The Experts below are selected from a list of 636033 Experts worldwide ranked by ideXlab platform

Woonbok Chung - One of the best experts on this subject based on the ideXlab platform.

  • abstract lb 214 interim results from a randomized phase 1 2 first in human fih study of pk pd guided escalating doses of sgi 110 a novel subcutaneous sq second generation hypomethylating agent hma in relapsed refractory mds and aml
    Cancer Research, 2012
    Co-Authors: Jean Pierre J Issa, Gail J Roboz, David A Rizzieri, Stefan Faderl, Casey Oconnell, Wendy Stock, Raoul Tibes, Elizabeth A Griffiths, Karen W L Yee, Woonbok Chung
    Abstract:

    SGI-110 is a novel second generation HMA, formulated as a low volume SQ injection. It is designed as a dinucleotide incorporating decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of its active component, decitabine by protecting decitabine from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically Effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage of the study will be a randomized Phase 2 dose expansion, once the BED and MTD have been determined. Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90 mg/m2 weekly x3 but are not yet fully evaluable. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE9s were neutropenia, thrombocytopenia, or anemia. There have been 3 remissions in relapsed AML subjects: 1 CR with weekly (60mg/m2) and 1 PR and 1 CR with daily (36 and 60 mg/m2 respectively). The PK profile showed efficient conversion of SGI-110 to decitabine achieving exposures in the therapeutic range as predicted from the SGI-110 rational design, characterized by decitabine AUC in therapeutic range (cohorts 4-5), lower Cmax, and longer Effective half life, as compared to historical data based on molar equivalent doses of IV decitabine. Dose-dependent hypomethylation induction in the first 5 cohorts was observed. The subject who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically Effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with achievable therapeutic exposures, longer apparent half life, and lower Cmax than predicted equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion Phase 2 stage after establishing the BED and MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-214. doi:1538-7445.AM2012-LB-214

Stewart Spies - One of the best experts on this subject based on the ideXlab platform.

  • biodistribution and dosimetry results from a phase iii prospectively randomized controlled trial of zevalin radioimmunotherapy for low grade follicular or transformed b cell non hodgkin s lymphoma
    Critical Reviews in Oncology Hematology, 2001
    Co-Authors: Gregory A Wiseman, Christine A White, Richard B Sparks, William D Erwin, Donald A Podoloff, Dominick Lamonica, Nancy L Bartlett, Anthony J Parker, William L Dunn, Stewart Spies
    Abstract:

    Abstract Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90 YZevalin™ ( 90 yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90 Y Zevalin radioimmunotherapy compared to rituximab (Rituxan®, MabThera®) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90 Y Zevalin administration is required for safe treatment in this patient population. Methods: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) 111 In Zevalin ( 111 indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90 Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m 2 rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of 111 In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90 Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m 2 weekly×4). Results: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data ( N =72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18–221 cGy), 216 cGy to lungs (94–457 cGy), 532 cGy to liver (range: 234–1856 cGy), 848 cGy to spleen (range: 76–1902 cGy), 15 cGy to kidneys (0.27–76 cGy) and 1484 cGy to tumor (range: 61–24 274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of Effective Half-Life (Half-Life) or residence time of 90 Y in blood, or radiation absorbed dose to the red marrow or total body. Conclusion: 90 Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90 Y Zevalin in this defined patient population without pre-treatment 111 In-based radiation dosimetry.

  • biodistribution and dosimetry results from a phase iii prospectively randomized controlled trial of zevalin radioimmunotherapy for low grade follicular or transformed b cell non hodgkin s lymphoma
    Critical Reviews in Oncology Hematology, 2001
    Co-Authors: Gregory A Wiseman, Christine A White, Richard B Sparks, William D Erwin, Donald A Podoloff, Dominick Lamonica, Nancy L Bartlett, Anthony J Parker, William L Dunn, Stewart Spies
    Abstract:

    Abstract Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90 YZevalin™ ( 90 yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90 Y Zevalin radioimmunotherapy compared to rituximab (Rituxan®, MabThera®) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90 Y Zevalin administration is required for safe treatment in this patient population. Methods: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) 111 In Zevalin ( 111 indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90 Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m 2 rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of 111 In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90 Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m 2 weekly×4). Results: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data ( N =72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18–221 cGy), 216 cGy to lungs (94–457 cGy), 532 cGy to liver (range: 234–1856 cGy), 848 cGy to spleen (range: 76–1902 cGy), 15 cGy to kidneys (0.27–76 cGy) and 1484 cGy to tumor (range: 61–24 274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of Effective Half-Life (Half-Life) or residence time of 90 Y in blood, or radiation absorbed dose to the red marrow or total body. Conclusion: 90 Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90 Y Zevalin in this defined patient population without pre-treatment 111 In-based radiation dosimetry.

Pharis Mohideen - One of the best experts on this subject based on the ideXlab platform.

  • multiple once daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers a randomized double blind placebo controlled cross over phase i study
    Endocrine, 2012
    Co-Authors: Christoph Beglinger, Y. Wang, Emmanuel Bouillaud, Christelle Darstein, Pharis Mohideen
    Abstract:

    A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600 μg sc qd for 14 days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection–site reactions (n = 18), diarrhea (n = 14) and nausea (n = 10), which were mostly mild or moderate in intensity. Pasireotide 600 μg sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3 days of dosing and PK exposures had a moderate accumulation of 20–40 % across doses. Pasireotide demonstrated fast absorption (Tmax,ss: 0.25–0.5 h), low clearance (CL/Fss: 8.10–9.03 L/h), long Effective Half-Life (T½,eff: ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 μg sc qd), and large volume of distribution (Vz/Fss: 251–1,091 L) at steady state. Dose proportionality was confirmed for Cmax,ss; other PK parameters (Cmax, AUC0–24 h and AUCtau) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600 μg sc qd. Gallbladder volume increased post-prandially with pasireotide 200 and 600 μg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 μg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.

Jean Pierre J Issa - One of the best experts on this subject based on the ideXlab platform.

  • abstract lb 214 interim results from a randomized phase 1 2 first in human fih study of pk pd guided escalating doses of sgi 110 a novel subcutaneous sq second generation hypomethylating agent hma in relapsed refractory mds and aml
    Cancer Research, 2012
    Co-Authors: Jean Pierre J Issa, Gail J Roboz, David A Rizzieri, Stefan Faderl, Casey Oconnell, Wendy Stock, Raoul Tibes, Elizabeth A Griffiths, Karen W L Yee, Woonbok Chung
    Abstract:

    SGI-110 is a novel second generation HMA, formulated as a low volume SQ injection. It is designed as a dinucleotide incorporating decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of its active component, decitabine by protecting decitabine from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically Effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage of the study will be a randomized Phase 2 dose expansion, once the BED and MTD have been determined. Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90 mg/m2 weekly x3 but are not yet fully evaluable. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE9s were neutropenia, thrombocytopenia, or anemia. There have been 3 remissions in relapsed AML subjects: 1 CR with weekly (60mg/m2) and 1 PR and 1 CR with daily (36 and 60 mg/m2 respectively). The PK profile showed efficient conversion of SGI-110 to decitabine achieving exposures in the therapeutic range as predicted from the SGI-110 rational design, characterized by decitabine AUC in therapeutic range (cohorts 4-5), lower Cmax, and longer Effective half life, as compared to historical data based on molar equivalent doses of IV decitabine. Dose-dependent hypomethylation induction in the first 5 cohorts was observed. The subject who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically Effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with achievable therapeutic exposures, longer apparent half life, and lower Cmax than predicted equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion Phase 2 stage after establishing the BED and MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-214. doi:1538-7445.AM2012-LB-214

Gilmour Morrison - One of the best experts on this subject based on the ideXlab platform.

  • a phase i randomized double blind placebo controlled single ascending dose multiple dose and food effect trial of the safety tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects
    CNS Drugs, 2018
    Co-Authors: Lesley Taylor, Barry E Gidal, Graham Blakey, Bola Tayo, Gilmour Morrison
    Abstract:

    A formal single ascending and multiple dose pharmacokinetic (PK) trial of cannabidiol (CBD) oral solution was required to determine the safety and tolerability of CBD, the maximum tolerated dose, and to examine the effect of food on CBD PK parameters. This trial assessed the safety, tolerability and PK of CBD oral solution in healthy adult volunteers, as well as the effect of food on CBD PK parameters. The study consisted of three arms: single ascending dose (1500, 3000, 4500 or 6000 mg CBD [n = 6 per group]/placebo [n = 8; 2 per CBD dose group]), multiple dose (750 or 1500 mg CBD [n = 9 per group]/placebo [n = 6; 3 per CBD dose group] twice daily), and food effect (1500 mg CBD single dose [n = 12]). All subjects completed all trial arms and were analyzed as planned. CBD was generally well tolerated. Diarrhea, nausea, headache, and somnolence were the most common adverse events (AEs) across all trial arms, with an increased incidence of some gastrointestinal and nervous system disorder AEs (most notably diarrhea and headache) apparent in subjects taking CBD compared with placebo. All AEs were of mild or moderate severity; none were severe or serious. There were no deaths or discontinuations in the trial. After single oral doses, CBD appeared rapidly in plasma; time to maximum plasma concentration (tmax) was approximately 4–5 h. The major circulating metabolite was 7-carboxy-CBD, then parent CBD, 7-hydroxy-CBD (active metabolite), and 6-hydroxy-CBD (a relatively minor metabolite). Plasma exposure to CBD [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to time t (AUCt)] increased in a less than dose-proportional manner (Cmax slope 0.73; AUCt slope 0.64). Oral clearance of CBD was high (1111–1909 L/h) and apparent volume of distribution was large (20,963–42,849 L). CBD reached steady state after approximately 2 days, with moderate accumulation (1.8- to 2.6-fold) after 750 and 1500 mg CBD twice daily. After 7 days, a twofold increase in CBD dose resulted in 1.6- and 1.9-fold increases in geometric mean Cmax and area under the plasma concentration-time curve over a dosing interval (AUCτ), respectively. CBD elimination was multiphasic; the terminal elimination Half-Life was approximately 60 h after 750 and 1500 mg CBD twice daily; and Effective Half-Life estimates ranged from 10 to 17 h. Cmax was 541.2 ng/mL and AUCτ was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (Cmax and AUCt) by 4.85- and 4.2-fold, respectively; there was no effect of food on tmax or terminal Half-Life. CBD was generally well tolerated. Most AEs were mild in severity; none were severe or serious. The safety and PK profile support twice-daily administration of CBD.