4665 Background: Galeterone is an oral steroid analog that suppresses prostate cancer growth by i... more 4665 Background: Galeterone is an oral steroid analog that suppresses prostate cancer growth by inhibiting CYP17, blocking androgen receptor and reducing androgen receptor levels. Methods: Open label, multicenter dose-finding study assessing the safety, pharmacokinetics and clinical effect of escalating doses of galeterone in chemotherapy naïve CRPC patients (pts). Pts were enrolled in cohorts from 650-2,600mg of galeterone daily for 12 wks. Study also explored effects of food supplement and scheduling. Pts remained on study until disease progression or dose limiting toxicity. Results: Pt characteristics included median age 69 (47-92), median PSA 24 (6-200), and 46.9% with metastases. 36 of 49 pts completed 12 wks of study with early discontinuation for toxicity (6), progression (5), or withdrawal of consent (2). Maximal tolerated dose was not reached. The frequency of AEs was 58% grade 1, 30% grade 2, 8% grade 3 and 1% grade 4. Transient LFT elevations were seen in 15 men (5 with s...
The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two d... more The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection. A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA (= 16) or IM-LA (= 16) in this phase I, open-label, parallel-group study. PK was assessedLA concentrations, and PDserum luteinizing hormone (LH) and testosterone (T) concentrations. The initial surge of LA was higher for IM-LA than SC-LA (C27 ± 4.919 ± 8.0 ng/ml, respectively), with a shorter t(1.0 ± 0.42.1 ± 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 5642 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by D...
e586 Background: Leuprolide acetate (LA), a LHRH agonist, is standard of care in ADT in prostate ... more e586 Background: Leuprolide acetate (LA), a LHRH agonist, is standard of care in ADT in prostate cancer and used to suppress serum testosterone (T) to castrate level. Previously, in a head-to-head comparison of long-acting, polymer-delivered, subcutaneously administered LA (SC-LA) and microsphere intramuscularly administered LA depot (IM-LA) in healthy subjects, SC-LA demonstrated extended drug delivery compared to IM-LA, as well as prolonged T suppression. The objective of this study was to evaluate the safety and pharmacokinetics (PK) of SC-LA in orchiectomized, advanced prostate cancer patients to confirm and compare PK results with the head-to-head study. Methods: In this open label, single dose study, male, orchiectomized prostate cancer patients (ages 45-85) received a single dose of 7.5 mg SC-LA (labeled for 1 month dose interval). Blood samples were taken at baseline and at all scheduled visits up to day 56. LA concentration in serum was analyzed with HPLC. PK parameters AUC...
222 Background: Men with advanced prostate cancer are being treated with androgen deprivation the... more 222 Background: Men with advanced prostate cancer are being treated with androgen deprivation therapy (ADT) for longer periods of time. The use of ADT can be limited by estrogen deficiency side effects, including a loss of bone and a higher incidence of fractures. GTx-758 is an ERα agonist that lowers serum free testosterone greater than an LHRH agonist. Herein we compare the effects of GTx-758 and leuprolide on markers of bone turnover, C-terminal telopeptides and bone specific alkaline phosphatase, in men with advanced prostate cancer treated with ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Serum samples were collected and analyzed by a reference laboratory. C-terminal telopeptides (pg/ml) and bone specific alkaline phosphatase (U/L) were measured as indicators of bone turnover. All p values describe the comparison of the GTx-758 treatment groups to the leuprolide treated men at ...
171 Background: The insulin pathway and, in particular, insulin-like growth factor-1 (IGF-1), has... more 171 Background: The insulin pathway and, in particular, insulin-like growth factor-1 (IGF-1), has been implicated in the development of prostate cancer, and serum IGF-1 levels have been associated with advanced disease. GTx-758, an ERα agonist that is being evaluated for the treatment of advanced prostate cancer, reduces serum total testosterone (T) and free T and increases SHBG. Herein, we compare the effects of GTx-758 and leuprolide on serum IGF-1 levels in men with advanced prostate cancer treated with ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Serum samples were collected from all of the men in the study and serum IGF-1 levels (ng/ml) were analyzed by a reference laboratory. All p values describe the comparison of GTx-758 treatment groups to the leuprolide treated men. Results: Through day 90, in men receiving the 1000 mg and 2000 mg doses of GTx-758 , serum IGF-1 levels were...
104 Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with adv... more 104 Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but patients develop castrate resistant prostate cancer (CRPC); one of the causes of which is ineffective castration. Total serum testosterone (T) does not accurately predict prostatic levels of T. Further reduction of androgens in men with CRPC can result in improvement of survival. Herein we compare the effects GTx-758 an oral, selective estrogen receptor alpha (ERα) agonist versus leuprolide on total and free (unbound) serum T levels in men with advanced prostate cancer. Methods: In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot (4 month), while men with CRPC (n=9) received 2000 mg GTx-758 daily. Serum concentrations of total T, free T, SHBG and PSA were determined at baseline and during treatment. Results: In ADT naïve advanced prostate cancer patients, 28 days of 1000 mg or 2000 mg daily GT...
The physics-based Lyon-Fedder-Mobarry (LFM) code simulates Earth's magnetospheric top... more The physics-based Lyon-Fedder-Mobarry (LFM) code simulates Earth's magnetospheric topology and dynamics by solving the equations of ideal MHD using input solar wind parameters at the upstream boundary. Comparison with electron phase space density evolution during storms using a radial diffusion code, as well as spacecraft measurements where available, will tell us when diffusion is insufficiently accurate for radiation belt simulation,
To determine whether an LHRH agonist, ATRIGEL(®) polymer-delivered, subcutaneous, leuprolide acet... more To determine whether an LHRH agonist, ATRIGEL(®) polymer-delivered, subcutaneous, leuprolide acetate (ADSC-LA) formulations suppressed testosterone to levels ≤20 ng/dL. Data from four open-label, fixed-dose studies were evaluated. Male patients aged 40-86 years with advanced prostatic adenocarcinoma, whom had not undergone prior ADT, were treated with a depot formulation of ADSC-LA: 7.5 mg [1 month (1M); N=120], 22.5 mg [3 months (3M); N=117], 30 mg [4 months (4M); N=90], or 45 mg [6 months (6M); N=111]. Serum testosterone was sampled at screening, baseline, 2, 4, 8 hours post-dosing, days 1, 2, 3, 7, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (24 weeks for 1M and 3M, 32 weeks for 4M, and 48 weeks for the 6M dose). The primary analyses were mean serum testosterone levels and proportion of patients who achieved serum testosterone levels ≤20 ng/dL. Mean serum testosterone levels at the end of study were consistently ≤20 ng/...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 2, 2015
Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen rece... more Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies (Androgen Receptor Modulation Optimized for Response-1 [ARMOR1] and ARMOR2 part 1) evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ...
A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly... more A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course. To assess the ability of an oral selective estrogen receptor α agonist (GTx-758) to lower testosterone concentrations compared with leuprolide while minimizing estrogen deficiency-related side effects of androgen-deprivation therapy. Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000mg/d, 2000mg/d, or leuprolide depot. GTx-758 and leuprolide. The primary end point was the proportion of patients achieving total testosterone ≤50 ng/dl by day 60. Secondary end points included serum free testosterone, prostate-specific antigen (PSA), sex hormone-binding globulin, hot flashes, bone turnover markers, and insulin-like growth factor (IGF)-1 levels. Of 159 randomized patients, leuprolide reduced total testosterone to ≤50 ng/dl in a greater proportion of patients than GTx-758 by day 60 (43.4%, 63.6%, and 88.2% of subjects receiving ...
European journal of cancer (Oxford, England : 1990), Jan 2, 2015
Bicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration... more Bicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). Prostate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18months. Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline's RandAll System. Subjects who completed 18months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blind...
4665 Background: Galeterone is an oral steroid analog that suppresses prostate cancer growth by i... more 4665 Background: Galeterone is an oral steroid analog that suppresses prostate cancer growth by inhibiting CYP17, blocking androgen receptor and reducing androgen receptor levels. Methods: Open label, multicenter dose-finding study assessing the safety, pharmacokinetics and clinical effect of escalating doses of galeterone in chemotherapy naïve CRPC patients (pts). Pts were enrolled in cohorts from 650-2,600mg of galeterone daily for 12 wks. Study also explored effects of food supplement and scheduling. Pts remained on study until disease progression or dose limiting toxicity. Results: Pt characteristics included median age 69 (47-92), median PSA 24 (6-200), and 46.9% with metastases. 36 of 49 pts completed 12 wks of study with early discontinuation for toxicity (6), progression (5), or withdrawal of consent (2). Maximal tolerated dose was not reached. The frequency of AEs was 58% grade 1, 30% grade 2, 8% grade 3 and 1% grade 4. Transient LFT elevations were seen in 15 men (5 with s...
The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two d... more The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection. A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA (= 16) or IM-LA (= 16) in this phase I, open-label, parallel-group study. PK was assessedLA concentrations, and PDserum luteinizing hormone (LH) and testosterone (T) concentrations. The initial surge of LA was higher for IM-LA than SC-LA (C27 ± 4.919 ± 8.0 ng/ml, respectively), with a shorter t(1.0 ± 0.42.1 ± 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 5642 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by D...
e586 Background: Leuprolide acetate (LA), a LHRH agonist, is standard of care in ADT in prostate ... more e586 Background: Leuprolide acetate (LA), a LHRH agonist, is standard of care in ADT in prostate cancer and used to suppress serum testosterone (T) to castrate level. Previously, in a head-to-head comparison of long-acting, polymer-delivered, subcutaneously administered LA (SC-LA) and microsphere intramuscularly administered LA depot (IM-LA) in healthy subjects, SC-LA demonstrated extended drug delivery compared to IM-LA, as well as prolonged T suppression. The objective of this study was to evaluate the safety and pharmacokinetics (PK) of SC-LA in orchiectomized, advanced prostate cancer patients to confirm and compare PK results with the head-to-head study. Methods: In this open label, single dose study, male, orchiectomized prostate cancer patients (ages 45-85) received a single dose of 7.5 mg SC-LA (labeled for 1 month dose interval). Blood samples were taken at baseline and at all scheduled visits up to day 56. LA concentration in serum was analyzed with HPLC. PK parameters AUC...
222 Background: Men with advanced prostate cancer are being treated with androgen deprivation the... more 222 Background: Men with advanced prostate cancer are being treated with androgen deprivation therapy (ADT) for longer periods of time. The use of ADT can be limited by estrogen deficiency side effects, including a loss of bone and a higher incidence of fractures. GTx-758 is an ERα agonist that lowers serum free testosterone greater than an LHRH agonist. Herein we compare the effects of GTx-758 and leuprolide on markers of bone turnover, C-terminal telopeptides and bone specific alkaline phosphatase, in men with advanced prostate cancer treated with ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Serum samples were collected and analyzed by a reference laboratory. C-terminal telopeptides (pg/ml) and bone specific alkaline phosphatase (U/L) were measured as indicators of bone turnover. All p values describe the comparison of the GTx-758 treatment groups to the leuprolide treated men at ...
171 Background: The insulin pathway and, in particular, insulin-like growth factor-1 (IGF-1), has... more 171 Background: The insulin pathway and, in particular, insulin-like growth factor-1 (IGF-1), has been implicated in the development of prostate cancer, and serum IGF-1 levels have been associated with advanced disease. GTx-758, an ERα agonist that is being evaluated for the treatment of advanced prostate cancer, reduces serum total testosterone (T) and free T and increases SHBG. Herein, we compare the effects of GTx-758 and leuprolide on serum IGF-1 levels in men with advanced prostate cancer treated with ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Serum samples were collected from all of the men in the study and serum IGF-1 levels (ng/ml) were analyzed by a reference laboratory. All p values describe the comparison of GTx-758 treatment groups to the leuprolide treated men. Results: Through day 90, in men receiving the 1000 mg and 2000 mg doses of GTx-758 , serum IGF-1 levels were...
104 Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with adv... more 104 Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but patients develop castrate resistant prostate cancer (CRPC); one of the causes of which is ineffective castration. Total serum testosterone (T) does not accurately predict prostatic levels of T. Further reduction of androgens in men with CRPC can result in improvement of survival. Herein we compare the effects GTx-758 an oral, selective estrogen receptor alpha (ERα) agonist versus leuprolide on total and free (unbound) serum T levels in men with advanced prostate cancer. Methods: In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot (4 month), while men with CRPC (n=9) received 2000 mg GTx-758 daily. Serum concentrations of total T, free T, SHBG and PSA were determined at baseline and during treatment. Results: In ADT naïve advanced prostate cancer patients, 28 days of 1000 mg or 2000 mg daily GT...
The physics-based Lyon-Fedder-Mobarry (LFM) code simulates Earth's magnetospheric top... more The physics-based Lyon-Fedder-Mobarry (LFM) code simulates Earth's magnetospheric topology and dynamics by solving the equations of ideal MHD using input solar wind parameters at the upstream boundary. Comparison with electron phase space density evolution during storms using a radial diffusion code, as well as spacecraft measurements where available, will tell us when diffusion is insufficiently accurate for radiation belt simulation,
To determine whether an LHRH agonist, ATRIGEL(®) polymer-delivered, subcutaneous, leuprolide acet... more To determine whether an LHRH agonist, ATRIGEL(®) polymer-delivered, subcutaneous, leuprolide acetate (ADSC-LA) formulations suppressed testosterone to levels ≤20 ng/dL. Data from four open-label, fixed-dose studies were evaluated. Male patients aged 40-86 years with advanced prostatic adenocarcinoma, whom had not undergone prior ADT, were treated with a depot formulation of ADSC-LA: 7.5 mg [1 month (1M); N=120], 22.5 mg [3 months (3M); N=117], 30 mg [4 months (4M); N=90], or 45 mg [6 months (6M); N=111]. Serum testosterone was sampled at screening, baseline, 2, 4, 8 hours post-dosing, days 1, 2, 3, 7, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (24 weeks for 1M and 3M, 32 weeks for 4M, and 48 weeks for the 6M dose). The primary analyses were mean serum testosterone levels and proportion of patients who achieved serum testosterone levels ≤20 ng/dL. Mean serum testosterone levels at the end of study were consistently ≤20 ng/...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 2, 2015
Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen rece... more Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies (Androgen Receptor Modulation Optimized for Response-1 [ARMOR1] and ARMOR2 part 1) evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ...
A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly... more A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course. To assess the ability of an oral selective estrogen receptor α agonist (GTx-758) to lower testosterone concentrations compared with leuprolide while minimizing estrogen deficiency-related side effects of androgen-deprivation therapy. Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000mg/d, 2000mg/d, or leuprolide depot. GTx-758 and leuprolide. The primary end point was the proportion of patients achieving total testosterone ≤50 ng/dl by day 60. Secondary end points included serum free testosterone, prostate-specific antigen (PSA), sex hormone-binding globulin, hot flashes, bone turnover markers, and insulin-like growth factor (IGF)-1 levels. Of 159 randomized patients, leuprolide reduced total testosterone to ≤50 ng/dl in a greater proportion of patients than GTx-758 by day 60 (43.4%, 63.6%, and 88.2% of subjects receiving ...
European journal of cancer (Oxford, England : 1990), Jan 2, 2015
Bicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration... more Bicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). Prostate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18months. Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline's RandAll System. Subjects who completed 18months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blind...
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