A phase I study of 17-allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies.
BACKGROUND
17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel.


METHODS
Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1.


RESULTS
Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 +/- 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 +/- 0.51.


CONCLUSIONS
The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.
Ramalingam
Suresh S
SS
Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. suresh.ramalingam@emory.edu
Egorin
Merrill J
MJ
Ramanathan
Ramesh K
RK
Remick
Scot C
SC
Sikorski
Rachel P
RP
Lagattuta
Theodore F
TF
Chatta
Gurkamal S
GS
Friedland
David M
DM
Stoller
Ronald G
RG
Potter
Douglas M
DM
Ivy
S Percy
SP
Belani
Chandra P
CP
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / 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; D004347:Drug Interactions; D005260:Female; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D017239:Paclitaxel