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17-Dimethylaminoethylamino-17-Demethoxygeldanamycin

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Merrill J. Egorin – One of the best experts on this subject based on the ideXlab platform.

  • Population pharmacokinetic analysis of 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors
    Cancer chemotherapy and pharmacology, 2012
    Co-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. Bies

    Abstract:

    Purpose
    To identify sources of exposure variability for the tumor growth inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis.

  • 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, 2010
    Co-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. Belani

    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 st…

  • 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, 2007
    Co-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. Belani

    Abstract:

    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

I. Judson – One of the best experts on this subject based on the ideXlab platform.

  • A phase I trial of the HSP90 inhibitor, alvespimycin (17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumours
    Journal of Clinical Oncology, 2009
    Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, Florence I. Raynaud, Paul Workman, Hendrik-tobias Arkenau, Anna Zetterlund, R. Beecham, I. Judson

    Abstract:

    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…

  • 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, 2007
    Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, J. Moreno-farre, Florence I. Raynaud, Paul Workman, Eatock Martin, Hendrik-tobias Arkenau, Heidi Steinfeldt, I. Judson

    Abstract:

    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.

  • 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, 2007
    Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, J. Moreno-farre, E. Gallerani, V. Davergne, Florence I. Raynaud, Paul Workman, I. Judson

    Abstract:

    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.

  • A phase I trial of the HSP90 inhibitor, alvespimycin (17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumours
    Journal of Clinical Oncology, 2009
    Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, Florence I. Raynaud, Paul Workman, Hendrik-tobias Arkenau, Anna Zetterlund, R. Beecham, I. Judson

    Abstract:

    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…

  • 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, 2007
    Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, J. Moreno-farre, Florence I. Raynaud, Paul Workman, Eatock Martin, Hendrik-tobias Arkenau, Heidi Steinfeldt, I. Judson

    Abstract:

    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.

  • 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, 2007
    Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, J. Moreno-farre, E. Gallerani, V. Davergne, Florence I. Raynaud, Paul Workman, I. Judson

    Abstract:

    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…