The Experts below are selected from a list of 1035 Experts worldwide ranked by ideXlab platform
Merrill J. Egorin - One of the best experts on this subject based on the ideXlab platform.
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Population pharmacokinetic analysis of 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors
Cancer chemotherapy and pharmacology, 2012Co-Authors: Abdulateef O. Aregbe, Percy Ivy, Eric A. Sherer, Merrill J. Egorin, Howard I. Scher, David B. Solit, Ramesh K. Ramanathan, Suresh S. Ramalingam, Chandra P. Belani, Robert R. BiesAbstract:Purpose To identify sources of exposure variability for the tumor growth inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis.
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Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin, an Inhibitor of Heat-Shock Protein 90, in Patients With Advanced Solid Tumors
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2010Co-Authors: Ramesh K. Ramanathan, Merrill J. Egorin, Suresh S. Ramalingam, Charles Erlichman, Scot C. Remick, C. L. Naret, Julianne L. Holleran, Cynthia J. Teneyck, S. Percy Ivy, Chandra P. BelaniAbstract: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 st...
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Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin, (17DMAG, NSC 707545), an inhibitor of heat shock protein 90 (HSP90), in patients with advanced solid tumors: Final results.
Molecular Cancer Therapeutics, 2007Co-Authors: Ramesh K. Ramanathan, Merrill J. Egorin, Charles Erlichman, Scot C. Remick, C. L. Naret, Julianne L. Holleran, S. Percy Ivy, Suresh Ramalingam, Cyntha Ten Eyck, Chandra P. BelaniAbstract:B212 Background: 17DMAG is a water-soluble and potent geldanamycin analog, which inhibits HSP90. The objectives of this first-in-human study were to: establish the dose-limiting toxicity (DLT); recommend a phase 2 dose; & characterize the PK & PD of 17DMAG. Methods: Patients (pts) were accrued to a modified accelerated schema. 17DMAG was given IV over 1 h daily x 5 (schedule A) or daily x 3 (schedule B) every 3 weeks. Plasma 17DMAG concentrations during cycle 1 were quantitated by LC/MS assay. HSP27, HSP70, and 4 client proteins CDK4, RAF-1, AKT, and ILK were assessed by western blot at baseline & 24 h on d 1. Pre- & post-treatment (at 24h) biopsies were done in selected patients at the phase 2 dose (n=7). Results: 56 pts were entered. Sequential cohorts of patients on schedule A received 1.5, 3, 6, 9, 12, 16 or 22 mg/m2/d (n = 26). On schedule B, the starting dose was 2.5 mg/m2/d. Based on safety information from schedule A, subsequent schedule B dose levels were 14, 19, 25, 34 & 46 mg/m2/d (n = 30). Dose-limiting toxicities on both schedules were pneumonitis, transaminitis, thrombocytopenia and fatigue. Selected grade ¾ toxicities are liver function test elevation (14%), pneumonitis (9%), diarrhea (4%), nausea (4%), fatigue (4%) & platelets (4%). No objective responses were noted, stable disease was seen in 4 pts. Day 1, 17DMAG PK were linear over 1.5-46 mg/m2 and Cmax increased linearly with dose (0.071-1.7 mg/ml). The AUC increased linearly with dose (0.7-14.7 mg/ml•h). Both clearance and T1/2 did not vary systematically with dose (79 + 40 ml/min/m2 and 24 + 15 h). The 24-h urinary excretion accounted for 20 + 9% of dose. The mean HSP70 and HSP27 were 114% (range 58-155) and 154% (range 71-229) of baseline respectively in PBMCs at 24 h at 12, 16, & 25 mg/m2. HSP27, HSP70, AKT and CDK4 levels were decreased in the majority of post treatment biopsy samples, but did not correlate to changes in corresponding PBMC samples. Conclusions: The recommended phase 2 of 17DMAG is 16 mg/ m2 x 5 days or 25 mg/ m2 x 3 days every 3 weeks. Therapy was well tolerated at the phase 2 doses. Reversible pneumonitis was a new DLT and not predicted by animal toxicology. Pneumonitis and transaminitis appear to be schedule-dependent. Cardiac toxicity was not seen. 17DMAG plasma PK are linear over the doses delivered to date, and there is a suggestion of a target effect as manifested by HSP and client protein changes in PMBCs and paired tumor biopsies. Support: U01CA099168-01, U01CA62502, U01CA69912, R01CA90390 & NIH/NCCR/GCRC grants #5M01 RR 00056 & M01 RR00080
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Phase I, pharmacokinetic (PK), & pharmacodynamic (PD) study of 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin, (17DMAG, NSC 707545) in patients with advanced solid tumors
Journal of Clinical Oncology, 2006Co-Authors: Merrill J. Egorin, Chandra P. Belani, Charles Erlichman, Scot C. Remick, C. L. Naret, Julianne L. Holleran, Cynthia J. Teneyck, S. Percy Ivy, Sakkaraiappan Ramalingam, R. K. RamanathanAbstract:3021 Background: 17DMAG is a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17AAG), the first geldanamycin compound to enter clinical trials. 17DMAG causes oncoprotein degradation by binding to heat shock protein 90 (HSP90) & has greater in-vitro activity than 17AAG. In animals treated with 17DMAG, liver toxicity is dose-limiting. The objectives of this first-in-human study are to: establish the dose-limiting toxicity (DLT); recommend a phase 2 dose; & characterize the PK & PD of 17DMAG. Methods: Using a modified accelerated schema, escalating doses of 17DMAG are given IV over 1 h daily x 5 (schedule A) or daily x 3 (schedule B) every 3 weeks. Plasma 17DMAG concentrations during cycle 1 are quantitated by LC/MS. HSP70 & ILK levels in peripheral mononuclear cells are measured by western blot at baseline & 24 h on d 1. Results: 37 pts have been enrolled. On schedule A, dose levels are 1.5, 3, 6, 9, 12 & 16 mg/m2/d (n = 20). On schedule B, the starting dose was 2.5 mg/m2/d. Based on safety i...
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Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Elizabeth R. Glaze, Amy L. Lambert, Adaline C. Smith, John G. Page, William D. Johnson, David L. Mccormick, Alan P. Brown, Barry S. Levine, Joseph M. Covey, Merrill J. EgorinAbstract:Purpose 17-DMAG is a hydrophilic derivative of the molecular chaperone inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG; NSC-330507), which is currently being evaluated for the treatment of cancer in clinical trials. 17-DMAG offers a potential advantage over 17-AAG because its aqueous solubility eliminates the need for complicated formulations that are currently used for administration of 17-AAG. In addition, 17-DMAG undergoes only limited metabolism compared to 17-AAG. The present results are from preclinical toxicity studies evaluating 17-DMAG in rats and dogs. Methods Doses of 0, 2.4, 12 and 24 mg/m^2 per day were administered to rats, while dogs received doses of 0, 8 or 16 mg/m^2 per day. In both species, 17-DMAG was administered i.v. (slow bolus for rats; 1-h infusion for dogs) daily for 5 days. An additional cohort of dogs received 16 mg/m^2 per day orally for 5 days. Clinical observations were noted, and standard hematology and clinical chemistry parameters were monitored. Selected tissues were evaluated microscopically for drug-related lesions. Tissue and plasma 17-DMAG concentrations were measured by HPLC/MS at selected time-points on days 1 and 5. Results Daily i.v. administration of 17-DMAG at doses of 24 mg/m^2 per day in rats or 16 mg/m^2 per day in dogs produced lethality on day 6, approximately 24 h following the last dose. Body weight loss was common in rats and dogs. Drug-related gastrointestinal, bone marrow and hepatic toxicities were also common in rats and dogs. Dogs also exhibited signs of renal and gallbladder toxicity. Plasma concentrations of 17-DMAG increased proportionately with dose in rats and disproportionately with dose in dogs. In rat tissues, however, only fourfold to sixfold increases in 17-DMAG concentrations were observed with a tenfold increase in dose. The highest concentrations of 17-DMAG were found in the liver of rats, with progressively lower concentrations in the spleen, lung, kidney and plasma. Regardless of the route of administration, higher drug concentrations were present in plasma (rat and dog) and tissue (rat) samples obtained on day 5 compared to those obtained on day 1. Although plasma concentrations decreased with time, 17-DMAG was still detected in dog plasma for at least 24 h after drug administration. Conclusions With the recent approval of 17-DMAG for clinical use, the data generated from these preclinical studies will provide guidance to clinicians as they administer this drug to their patients. The MTD of 17-DMAG was 12 mg/m^2 per day in rats and 8 mg/m^2 per day in dogs; therefore, the recommended starting dose for phase I trial is 1.3 mg/m^2 per day for 5 days. Gastrointestinal and bone marrow toxicity were dose-limiting in rats, and gastrointestinal, renal, gallbladder and bone marrow toxicity were dose-limiting in dogs. All adverse effects were fully reversible in surviving animals after treatment was complete.
I. Judson - One of the best experts on this subject based on the ideXlab platform.
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A phase I trial of the HSP90 inhibitor, alvespimycin (17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumours
Journal of Clinical Oncology, 2009Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, Florence I. Raynaud, Paul Workman, Hendrik-tobias Arkenau, Anna Zetterlund, R. Beecham, I. JudsonAbstract:3534 Background: alvespimycin (17-Dimethylaminoethylamino-17-Demethoxygeldanamycin, 17-DMAG) inhibits N-terminal ATPase activity of Heat Shock Protein 90 (HSP90). Chaperone interactions are altered such that client proteins are targeted for degradation. The plethora of HSP90 client proteins offers the potential of simultaneous blockade across multiple, oncogenic signalling pathways. Methods: the maximum tolerated dose, at which ≤ 1/6 patients experienced dose limiting toxicity (DLT) was determined by dose-doubling (3+3) design. PK and PD biomarker data were used to define a biologically effective dose (BED). PK (LC/MS/MS) and PD (western blot) assays were validated and compliant with European clinical trial legislation. Cancer Research UK and the NCI were co-sponsors. Results: twenty five patients, median age 58 (range 38–78) years, received 475 infusions at doses between 2.5 and 106 mg/m2. Dose doubling was possible to 80mg/m2 when grade 2 toxicity, including dry eye and blurred vision (2/5 patients) occ...
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A phase I trial of the heat shock protein 90 (HSP90) inhibitor alvespimycin (17-Dimethylaminoethylamino-17-Demethoxygeldanamycin 17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumors
Molecular Cancer Therapeutics, 2007Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, J. Moreno-farre, Florence I. Raynaud, Paul Workman, Eatock Martin, Hendrik-tobias Arkenau, Heidi Steinfeldt, I. JudsonAbstract:PR-6 This phase I trial was designed to determine the recommended phase II dose of Alvespimycin (17-DMAG) based on the drug’s toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) profile in patients with advanced solid tumors. Alvespimycin is a geldanamycin analogue that inhibits the N-terminal ATPase activity of HSP90. In turn the interactions of client protein and chaperone proteins are altered such that client proteins (eg CDK-4, LCK or ERB B2) are degraded. The multitude of oncogenic HSP90 client proteins offers the potential of combinatorial blockade across multiple, cancer-causing signalling pathways in cancer. Alvespimycin was administered weekly to patients with advanced, solid tumors using a dose-doubling 3 + 3 phase I design. PK analyses were done by an LC/MS/MS method and PD samples were analysed for changes in protein expression by western blotting. Assays were validated to comply with European clinical trial legislation. Seventeen patients, 10 male and 7 female with a mean age of 57 years (range 39 - 79) have received 270 weekly infusions (mean 15.9 weeks, range 2 - 58) at dose levels of 2.5mg/m2, 5mg/m2, 20mg/m2, 40mg/m2 & 80mg/m2. No dose-limiting (DLT) or drug related grade 3 or 4 toxicity has occurred in 17 patients eligible for toxicity assessment. Grade 2 ophthalmic toxicity has occurred in 2 of the 4 patients given 80mg/m2. PK data were as follows, t½ 24.3 ± 10.1 hr, clearance 26.3 ± 33.7 L/hr (range 8.26 - 152.94), Vss 521 ± 454 L (mean±SD, n=17 including 2 patients who underwent intra-patient dose-escalation). Both area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with Alvespimycin dose (r2 0.77 & 0.74, respectively). In peripheral blood mononuclear cells HSP72 protein expression was induced by doses of ≥ 20mg/m2, client protein expression (LCK) was modulated at doses of ≥ 40mg/m2. Tumour samples (pre and 24-hour post 80mg/m2 dose, n=2), demonstrate robust induction of HSP72 protein expression in both patients and client protein expression depletion in one (CDK-4). A confirmed partial response (by PSA and RECIST) has occurred in a patient with hormone refractory prostate cancer (HRPC), who remains on study after 58 weeks. Eight patients have been on trial for ≥ 16 weeks including two patients with stable disease for 36 weeks (HRPC) and 30 weeks (malignant melanoma). Intravenous, weekly, Alvespimycin doses up to 80mg/m2 are not associated with DLT. PK are acceptable and the pharmacological signature of HSP90 inhibition has been detected in tumour samples taken after Alvespimycin. Potential clinical activity has been demonstrated. The PK-PD-clinical data are consistent with active concentrations of Alvespimycin being achieved but in order to define MTD further dose-escalation is required. This study was co-sponsored by NCI/CTEP and Cancer Research UK.
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A phase I trial of the heat shock protein 90 (HSP90) inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17- DMAG, alvespimycin) administered weekly
Journal of Clinical Oncology, 2007Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, J. Moreno-farre, E. Gallerani, V. Davergne, Florence I. Raynaud, Paul Workman, I. JudsonAbstract:3568 Background: The geldanamycin analogue 17-DMAG inhibits the ATPase activity of HSP90, thus altering client protein & chaperone interactions and targeting client proteins for degradation. The plethora of oncogenic HSP90 client proteins offers the potential of combinatorial blockade across multiple, cancer causing signalling pathways in cancer. Methods: 17-DMAG was administered weekly to patients with advanced, solid tumours using a dose-doubling 3 + 3 Phase I design. The pharmacokinetic (PK) and pharmacodynamic (PD) analyses undertaken were validated to comply with U.K clinical trial legislation. Results: 10 patients, 7 male and 3 female with a mean age of 60 years (range 38 - 78) have received 107 infusions (mean 10.7 weeks, range 2 - 30) at dose levels of 2.5mg/m2, 5mg/m2 & 20mg/m2. No dose-limiting or drug related grade 3 or 4 toxicity has occurred in 9 patients eligible for toxicity assessment. A linear relationship exists between dose and AUC and Cmax (see table). Hsp72 induction and CDK4 depletio...
Paul Workman - One of the best experts on this subject based on the ideXlab platform.
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A phase I trial of the HSP90 inhibitor, alvespimycin (17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumours
Journal of Clinical Oncology, 2009Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, Florence I. Raynaud, Paul Workman, Hendrik-tobias Arkenau, Anna Zetterlund, R. Beecham, I. JudsonAbstract:3534 Background: alvespimycin (17-Dimethylaminoethylamino-17-Demethoxygeldanamycin, 17-DMAG) inhibits N-terminal ATPase activity of Heat Shock Protein 90 (HSP90). Chaperone interactions are altered such that client proteins are targeted for degradation. The plethora of HSP90 client proteins offers the potential of simultaneous blockade across multiple, oncogenic signalling pathways. Methods: the maximum tolerated dose, at which ≤ 1/6 patients experienced dose limiting toxicity (DLT) was determined by dose-doubling (3+3) design. PK and PD biomarker data were used to define a biologically effective dose (BED). PK (LC/MS/MS) and PD (western blot) assays were validated and compliant with European clinical trial legislation. Cancer Research UK and the NCI were co-sponsors. Results: twenty five patients, median age 58 (range 38–78) years, received 475 infusions at doses between 2.5 and 106 mg/m2. Dose doubling was possible to 80mg/m2 when grade 2 toxicity, including dry eye and blurred vision (2/5 patients) occ...
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A phase I trial of the heat shock protein 90 (HSP90) inhibitor alvespimycin (17-Dimethylaminoethylamino-17-Demethoxygeldanamycin 17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumors
Molecular Cancer Therapeutics, 2007Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, J. Moreno-farre, Florence I. Raynaud, Paul Workman, Eatock Martin, Hendrik-tobias Arkenau, Heidi Steinfeldt, I. JudsonAbstract:PR-6 This phase I trial was designed to determine the recommended phase II dose of Alvespimycin (17-DMAG) based on the drug’s toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) profile in patients with advanced solid tumors. Alvespimycin is a geldanamycin analogue that inhibits the N-terminal ATPase activity of HSP90. In turn the interactions of client protein and chaperone proteins are altered such that client proteins (eg CDK-4, LCK or ERB B2) are degraded. The multitude of oncogenic HSP90 client proteins offers the potential of combinatorial blockade across multiple, cancer-causing signalling pathways in cancer. Alvespimycin was administered weekly to patients with advanced, solid tumors using a dose-doubling 3 + 3 phase I design. PK analyses were done by an LC/MS/MS method and PD samples were analysed for changes in protein expression by western blotting. Assays were validated to comply with European clinical trial legislation. Seventeen patients, 10 male and 7 female with a mean age of 57 years (range 39 - 79) have received 270 weekly infusions (mean 15.9 weeks, range 2 - 58) at dose levels of 2.5mg/m2, 5mg/m2, 20mg/m2, 40mg/m2 & 80mg/m2. No dose-limiting (DLT) or drug related grade 3 or 4 toxicity has occurred in 17 patients eligible for toxicity assessment. Grade 2 ophthalmic toxicity has occurred in 2 of the 4 patients given 80mg/m2. PK data were as follows, t½ 24.3 ± 10.1 hr, clearance 26.3 ± 33.7 L/hr (range 8.26 - 152.94), Vss 521 ± 454 L (mean±SD, n=17 including 2 patients who underwent intra-patient dose-escalation). Both area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with Alvespimycin dose (r2 0.77 & 0.74, respectively). In peripheral blood mononuclear cells HSP72 protein expression was induced by doses of ≥ 20mg/m2, client protein expression (LCK) was modulated at doses of ≥ 40mg/m2. Tumour samples (pre and 24-hour post 80mg/m2 dose, n=2), demonstrate robust induction of HSP72 protein expression in both patients and client protein expression depletion in one (CDK-4). A confirmed partial response (by PSA and RECIST) has occurred in a patient with hormone refractory prostate cancer (HRPC), who remains on study after 58 weeks. Eight patients have been on trial for ≥ 16 weeks including two patients with stable disease for 36 weeks (HRPC) and 30 weeks (malignant melanoma). Intravenous, weekly, Alvespimycin doses up to 80mg/m2 are not associated with DLT. PK are acceptable and the pharmacological signature of HSP90 inhibition has been detected in tumour samples taken after Alvespimycin. Potential clinical activity has been demonstrated. The PK-PD-clinical data are consistent with active concentrations of Alvespimycin being achieved but in order to define MTD further dose-escalation is required. This study was co-sponsored by NCI/CTEP and Cancer Research UK.
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A phase I trial of the heat shock protein 90 (HSP90) inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17- DMAG, alvespimycin) administered weekly
Journal of Clinical Oncology, 2007Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, J. Moreno-farre, E. Gallerani, V. Davergne, Florence I. Raynaud, Paul Workman, I. JudsonAbstract:3568 Background: The geldanamycin analogue 17-DMAG inhibits the ATPase activity of HSP90, thus altering client protein & chaperone interactions and targeting client proteins for degradation. The plethora of oncogenic HSP90 client proteins offers the potential of combinatorial blockade across multiple, cancer causing signalling pathways in cancer. Methods: 17-DMAG was administered weekly to patients with advanced, solid tumours using a dose-doubling 3 + 3 Phase I design. The pharmacokinetic (PK) and pharmacodynamic (PD) analyses undertaken were validated to comply with U.K clinical trial legislation. Results: 10 patients, 7 male and 3 female with a mean age of 60 years (range 38 - 78) have received 107 infusions (mean 10.7 weeks, range 2 - 30) at dose levels of 2.5mg/m2, 5mg/m2 & 20mg/m2. No dose-limiting or drug related grade 3 or 4 toxicity has occurred in 9 patients eligible for toxicity assessment. A linear relationship exists between dose and AUC and Cmax (see table). Hsp72 induction and CDK4 depletio...
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Development and validation of a liquid chromatography/tandem mass spectrometry method for the determination of the novel anticancer agent 17-DMAG in human plasma.
Rapid communications in mass spectrometry : RCM, 2006Co-Authors: J. Moreno-farre, Simon Pacey, Paul Workman, Yasmin Asad, Florence I. RaynaudAbstract:An accurate, sensitive, robust and selective liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the determination of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin hydrochloride (17-DMAG) in human plasma has been developed and validated. Plasma samples were prepared by liquid/liquid extraction with ethyl acetate. The chromatographic separation was achieved within 9 min on a Synergy Polar column with a linear gradient and a mobile phase consisting of methanol and 0.1% formic acid in water. Detection of 17-DMAG and the internal standard (IS), olomoucine, was achieved by MS/MS with electrospray ionisation in positive ion mode. The calibration curve, ranging from 1.89 to 1890 nM, was linear r > 0.994 using a 1/y2 weighted linear regression. The assay showed no significant interferences from endogenous compounds. The lower limit of quantitation (LLOQ) was 1.89 nM, using 250 microL of plasma, with inter-assay precision (%RSD) and accuracy (%RE) values of 11.6% and -5.8%, respectively. Intra-assay precision ranged from 7.8-13.6%. The method described here is being used to evaluate the pharmacokinetic profiles of 17-DMAG given as a once weekly infusion in patients with advanced solid tumours.
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Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis
Molecular cancer therapeutics, 2006Co-Authors: Sharon Sanderson, Paul Workman, Melanie Valenti, Sharon Gowan, Lisa Patterson, Zahida Ahmad, Suzanne A EcclesAbstract:Heat shock protein 90 (Hsp90) is a molecular chaperone involved in maintaining the correct conformation and stability of its client proteins. This study investigated the effects of Hsp90 inhibitors on client protein expression and key cellular functions required for tumor angiogenesis. The benzoquinone ansamycin Hsp90 inhibitors geldanamycin and/or its derivatives 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin inhibited production of vascular endothelial growth factor (VEGF)-A by tumor cells and blocked proliferative responses of human endothelial cells at nanomolar concentrations. 17-AAG also significantly reduced endothelial cell migration, tubular differentiation, invasion through Matrigel, and secretion of urokinase-type plasminogen activator at concentrations at or below those that inhibited proliferation. 17-AAG significantly reduced expression of VEGF receptor (VEGFR)-2 and established Hsp90 client proteins in human endothelial cells in vitro as well as in mouse vena cava, mesenteric vessels, and blood vessels within human tumor xenografts in vivo; this was associated with decreased tumor microvessel density. Finally, we showed for the first time that Hsp90 inhibitors also reduce expression of VEGFR-1 on human vascular endothelial cells, VEGFR-3 on lymphatic endothelial cells in vitro, and all three VEGFRs on mouse vasculature in vivo. Thus, we identify Hsp90 inhibitors as important regulators of many aspects of tumor angiogenesis (and potentially lymphangiogenesis) and suggest that they may provide therapeutic benefit not only via direct effects on tumor cells but also indirectly by inhibiting the production of angiogenic cytokines and responses of activated endothelial cells that contribute to tumor progression and metastasis.
Simon Pacey - One of the best experts on this subject based on the ideXlab platform.
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A Phase I study of the Heat Shock Protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced, solid tumors.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2011Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, J. Moreno-farre, Hendrik-tobias Arkenau, Anna Zetterlund, Anthea Hardcastle, Udai Banerji, Belle RoelsAbstract:Purpose: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). Patients and Methods: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. Results: Twenty-five patients received 17-DMAG (range 2.5–106 mg/m 2 ). At 106 mg/m 2 of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m 2 . Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m 2 or less. In peripheral blood mononuclear cells significant ( P 2 ) and sustained for 96 hours (≥40 mg/m 2 ). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m 2 client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively). Couclusions: The recommended phase II dose of 17-DMAG is 80 mg/m 2 weekly i.v. Clin Cancer Res; 17(6); 1561–70. ©2011 AACR .
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A phase I trial of the HSP90 inhibitor, alvespimycin (17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumours
Journal of Clinical Oncology, 2009Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, Florence I. Raynaud, Paul Workman, Hendrik-tobias Arkenau, Anna Zetterlund, R. Beecham, I. JudsonAbstract:3534 Background: alvespimycin (17-Dimethylaminoethylamino-17-Demethoxygeldanamycin, 17-DMAG) inhibits N-terminal ATPase activity of Heat Shock Protein 90 (HSP90). Chaperone interactions are altered such that client proteins are targeted for degradation. The plethora of HSP90 client proteins offers the potential of simultaneous blockade across multiple, oncogenic signalling pathways. Methods: the maximum tolerated dose, at which ≤ 1/6 patients experienced dose limiting toxicity (DLT) was determined by dose-doubling (3+3) design. PK and PD biomarker data were used to define a biologically effective dose (BED). PK (LC/MS/MS) and PD (western blot) assays were validated and compliant with European clinical trial legislation. Cancer Research UK and the NCI were co-sponsors. Results: twenty five patients, median age 58 (range 38–78) years, received 475 infusions at doses between 2.5 and 106 mg/m2. Dose doubling was possible to 80mg/m2 when grade 2 toxicity, including dry eye and blurred vision (2/5 patients) occ...
