Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers.
OBJECTIVE
The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week.


METHODS
Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly x 3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 mg/m(2) and for schedule B (twice weekly x 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m(2). Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins.


RESULTS
Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m(2), DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m(2) developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in >5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2.


CONCLUSIONS
The recommended phase II doses of 17AAG are 175 to 200 mg/m(2) when given twice a week and consistently cause elevations in PBMC HSP70.
Ramanathan
Ramesh K
RK
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA. ramanathanrk@upmc.edu
Egorin
Merrill J
MJ
Eiseman
Julie L
JL
Ramalingam
Suresh
S
Friedland
David
D
Agarwala
Sanjiv S
SS
Ivy
S Percy
SP
Potter
Douglas M
DM
Chatta
Gurkamal
G
Zuhowski
Eleanor G
EG
Stoller
Ronald G
RG
Naret
Cynthia
C
Guo
Jianxia
J
Belani
Chandra P
CP
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001773:Blood Cells / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000097:blood / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017211:Treatment Failure
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin