A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer.
OBJECTIVE
To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins.


METHODS
A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one.


RESULTS
Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m2. Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m2. There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1 significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells.


CONCLUSIONS
The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m2. Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.
Nowakowski
Grzegorz S
GS
Department of Oncology, Cancer Center Statistics, Mayo Clinic, Rochester, Minnesota 55905, USA.
McCollum
Andrea K
AK
Ames
Matthew M
MM
Mandrekar
Sumithra J
SJ
Reid
Joel M
JM
Adjei
Alex A
AA
Toft
David O
DO
Safgren
Stephanie L
SL
Erlichman
Charles
C
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D016227:Benzoquinones / Q000008:administration & dosage / Q000633:toxicity*; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000633:toxicity*; D008017:Life Expectancy; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018579:Patient Selection
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin