Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer

Matthew Philip Goetz, David Toft, Joel M Reid, Matthew Ames, Bridget Stensgard, Stephanie Safgren, Araba A. Adjei, Jeff A Sloan, Pamela Atherton, Vlad Vasile, Sandra Salazaar, Alex Adjei, Gary Croghan, Charles Erlichman

Research output: Contribution to journalArticle

296 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1078-1087
Number of pages10
JournalJournal of Clinical Oncology
Volume23
Issue number6
DOIs
StatePublished - Feb 20 2005

Fingerprint

tanespimycin
Cytochrome P-450 CYP3A
Neoplasms
Maximum Tolerated Dose
Blood Cells
Pharmacokinetics
HSP70 Heat-Shock Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. / Goetz, Matthew Philip; Toft, David; Reid, Joel M; Ames, Matthew; Stensgard, Bridget; Safgren, Stephanie; Adjei, Araba A.; Sloan, Jeff A; Atherton, Pamela; Vasile, Vlad; Salazaar, Sandra; Adjei, Alex; Croghan, Gary; Erlichman, Charles.

In: Journal of Clinical Oncology, Vol. 23, No. 6, 20.02.2005, p. 1078-1087.

Research output: Contribution to journalArticle

Goetz, MP, Toft, D, Reid, JM, Ames, M, Stensgard, B, Safgren, S, Adjei, AA, Sloan, JA, Atherton, P, Vasile, V, Salazaar, S, Adjei, A, Croghan, G & Erlichman, C 2005, 'Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer', Journal of Clinical Oncology, vol. 23, no. 6, pp. 1078-1087. https://doi.org/10.1200/JCO.2005.09.119
Goetz, Matthew Philip ; Toft, David ; Reid, Joel M ; Ames, Matthew ; Stensgard, Bridget ; Safgren, Stephanie ; Adjei, Araba A. ; Sloan, Jeff A ; Atherton, Pamela ; Vasile, Vlad ; Salazaar, Sandra ; Adjei, Alex ; Croghan, Gary ; Erlichman, Charles. / Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 6. pp. 1078-1087.
@article{42161b85a45440b8856d9738106afe69,
title = "Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer",
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.",
author = "Goetz, {Matthew Philip} and David Toft and Reid, {Joel M} and Matthew Ames and Bridget Stensgard and Stephanie Safgren and Adjei, {Araba A.} and Sloan, {Jeff A} and Pamela Atherton and Vlad Vasile and Sandra Salazaar and Alex Adjei and Gary Croghan and Charles Erlichman",
year = "2005",
month = "2",
day = "20",
doi = "10.1200/JCO.2005.09.119",
language = "English (US)",
volume = "23",
pages = "1078--1087",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "6",

}

TY - JOUR

T1 - Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer

AU - Goetz, Matthew Philip

AU - Toft, David

AU - Reid, Joel M

AU - Ames, Matthew

AU - Stensgard, Bridget

AU - Safgren, Stephanie

AU - Adjei, Araba A.

AU - Sloan, Jeff A

AU - Atherton, Pamela

AU - Vasile, Vlad

AU - Salazaar, Sandra

AU - Adjei, Alex

AU - Croghan, Gary

AU - Erlichman, Charles

PY - 2005/2/20

Y1 - 2005/2/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=20044384168&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20044384168&partnerID=8YFLogxK

U2 - 10.1200/JCO.2005.09.119

DO - 10.1200/JCO.2005.09.119

M3 - Article

C2 - 15718306

AN - SCOPUS:20044384168

VL - 23

SP - 1078

EP - 1087

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 6

ER -