The Experts below are selected from a list of 144 Experts worldwide ranked by ideXlab platform

Christian Nanoff - One of the best experts on this subject based on the ideXlab platform.

  • Hyponatremia and V2 vasopressin receptor upregulation: a result of HSP90 inhibition
    Cancer Chemotherapy and Pharmacology, 2017
    Co-Authors: Qiong Yang, Florian Puhm, Michael Freissmuth, Christian Nanoff
    Abstract:

    Purpose Small-molecule inhibitors of heat-shock protein 90 (HSP90) have been under development as chemotherapeutic agents. The adverse events reported from early clinical trials included hyponatremia. Given the limited number of patients enrolled, the number of hyponatremia incidents was remarkable and repeatedly, the event was judged as severe. Inappropriate V2 vasopressin receptor stimulation is an established cause of hyponatremia. We explored the hypothesis that HSP90 inhibition produces hypersensitivity to vasopressin by upregulating V2-receptors.MethodsExperiments were carried out in cell culture using HEK293 cells with heterologous expression of the human V2-receptor and HELA cells with an endogenous V2-receptor complement. We tested the effect of HSP90 inhibition by three structurally unrelated compounds (Alvespimycin, luminespib, radicicol) and asserted its specificity in cells depleted of cytosolic HSP90 (by RNA interference). Assays encompassed surface V2-receptor density and vasopressin-stimulated formation of cyclic AMP (cAMP).ResultsThe results demonstrate a twofold increase in cell-surface receptor density following pre-incubation with each of the HSP90 inhibitors. The effect had a concentration-dependence consistent with the individual potencies to inhibit HSP90. Similarly, depletion of cytosolic HSP90 increased surface-receptor density and at the same time, reduced the inhibitor effect. Upregulated V2-receptors were fully functional; hence, in culture treated with an HSP90 inhibitor, addition of vasopressin resulted in higher levels of cAMP than in controls.ConclusionSince formation of cAMP is the first signalling step in raising water permeability of the collecting duct epithelia, we suggest that V2-receptor upregulation generates hypersensitivity to vasopressin linking HSP90 inhibition to the development of hyponatremia.

  • Hyponatremia and V2 vasopressin receptor upregulation: a result of HSP90 inhibition
    Cancer Chemotherapy and Pharmacology, 2017
    Co-Authors: Qiong Yang, Florian Puhm, Michael Freissmuth, Christian Nanoff
    Abstract:

    Small-molecule inhibitors of heat-shock protein 90 (HSP90) have been under development as chemotherapeutic agents. The adverse events reported from early clinical trials included hyponatremia. Given the limited number of patients enrolled, the number of hyponatremia incidents was remarkable and repeatedly, the event was judged as severe. Inappropriate V2 vasopressin receptor stimulation is an established cause of hyponatremia. We explored the hypothesis that HSP90 inhibition produces hypersensitivity to vasopressin by upregulating V2-receptors. Experiments were carried out in cell culture using HEK293 cells with heterologous expression of the human V2-receptor and HELA cells with an endogenous V2-receptor complement. We tested the effect of HSP90 inhibition by three structurally unrelated compounds (Alvespimycin, luminespib, radicicol) and asserted its specificity in cells depleted of cytosolic HSP90 (by RNA interference). Assays encompassed surface V2-receptor density and vasopressin-stimulated formation of cyclic AMP (cAMP). The results demonstrate a twofold increase in cell-surface receptor density following pre-incubation with each of the HSP90 inhibitors. The effect had a concentration-dependence consistent with the individual potencies to inhibit HSP90. Similarly, depletion of cytosolic HSP90 increased surface-receptor density and at the same time, reduced the inhibitor effect. Upregulated V2-receptors were fully functional; hence, in culture treated with an HSP90 inhibitor, addition of vasopressin resulted in higher levels of cAMP than in controls. Since formation of cAMP is the first signalling step in raising water permeability of the collecting duct epithelia, we suggest that V2-receptor upregulation generates hypersensitivity to vasopressin linking HSP90 inhibition to the development of hyponatremia.

Alison L. Hannah - One of the best experts on this subject based on the ideXlab platform.

