Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies.
OBJECTIVE
Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer.


METHODS
17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs).


RESULTS
A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable.


CONCLUSIONS
Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.
Kummar
Shivaani
S
Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. kummars@mail.nih.gov
Gutierrez
Martin E
ME
Gardner
Erin R
ER
Chen
Xiaohong
X
Figg
William D
WD
Zajac-Kaye
Maria
M
Chen
Min
M
Steinberg
Seth M
SM
Muir
Christine A
CA
Yancey
Mary Ann
MA
Horneffer
Yvonne R
YR
Juwara
Lamin
L
Melillo
Giovanni
G
Ivy
S Percy
SP
Merino
Maria
M
Neckers
Len
L
Steeg
Patricia S
PS
Conley
Barbara A
BA
Giaccone
Giuseppe
G
Doroshow
James H
JH
Murgo
Anthony J
AJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D055815:Young Adult
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin