Phase I pharmacokinetic and pharmacodynamic study of 17- dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors

Ramesk K Ramanathan, Merrill J. Egorin, Charles Erlichman, Scot C. Remick, Suresh S. Ramalingam, Cynthia Naret, Julianne L. Holleran, Cynthia J. TenEyck, S. Percy Ivy, Chandra P. Belani

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Purpose: To define the maximum tolerated dose, toxicities, pharmacokinetics, and pharmacodynamics of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17DMAG). Methods: 17DMAG was given intravenously over 1 hour daily for 5 days (schedule A) or daily for 3 days (schedule B) every 3 weeks. Plasma 17DMAG concentrations were measured by liquid chromatography/ mass spectrometry. Heat-shock proteins (HSPs) and client proteins were evaluated at baseline and after treatment on day 1 in peripheral blood mononuclear cells (PBMCs) and in pre-and post-treatment (24 hours) biopsies done during cycle 1 at the recommended phase II dose (n = 7). Results: Fifty-six patients were entered: 26 on schedule A; 30 on schedule B. The recommended phase II doses for schedules A and B were 16 mg/m2 and 25 mg/m2, respectively. Grade 3/4 toxicities included liver function test elevation (14%), pneumonitis (9%), diarrhea (4%), nausea (4%), fatigue (4%) and thrombocytopenia (4%). There were no objective responses. Four patients had stable disease. 17DMAG half-life was 24 ± 15 hours. 17DMAG area under the curve (range, 0.7 to 14.7 mg/mL x h) increased linearly with dose. The median HSP90, HSP70, and integrin-linked kinase levels were 87.5% (n = 14), 124% (n = 20), and 99.5% (n = 20) of baseline. Changes in HSPs and client proteins in tumor biopsies were not consistent between baseline and 24 hours nor did they change in the same direction as those in PBMCs collected at the time of biopsy. Conclusion: The recommended phase II doses of 17DMAG (16 mg/m2 × 5 days or 25 mg/m2 × 3 days, every 3 weeks) are well tolerated and suitable for further evaluation.

Original languageEnglish (US)
Pages (from-to)1520-1526
Number of pages7
JournalJournal of Clinical Oncology
Volume28
Issue number9
DOIs
StatePublished - Mar 20 2010
Externally publishedYes

Fingerprint

17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
HSP90 Heat-Shock Proteins
Pharmacokinetics
Appointments and Schedules
Neoplasms
Heat-Shock Proteins
Biopsy
Blood Cells
Maximum Tolerated Dose
Liver Function Tests
Liquid Chromatography
Nausea
Area Under Curve
Fatigue
Half-Life
Diarrhea
Mass Spectrometry
Pneumonia
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Phase I pharmacokinetic and pharmacodynamic study of 17- dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors. / Ramanathan, Ramesk K; Egorin, Merrill J.; Erlichman, Charles; Remick, Scot C.; Ramalingam, Suresh S.; Naret, Cynthia; Holleran, Julianne L.; TenEyck, Cynthia J.; Ivy, S. Percy; Belani, Chandra P.

In: Journal of Clinical Oncology, Vol. 28, No. 9, 20.03.2010, p. 1520-1526.

Research output: Contribution to journalArticle

Ramanathan, Ramesk K ; Egorin, Merrill J. ; Erlichman, Charles ; Remick, Scot C. ; Ramalingam, Suresh S. ; Naret, Cynthia ; Holleran, Julianne L. ; TenEyck, Cynthia J. ; Ivy, S. Percy ; Belani, Chandra P. / Phase I pharmacokinetic and pharmacodynamic study of 17- dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 9. pp. 1520-1526.
@article{9ea3c7f15d314db487b6eb0c9c831c7a,
title = "Phase I pharmacokinetic and pharmacodynamic study of 17- dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors",
abstract = "Purpose: To define the maximum tolerated dose, toxicities, pharmacokinetics, and pharmacodynamics of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17DMAG). Methods: 17DMAG was given intravenously over 1 hour daily for 5 days (schedule A) or daily for 3 days (schedule B) every 3 weeks. Plasma 17DMAG concentrations were measured by liquid chromatography/ mass spectrometry. Heat-shock proteins (HSPs) and client proteins were evaluated at baseline and after treatment on day 1 in peripheral blood mononuclear cells (PBMCs) and in pre-and post-treatment (24 hours) biopsies done during cycle 1 at the recommended phase II dose (n = 7). Results: Fifty-six patients were entered: 26 on schedule A; 30 on schedule B. The recommended phase II doses for schedules A and B were 16 mg/m2 and 25 mg/m2, respectively. Grade 3/4 toxicities included liver function test elevation (14{\%}), pneumonitis (9{\%}), diarrhea (4{\%}), nausea (4{\%}), fatigue (4{\%}) and thrombocytopenia (4{\%}). There were no objective responses. Four patients had stable disease. 17DMAG half-life was 24 ± 15 hours. 17DMAG area under the curve (range, 0.7 to 14.7 mg/mL x h) increased linearly with dose. The median HSP90, HSP70, and integrin-linked kinase levels were 87.5{\%} (n = 14), 124{\%} (n = 20), and 99.5{\%} (n = 20) of baseline. Changes in HSPs and client proteins in tumor biopsies were not consistent between baseline and 24 hours nor did they change in the same direction as those in PBMCs collected at the time of biopsy. Conclusion: The recommended phase II doses of 17DMAG (16 mg/m2 × 5 days or 25 mg/m2 × 3 days, every 3 weeks) are well tolerated and suitable for further evaluation.",
author = "Ramanathan, {Ramesk K} and Egorin, {Merrill J.} and Charles Erlichman and Remick, {Scot C.} and Ramalingam, {Suresh S.} and Cynthia Naret and Holleran, {Julianne L.} and TenEyck, {Cynthia J.} and Ivy, {S. Percy} and Belani, {Chandra P.}",
year = "2010",
month = "3",
day = "20",
doi = "10.1200/JCO.2009.25.0415",
language = "English (US)",
volume = "28",
pages = "1520--1526",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "9",

