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Charles E Myers - One of the best experts on this subject based on the ideXlab platform.
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antitumor activity of suramin in hormone refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables
Cancer, 1995Co-Authors: Nancy A. Dawson, Donna Headlee, Alain Thibault, Charles E Myers, Raymond C. Bergan, Michael R Cooper, William D Figg, Edward A. Sausville, Seth M Steinberg, Oliver SartorAbstract:Background. A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. Methods. Fifty-four patients whose Disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose Disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 ρg/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and Soft-Tissue Disease response. Results. Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/ or a partial response of measurable Soft-Tissue Disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no Soft-Tissue Disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months. Conclusion. Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeatic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin. Cancer 1995; 76:453–62.
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surprising activity of flutamide withdrawal when combined with aminoglutethimide in treatment of hormone refractory prostate cancer
Journal of the National Cancer Institute, 1994Co-Authors: Oliver Sartor, Donna Headlee, Alain Thibault, Michael R Cooper, William D Figg, Seth M Steinberg, Anne Tompkins, M Weinberger, W M Linehan, Charles E MyersAbstract:BACKGROUND The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed. PURPOSE We investigated a combination of flutamide withdrawal and aminoglutethimide in suramin- and hydrocortisone-pretreated patients with "hormone-refractory" prostate cancer. METHODS Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminoglutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients. Because of suramin-induced adrenal insufficiency, all patients had previously received, and continued to receive, physiological doses of hydrocortisone. Treatment of all non-surgically castrated patients had previously failed; however, these patients continued to receive depot leuprolide. RESULTS In 14 (48%) of 29 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, Soft-Tissue masses, bone scans, and symptoms were also noted. Factors associated with response included prolonged flutamide pretreatment, a markedly elevated pretreatment PSA, and the absence of Soft-Tissue Disease. CONCLUSIONS Flutamide withdrawal, when combined with the simultaneous administration of aminoglutethimide, is a therapeutically active approach in patients with "hormone-refractory" prostate cancer. IMPLICATIONS On the basis of these and additional data, we hypothesize that prolonged exposure to flutamide results in the selective proliferation of cancer cells containing a mutant androgen receptor that aberrantly recognizes flutamide metabolites and nonandrogenic steroids as androgenic stimuli.
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suramin a novel growth factor antagonist with activity in hormone refractory metastatic prostate cancer
Journal of Clinical Oncology, 1992Co-Authors: Charles E Myers, Nancy A. Dawson, Michael R Cooper, Seth M Steinberg, C A Stein, Renato V Larocca, Mcclellan M Walther, G Weiss, Peter L Choyke, M UhrichAbstract:PURPOSESuramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy.PATIENTS AND METHODSSuramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2.RESULTSIn 17 patients with measurable Soft Tissue Disease, three had complete disappearance of Soft Tissue Disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable Disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). ...
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suramin a novel growth factor antagonist with activity in hormone refractory metastatic prostate cancer
Journal of Clinical Oncology, 1992Co-Authors: Charles E Myers, Nancy A. Dawson, Michael R Cooper, Seth M Steinberg, C A Stein, Renato V Larocca, Mcclellan M Walther, G Weiss, P Choyke, M M UhrichAbstract:Purpose Suramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy. Patients and methods Suramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2. Results In 17 patients with measurable Soft Tissue Disease, three had complete disappearance of Soft Tissue Disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable Disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). The remaining 21 patients had Disease limited to bone, and only one of these experienced resolution of more than 50% of all lesions on bone scan. Of these 21 patients, pretreatment PSA decreased by 75% or more in eight (38%) and normalized in five (25%). Median time to progression for all patients was 26.3 weeks, and median survival was 42.3 weeks. Patients with bone involvement alone exhibited a better survival than patients with Soft Tissue involvement (P2 = .02). Survival was strongly correlated (P2 = .0001) with a decline in the pretreatment PSA of greater than or equal to 75% by the eighth week on therapy, with nearly an 85% survival at 1 year compared with a 20% survival for those whose pretreatment PSA did not decline by that amount. Conclusion We conclude that suramin is an active agent in hormone-refractory prostate carcinoma.
Seth M Steinberg - One of the best experts on this subject based on the ideXlab platform.
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phase ii trial of suramin leuprolide and flutamide in previously untreated metastatic prostate cancer
Journal of Clinical Oncology, 1997Co-Authors: Nancy Dawson, Raymond C. Bergan, Michael R Cooper, William D Figg, Oliver Sartor, Seth M Steinberg, Adrian M Senderowicz, Anne Tompkins, B Weinberger, Edward A. SausvilleAbstract:PURPOSETo assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer.PATIENTS AND METHODSPatients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until Disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone.RESULTSFifty patients were entered onto the study: 48 with stage D2 and two with stage D1 Disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable Soft Tissue Disease. Forty-one (82%) had severe Disease. The overall response rate in 49 assessable...
