effects
D000970:Antineoplastic Agents; D016227:Benzoquinones; D015850:Interleukin-6; D016209:Interleukin-8; D047029:Lactams, Macrocyclic; C085344:SERPIN-B5; D015843:Serpins; C112765:tanespimycin; D017430:Prostate-Specific Antigen