Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies.
OBJECTIVE
To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials.


METHODS
This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated.


RESULTS
The highest dose level reached was 450 mg/m(2)/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m(2)/week and two at 450 mg/m(2)/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m(2)/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r(2) = .71) over the dose range 10 to 450 mg/m(2)/week, with peak plasma concentrations of 8,998 mug/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m(2)/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment.


CONCLUSIONS
It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m(2)/week. We recommend this dose for phase II clinical trials.
Banerji
Udai
U
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, Surrey SM2 5NG, UK.
O'Donnell
Anne
A
Scurr
Michelle
M
Pacey
Simon
S
Stapleton
Sarah
S
Asad
Yasmin
Y
Simmons
Laura
L
Maloney
Alison
A
Raynaud
Florence
F
Campbell
Maeli
M
Walton
Michael
M
Lakhani
Sunil
S
Kaye
Stanley
S
Workman
Paul
P
Judson
Ian
I
D000328:Adult; D000368:Aged; D016227:Benzoquinones; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016896:Treatment Outcome
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin