Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.
OBJECTIVE
We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity.


METHODS
An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity.


RESULTS
Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance.


CONCLUSIONS
The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.
Goetz
Matthew P
MP
Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Toft
David
D
Reid
Joel
J
Ames
Matthew
M
Stensgard
Bridget
B
Safgren
Stephanie
S
Adjei
Araba A
AA
Sloan
Jeff
J
Atherton
Pamela
P
Vasile
Vlad
V
Salazaar
Sandra
S
Adjei
Alex
A
Croghan
Gary
G
Erlichman
Charles
C
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D016227:Benzoquinones; D015415:Biomarkers / Q000032:analysis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004334:Drug Administration Schedule; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy*; D011110:Polymorphism, Genetic; D017828:Rifabutin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D015415:Biomarkers; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human