  • A Phase I Dose-Escalation Trial of Trastuzumab and Alvespimycin Hydrochloride (KOS-1022; 17 DMAG) in the Treatment of Advanced Solid Tumors
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2012
    Co-Authors: Komal Jhaveri, Ziyang Zhong, K. Miller, Lee S. Rosen, Bryan P. Schneider, Linnea Chap, Alison L. Hannah, Clifford A. Hudis, Shanu Modi
    Abstract:

    Purpose: We conducted a phase I dose-escalation study to define the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics of Alvespimycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, given in combination with trastuzumab. Experimental Design: Patients were treated with trastuzumab followed by intravenous Alvespimycin on a weekly schedule. Hsp90 client proteins were measured at baseline and serially in peripheral blood lymphocytes (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible. Results: Twenty-eight patients (25, breast; 3, ovarian) were enrolled onto three dose cohorts: 60 ( n = 9), 80 ( n = 13), and 100 mg/m 2 ( n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m 2 ), and reversible grade III keratitis in two patients (80 mg/m 2 ). Drug-related grade III toxicity included one episode each of fatigue, diarrhea, myalgia, and back pain. Common mild to moderate toxicities included diarrhea, fatigue, myalgia, arthralgia, nausea, blurry vision, headache, back pain, and dry eyes. There was one partial response and seven cases of stable disease (range, 4–10 months), all in HER2+ MBC. In addition, an ovarian cancer patient had complete resolution of ascites and pleural effusion that lasted 24.8 months. There was no change in PK upon weekly dosing. Hsp70 effect continued to increase across four weeks and was most pronounced at 80 and 100 mg/m 2 . Conclusion: The combination of Alvespimycin and trastuzumab is safe and tolerable at MTD. Antitumor activity was seen in patients with refractory HER2+ MBC and ovarian cancer. The recommended dose of Alvespimycin for further study in this combination is 80 mg/m 2 weekly. Clin Cancer Res; 18(18); 5090–8. ©2012 AACR .

  • phase i study of the heat shock protein 90 inhibitor Alvespimycin kos 1022 17 dmag administered intravenously twice weekly to patients with acute myeloid leukemia
    Leukemia, 2010
    Co-Authors: J Lancet, Ziyang Zhong, I Gojo, M Burton, M Quinn, S M Tighe, K Kersey, M X Albitar, Kapil N Bhalla, Alison L. Hannah
    Abstract:

    Phase I study of the heat shock protein 90 inhibitor Alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia

  • First use of an oral Hsp90 inhibitor in patients (Pts) with solid tumors: Alvespimycin (A) administered QOD or Q
    Journal of Clinical Oncology, 2008
    Co-Authors: Keith T. Flaherty, Z Zhong, Alison L. Hannah, Lia Gore, A. N. Avadhani, Jennifer L. Spratlin, K. Harlacker, R. G. Johnson, P. J. O'dwyer, S. G. Eckhardt
    Abstract:

    2502 Background: A, a water soluble Hsp90 inhibitor, is currently under clinical development using intravenous and oral (PO) dosing. Objectives of this study were to determine the DLT, MTD, recommended phase II dose (RP2D), PK and PD of A using 2 schedules of administration in pts with advanced solid tumors. Methods: A is orally administered QOD or QD for 4 out of 6 weeks. An initial IV dose was given to calculate absolute bioavailability (F); PK is evaluated on Days 1 and 21 of oral dosing. PBMCs were collected to investigate changes in intracellular signaling proteins by immunoblot. Results: 47 pts were enrolled: 31 pts (QOD at 5, 10, 20, 30, 40, and 50 mg) and 15 pts (QD at 10, 20, and 30 mg). Demographics: 20/27 male/female, median age 58 (19–89), ECOG 0/1 in 24/23 pts. Common drug-related toxicities (n=47): fatigue 43%, nausea 28%, anorexia 21%, diarrhea 19%, peripheral edema 19%, and arthralgia 15%. Potential drug-related grade 3–4 toxicities (2 each): anemia, thrombocytopenia, fatigue, peripheral e...

  • Phase I trial of Alvespimycin (KOS-1022; 17-DMAG) and trastuzumab (T)
    Journal of Clinical Oncology, 2007
    Co-Authors: K. Miller, K Kersey, Lee S. Rosen, Bryan P. Schneider, Linnea Chap, Alison L. Hannah, Shanu Modi, J. Roy, M. Paulsen, Clifford A. Hudis
    Abstract:

    1115 Background: Alvespimycin (A) inhibits the activity of Hsp90, resulting in degradation of client proteins, such as the HER2 receptor. In vivo, Hsp90 inhibition induces rapid degradation of HER2 with loss of pAKT, cyclin D2 and tumor growth inhibition. Methods: Pts receive standard weekly doses of T followed by A in escalating doses via IV doses over 1 hr. Define the recommended dose (RP2D), toxicity and signs of activity of T+A in pts with solid tumors. PK: assessed after the 1st and 4th infusion. PBLs: purified to investigate changes in intracellular signaling proteins by immunoblot. The RP2D will produce DLT in no more than 1/6 evaluable pts. Results: 21 pts enrolled in 3 cohorts (60, 80 and 100 mg/m2). Median age 53 yrs, range 31–75; median KPS 90; prior regimens not including hormonal therapy: median 6, range 1–13; prior T-regimens for MBC pts: median 3, range 0–9. Diagnoses: HER2+ MBC (n=18), ovarian (n=3). DLT was observed at the highest dose, consisting of 1 pt with hypoxia and ↓LVEF; an additi...

  • Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of oral Alvespimycin (A; KOS-1022; 17-DMAG): Two different schedules in patients with advanced malignancies
    Journal of Clinical Oncology, 2007
    Co-Authors: Keith T. Flaherty, Z Zhong, Alison L. Hannah, A. N. Avadhani, K. Harlacker, R. G. Johnson, P. J. O'dwyer, L. Gore, Stephen Leong, S. G. Eckhardt
    Abstract:

    14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), based on in vitro cytotoxicity or the MTD in toxicology studies; it is water-s...

Qiong Yang - One of the best experts on this subject based on the ideXlab platform.

  • Hyponatremia and V2 vasopressin receptor upregulation: a result of HSP90 inhibition
    Cancer Chemotherapy and Pharmacology, 2017
    Co-Authors: Qiong Yang, Florian Puhm, Michael Freissmuth, Christian Nanoff
    Abstract:

    Purpose Small-molecule inhibitors of heat-shock protein 90 (HSP90) have been under development as chemotherapeutic agents. The adverse events reported from early clinical trials included hyponatremia. Given the limited number of patients enrolled, the number of hyponatremia incidents was remarkable and repeatedly, the event was judged as severe. Inappropriate V2 vasopressin receptor stimulation is an established cause of hyponatremia. We explored the hypothesis that HSP90 inhibition produces hypersensitivity to vasopressin by upregulating V2-receptors.MethodsExperiments were carried out in cell culture using HEK293 cells with heterologous expression of the human V2-receptor and HELA cells with an endogenous V2-receptor complement. We tested the effect of HSP90 inhibition by three structurally unrelated compounds (Alvespimycin, luminespib, radicicol) and asserted its specificity in cells depleted of cytosolic HSP90 (by RNA interference). Assays encompassed surface V2-receptor density and vasopressin-stimulated formation of cyclic AMP (cAMP).ResultsThe results demonstrate a twofold increase in cell-surface receptor density following pre-incubation with each of the HSP90 inhibitors. The effect had a concentration-dependence consistent with the individual potencies to inhibit HSP90. Similarly, depletion of cytosolic HSP90 increased surface-receptor density and at the same time, reduced the inhibitor effect. Upregulated V2-receptors were fully functional; hence, in culture treated with an HSP90 inhibitor, addition of vasopressin resulted in higher levels of cAMP than in controls.ConclusionSince formation of cAMP is the first signalling step in raising water permeability of the collecting duct epithelia, we suggest that V2-receptor upregulation generates hypersensitivity to vasopressin linking HSP90 inhibition to the development of hyponatremia.

  • Hyponatremia and V2 vasopressin receptor upregulation: a result of HSP90 inhibition
    Cancer Chemotherapy and Pharmacology, 2017
    Co-Authors: Qiong Yang, Florian Puhm, Michael Freissmuth, Christian Nanoff
    Abstract:

    Small-molecule inhibitors of heat-shock protein 90 (HSP90) have been under development as chemotherapeutic agents. The adverse events reported from early clinical trials included hyponatremia. Given the limited number of patients enrolled, the number of hyponatremia incidents was remarkable and repeatedly, the event was judged as severe. Inappropriate V2 vasopressin receptor stimulation is an established cause of hyponatremia. We explored the hypothesis that HSP90 inhibition produces hypersensitivity to vasopressin by upregulating V2-receptors. Experiments were carried out in cell culture using HEK293 cells with heterologous expression of the human V2-receptor and HELA cells with an endogenous V2-receptor complement. We tested the effect of HSP90 inhibition by three structurally unrelated compounds (Alvespimycin, luminespib, radicicol) and asserted its specificity in cells depleted of cytosolic HSP90 (by RNA interference). Assays encompassed surface V2-receptor density and vasopressin-stimulated formation of cyclic AMP (cAMP). The results demonstrate a twofold increase in cell-surface receptor density following pre-incubation with each of the HSP90 inhibitors. The effect had a concentration-dependence consistent with the individual potencies to inhibit HSP90. Similarly, depletion of cytosolic HSP90 increased surface-receptor density and at the same time, reduced the inhibitor effect. Upregulated V2-receptors were fully functional; hence, in culture treated with an HSP90 inhibitor, addition of vasopressin resulted in higher levels of cAMP than in controls. Since formation of cAMP is the first signalling step in raising water permeability of the collecting duct epithelia, we suggest that V2-receptor upregulation generates hypersensitivity to vasopressin linking HSP90 inhibition to the development of hyponatremia.

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...

Simon Pacey - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2011
    Co-Authors: Simon Pacey, Richard Wilson, Michael I. Walton, Martin Eatock, J. Moreno-farre, Hendrik-tobias Arkenau, Anna Zetterlund, Anthea Hardcastle, Udai Banerji, Belle Roels
    Abstract:

    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 .

  • 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...