}

TY - JOUR

T1 - Phase I pharmacokinetic and pharmacodynamic study of 17- dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors

AU - Ramanathan, Ramesk K

AU - Egorin, Merrill J.

AU - Erlichman, Charles

AU - Remick, Scot C.

AU - Ramalingam, Suresh S.

AU - Naret, Cynthia

AU - Holleran, Julianne L.

AU - TenEyck, Cynthia J.

AU - Ivy, S. Percy

AU - Belani, Chandra P.

PY - 2010/3/20

Y1 - 2010/3/20

N2 - Purpose: To define the maximum tolerated dose, toxicities, pharmacokinetics, and pharmacodynamics of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17DMAG). Methods: 17DMAG was given intravenously over 1 hour daily for 5 days (schedule A) or daily for 3 days (schedule B) every 3 weeks. Plasma 17DMAG concentrations were measured by liquid chromatography/ mass spectrometry. Heat-shock proteins (HSPs) and client proteins were evaluated at baseline and after treatment on day 1 in peripheral blood mononuclear cells (PBMCs) and in pre-and post-treatment (24 hours) biopsies done during cycle 1 at the recommended phase II dose (n = 7). Results: Fifty-six patients were entered: 26 on schedule A; 30 on schedule B. The recommended phase II doses for schedules A and B were 16 mg/m2 and 25 mg/m2, respectively. Grade 3/4 toxicities included liver function test elevation (14%), pneumonitis (9%), diarrhea (4%), nausea (4%), fatigue (4%) and thrombocytopenia (4%). There were no objective responses. Four patients had stable disease. 17DMAG half-life was 24 ± 15 hours. 17DMAG area under the curve (range, 0.7 to 14.7 mg/mL x h) increased linearly with dose. The median HSP90, HSP70, and integrin-linked kinase levels were 87.5% (n = 14), 124% (n = 20), and 99.5% (n = 20) of baseline. Changes in HSPs and client proteins in tumor biopsies were not consistent between baseline and 24 hours nor did they change in the same direction as those in PBMCs collected at the time of biopsy. Conclusion: The recommended phase II doses of 17DMAG (16 mg/m2 × 5 days or 25 mg/m2 × 3 days, every 3 weeks) are well tolerated and suitable for further evaluation.

AB - Purpose: To define the maximum tolerated dose, toxicities, pharmacokinetics, and pharmacodynamics of 17-dimethylaminoethylamino-17- demethoxygeldanamycin (17DMAG). Methods: 17DMAG was given intravenously over 1 hour daily for 5 days (schedule A) or daily for 3 days (schedule B) every 3 weeks. Plasma 17DMAG concentrations were measured by liquid chromatography/ mass spectrometry. Heat-shock proteins (HSPs) and client proteins were evaluated at baseline and after treatment on day 1 in peripheral blood mononuclear cells (PBMCs) and in pre-and post-treatment (24 hours) biopsies done during cycle 1 at the recommended phase II dose (n = 7). Results: Fifty-six patients were entered: 26 on schedule A; 30 on schedule B. The recommended phase II doses for schedules A and B were 16 mg/m2 and 25 mg/m2, respectively. Grade 3/4 toxicities included liver function test elevation (14%), pneumonitis (9%), diarrhea (4%), nausea (4%), fatigue (4%) and thrombocytopenia (4%). There were no objective responses. Four patients had stable disease. 17DMAG half-life was 24 ± 15 hours. 17DMAG area under the curve (range, 0.7 to 14.7 mg/mL x h) increased linearly with dose. The median HSP90, HSP70, and integrin-linked kinase levels were 87.5% (n = 14), 124% (n = 20), and 99.5% (n = 20) of baseline. Changes in HSPs and client proteins in tumor biopsies were not consistent between baseline and 24 hours nor did they change in the same direction as those in PBMCs collected at the time of biopsy. Conclusion: The recommended phase II doses of 17DMAG (16 mg/m2 × 5 days or 25 mg/m2 × 3 days, every 3 weeks) are well tolerated and suitable for further evaluation.

UR - http://www.scopus.com/inward/record.url?scp=77951907072&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951907072&partnerID=8YFLogxK

U2 - 10.1200/JCO.2009.25.0415

DO - 10.1200/JCO.2009.25.0415

M3 - Article

VL - 28

SP - 1520

EP - 1526

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 9

ER -