Back to Search
Start Over
Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer
- Source :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 23(6)
- Publication Year :
- 2005
-
Abstract
- Purpose We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. Patients and Methods An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Results Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m2 were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t1/2) of 17-AAG were 11.6 L/h/m2 and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t1/2 of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. Conclusion The MTD of weekly 17-AAG is 308 mg/m2. 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.
- Subjects :
- Adult
Male
Cancer Research
Maximum Tolerated Dose
Anemia
Bilirubin
Nausea
Lactams, Macrocyclic
Antineoplastic Agents
Pharmacology
Tanespimycin
Peripheral blood mononuclear cell
Drug Administration Schedule
chemistry.chemical_compound
Pharmacokinetics
Cytochrome P-450 Enzyme System
Neoplasms
polycyclic compounds
medicine
Benzoquinones
NAD(P)H Dehydrogenase (Quinone)
Cytochrome P-450 CYP3A
Humans
HSP90 Heat-Shock Proteins
Aged
Polymorphism, Genetic
business.industry
Middle Aged
medicine.disease
Oncology
chemistry
Rifabutin
Immunology
Toxicity
Vomiting
Female
medicine.symptom
business
Biomarkers
Subjects
Details
- ISSN :
- 0732183X
- Volume :
- 23
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Accession number :
- edsair.doi.dedup.....4a905be07fc265f31a9157dff5e75aa2