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A phase I trial of the heat shock protein 90 (HSP90) inhibitor alvespimycin (17-Dimethylaminoethylamino-17-Demethoxygeldanamycin 17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumors
Molecular Cancer Therapeutics, 2007Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, J. Moreno-farre, Florence I. Raynaud, Paul Workman, Eatock Martin, Hendrik-tobias Arkenau, Heidi Steinfeldt, I. JudsonAbstract:PR-6 This phase I trial was designed to determine the recommended phase II dose of Alvespimycin (17-DMAG) based on the drug’s toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) profile in patients with advanced solid tumors. Alvespimycin is a geldanamycin analogue that inhibits the N-terminal ATPase activity of HSP90. In turn the interactions of client protein and chaperone proteins are altered such that client proteins (eg CDK-4, LCK or ERB B2) are degraded. The multitude of oncogenic HSP90 client proteins offers the potential of combinatorial blockade across multiple, cancer-causing signalling pathways in cancer. Alvespimycin was administered weekly to patients with advanced, solid tumors using a dose-doubling 3 + 3 phase I design. PK analyses were done by an LC/MS/MS method and PD samples were analysed for changes in protein expression by western blotting. Assays were validated to comply with European clinical trial legislation. Seventeen patients, 10 male and 7 female with a mean age of 57 years (range 39 - 79) have received 270 weekly infusions (mean 15.9 weeks, range 2 - 58) at dose levels of 2.5mg/m2, 5mg/m2, 20mg/m2, 40mg/m2 & 80mg/m2. No dose-limiting (DLT) or drug related grade 3 or 4 toxicity has occurred in 17 patients eligible for toxicity assessment. Grade 2 ophthalmic toxicity has occurred in 2 of the 4 patients given 80mg/m2. PK data were as follows, t½ 24.3 ± 10.1 hr, clearance 26.3 ± 33.7 L/hr (range 8.26 - 152.94), Vss 521 ± 454 L (mean±SD, n=17 including 2 patients who underwent intra-patient dose-escalation). Both area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with Alvespimycin dose (r2 0.77 & 0.74, respectively). In peripheral blood mononuclear cells HSP72 protein expression was induced by doses of ≥ 20mg/m2, client protein expression (LCK) was modulated at doses of ≥ 40mg/m2. Tumour samples (pre and 24-hour post 80mg/m2 dose, n=2), demonstrate robust induction of HSP72 protein expression in both patients and client protein expression depletion in one (CDK-4). A confirmed partial response (by PSA and RECIST) has occurred in a patient with hormone refractory prostate cancer (HRPC), who remains on study after 58 weeks. Eight patients have been on trial for ≥ 16 weeks including two patients with stable disease for 36 weeks (HRPC) and 30 weeks (malignant melanoma). Intravenous, weekly, Alvespimycin doses up to 80mg/m2 are not associated with DLT. PK are acceptable and the pharmacological signature of HSP90 inhibition has been detected in tumour samples taken after Alvespimycin. Potential clinical activity has been demonstrated. The PK-PD-clinical data are consistent with active concentrations of Alvespimycin being achieved but in order to define MTD further dose-escalation is required. This study was co-sponsored by NCI/CTEP and Cancer Research UK.
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A phase I trial of the heat shock protein 90 (HSP90) inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17- DMAG, alvespimycin) administered weekly
Journal of Clinical Oncology, 2007Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, J. Moreno-farre, E. Gallerani, V. Davergne, Florence I. Raynaud, Paul Workman, I. JudsonAbstract:3568 Background: The geldanamycin analogue 17-DMAG inhibits the ATPase activity of HSP90, thus altering client protein & chaperone interactions and targeting client proteins for degradation. The plethora of oncogenic HSP90 client proteins offers the potential of combinatorial blockade across multiple, cancer causing signalling pathways in cancer. Methods: 17-DMAG was administered weekly to patients with advanced, solid tumours using a dose-doubling 3 + 3 Phase I design. The pharmacokinetic (PK) and pharmacodynamic (PD) analyses undertaken were validated to comply with U.K clinical trial legislation. Results: 10 patients, 7 male and 3 female with a mean age of 60 years (range 38 - 78) have received 107 infusions (mean 10.7 weeks, range 2 - 30) at dose levels of 2.5mg/m2, 5mg/m2 & 20mg/m2. No dose-limiting or drug related grade 3 or 4 toxicity has occurred in 9 patients eligible for toxicity assessment. A linear relationship exists between dose and AUC and Cmax (see table). Hsp72 induction and CDK4 depletio...
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Development and validation of a liquid chromatography/tandem mass spectrometry method for the determination of the novel anticancer agent 17-DMAG in human plasma.
