Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers.
OBJECTIVE
17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics.


METHODS
Escalating doses of 17AAG were given i.v. over 1 or 2 hours on a weekly x 3 schedule every 4 weeks to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance liquid chromatography. Expression of HSP70 and HSP90 in peripheral blood mononuclear cells was measured by Western blot.


RESULTS
Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum tolerated dose was 295 mg/m2. Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m2. Common drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea, nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5% of patients. Hematologic toxicity was minimal. No objective responses were observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area under the curve of 17AG, the active major metabolite of 17AAG, increased with 17AAG dose, but the relationships were more variable than with 17AAG. 17AAG and 17AG in plasma were >90% protein bound. There were no consistent changes in peripheral blood mononuclear cell HSP90 or HSP70 content.


CONCLUSIONS
17AAG doses between 10 and 295 mg/m2 are well tolerated. 17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers. The dose recommended for future studies is 295 mg/m2 weekly x 3, repeated every 4 weeks.
Ramanathan
Ramesh K
RK
Molecular Therapeutics/Drug Discovery Program, Biostatistics Department, Graduate School of Public Health, and Biostatistics Facility, University of Pittsburgh Cancer Institute, PA 15232, USA. ramnathanrk@upmc.edu
Trump
Donald L
DL
Eiseman
Julie L
JL
Belani
Chandra P
CP
Agarwala
Sanjiv S
SS
Zuhowski
Eleanor G
EG
Lan
Jing
J
Potter
Douglas M
DM
Ivy
S Percy
SP
Ramalingam
Sakkaraiappan
S
Brufsky
Adam M
AM
Wong
Michael K K
MK
Tutchko
Susan
S
Egorin
Merrill J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D016227:Benzoquinones; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D018840:HSP70 Heat-Shock Proteins / Q000097:blood; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D047029:Lactams, Macrocyclic; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011374:Progesterone / Q000097:blood; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017828:Rifabutin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017828:Rifabutin; D013739:Testosterone; D011374:Progesterone; C112765:tanespimycin; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D017346:Protein Serine-Threonine Kinases; D006854:Hydrocortisone