Rapid communications in mass spectrometry : RCM, 2006Co-Authors: J. Moreno-farre, Simon Pacey, Paul Workman, Yasmin Asad, Florence I. RaynaudAbstract:An accurate, sensitive, robust and selective liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the determination of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin hydrochloride (17-DMAG) in human plasma has been developed and validated. Plasma samples were prepared by liquid/liquid extraction with ethyl acetate. The chromatographic separation was achieved within 9 min on a Synergy Polar column with a linear gradient and a mobile phase consisting of methanol and 0.1% formic acid in water. Detection of 17-DMAG and the internal standard (IS), olomoucine, was achieved by MS/MS with electrospray ionisation in positive ion mode. The calibration curve, ranging from 1.89 to 1890 nM, was linear r > 0.994 using a 1/y2 weighted linear regression. The assay showed no significant interferences from endogenous compounds. The lower limit of quantitation (LLOQ) was 1.89 nM, using 250 microL of plasma, with inter-assay precision (%RSD) and accuracy (%RE) values of 11.6% and -5.8%, respectively. Intra-assay precision ranged from 7.8-13.6%. The method described here is being used to evaluate the pharmacokinetic profiles of 17-DMAG given as a once weekly infusion in patients with advanced solid tumours.
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inhibition of hif reduces bladder hypertrophy and improves bladder function in murine model of partial bladder outlet obstruction
The Journal of Urology, 2016Co-Authors: Nao Iguchi, Anna P Malykhina, Duncan T WilcoxAbstract:Purpose: Posterior urethral valves are the most common cause of partial bladder outlet obstruction in the pediatric population. However, to our knowledge the etiology and the detailed mechanisms underlying pathological changes in the bladder following partial bladder outlet obstruction remain to be elucidated. Recent findings suggest that hypoxia and associated up-regulation of HIFs (hypoxia-inducible factors) have a key role in partial bladder outlet obstruction induced pathology in the bladder. We examined the effects of pharmacological inhibition of HIF pathways by 17-DMAG (17-(dimethylaminoethylamino)-17-demethoxygeldanamycin) in pathophysiological phenotypes after partial bladder outlet obstruction.Materials and Methods: Partial bladder outlet obstruction was surgically created in male C57BL/6J mice. The animals received oral administration of 17-DMAG or vehicle daily starting from the initiation of obstruction up to 5 days. Sham operated mice served as controls. Bladders were harvested from each gro...
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Inhibition of HIF Reduces Bladder Hypertrophy and Improves Bladder Function in Murine Model of Partial Bladder Outlet Obstruction.
The Journal of urology, 2016Co-Authors: Nao Iguchi, Anna P Malykhina, Duncan T WilcoxAbstract:Posterior urethral valves are the most common cause of partial bladder outlet obstruction in the pediatric population. However, to our knowledge the etiology and the detailed mechanisms underlying pathological changes in the bladder following partial bladder outlet obstruction remain to be elucidated. Recent findings suggest that hypoxia and associated up-regulation of HIFs (hypoxia-inducible factors) have a key role in partial bladder outlet obstruction induced pathology in the bladder. We examined the effects of pharmacological inhibition of HIF pathways by 17-DMAG (17-(dimethylaminoethylamino)-17-demethoxygeldanamycin) in pathophysiological phenotypes after partial bladder outlet obstruction. Partial bladder outlet obstruction was surgically created in male C57BL/6J mice. The animals received oral administration of 17-DMAG or vehicle daily starting from the initiation of obstruction up to 5 days. Sham operated mice served as controls. Bladders were harvested from each group 2, 4 and 7 days postoperatively, and analyzed for histological and biochemical changes. Bladder function was assessed by in vitro muscle contractility recordings. Partial bladder outlet obstruction caused a significant increase in the bladder mass accompanying enhanced collagen deposition in the bladder wall while 17-DMAG treatment suppressed those increases. Treatment with 17-DMAG attenuated the degree of up-regulation of HIFs and their target genes involving the development of tissue fibrosis in obstructed bladders. Treatment with 17-DMAG improved the decreased responses of obstructed bladder strips to electrical field stimulation and KCl. In vivo 17-DMAG treatment decreased partial bladder outlet obstruction induced pathophysiological changes in the bladder. HIF pathway inhibition has a potential clinical implication for the development of novel pharmacological therapies to treat bladder pathology associated with partial bladder outlet obstruction. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.