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antitumor activity of suramin in hormone refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables
Cancer, 1995Co-Authors: Nancy A. Dawson, Donna Headlee, Alain Thibault, Charles E Myers, Raymond C. Bergan, Michael R Cooper, William D Figg, Edward A. Sausville, Seth M Steinberg, Oliver SartorAbstract:Background. A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. Methods. Fifty-four patients whose Disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose Disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 ρg/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and Soft-Tissue Disease response. Results. Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/ or a partial response of measurable Soft-Tissue Disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no Soft-Tissue Disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months. Conclusion. Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeatic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin. Cancer 1995; 76:453–62.
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surprising activity of flutamide withdrawal when combined with aminoglutethimide in treatment of hormone refractory prostate cancer
Journal of the National Cancer Institute, 1994Co-Authors: Oliver Sartor, Donna Headlee, Alain Thibault, Michael R Cooper, William D Figg, Seth M Steinberg, Anne Tompkins, M Weinberger, W M Linehan, Charles E MyersAbstract:BACKGROUND The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed. PURPOSE We investigated a combination of flutamide withdrawal and aminoglutethimide in suramin- and hydrocortisone-pretreated patients with "hormone-refractory" prostate cancer. METHODS Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminoglutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients. Because of suramin-induced adrenal insufficiency, all patients had previously received, and continued to receive, physiological doses of hydrocortisone. Treatment of all non-surgically castrated patients had previously failed; however, these patients continued to receive depot leuprolide. RESULTS In 14 (48%) of 29 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, Soft-Tissue masses, bone scans, and symptoms were also noted. Factors associated with response included prolonged flutamide pretreatment, a markedly elevated pretreatment PSA, and the absence of Soft-Tissue Disease. CONCLUSIONS Flutamide withdrawal, when combined with the simultaneous administration of aminoglutethimide, is a therapeutically active approach in patients with "hormone-refractory" prostate cancer. IMPLICATIONS On the basis of these and additional data, we hypothesize that prolonged exposure to flutamide results in the selective proliferation of cancer cells containing a mutant androgen receptor that aberrantly recognizes flutamide metabolites and nonandrogenic steroids as androgenic stimuli.
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suramin a novel growth factor antagonist with activity in hormone refractory metastatic prostate cancer
Journal of Clinical Oncology, 1992Co-Authors: Charles E Myers, Nancy A. Dawson, Michael R Cooper, Seth M Steinberg, C A Stein, Renato V Larocca, Mcclellan M Walther, G Weiss, Peter L Choyke, M UhrichAbstract:PURPOSESuramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy.PATIENTS AND METHODSSuramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2.RESULTSIn 17 patients with measurable Soft Tissue Disease, three had complete disappearance of Soft Tissue Disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable Disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). ...
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suramin a novel growth factor antagonist with activity in hormone refractory metastatic prostate cancer
Journal of Clinical Oncology, 1992Co-Authors: Charles E Myers, Nancy A. Dawson, Michael R Cooper, Seth M Steinberg, C A Stein, Renato V Larocca, Mcclellan M Walther, G Weiss, P Choyke, M M UhrichAbstract:Purpose Suramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy. Patients and methods Suramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2. Results In 17 patients with measurable Soft Tissue Disease, three had complete disappearance of Soft Tissue Disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable Disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). The remaining 21 patients had Disease limited to bone, and only one of these experienced resolution of more than 50% of all lesions on bone scan. Of these 21 patients, pretreatment PSA decreased by 75% or more in eight (38%) and normalized in five (25%). Median time to progression for all patients was 26.3 weeks, and median survival was 42.3 weeks. Patients with bone involvement alone exhibited a better survival than patients with Soft Tissue involvement (P2 = .02). Survival was strongly correlated (P2 = .0001) with a decline in the pretreatment PSA of greater than or equal to 75% by the eighth week on therapy, with nearly an 85% survival at 1 year compared with a 20% survival for those whose pretreatment PSA did not decline by that amount. Conclusion We conclude that suramin is an active agent in hormone-refractory prostate carcinoma.
Michael R Cooper - One of the best experts on this subject based on the ideXlab platform.
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phase ii trial of suramin leuprolide and flutamide in previously untreated metastatic prostate cancer
Journal of Clinical Oncology, 1997Co-Authors: Nancy Dawson, Raymond C. Bergan, Michael R Cooper, William D Figg, Oliver Sartor, Seth M Steinberg, Adrian M Senderowicz, Anne Tompkins, B Weinberger, Edward A. SausvilleAbstract:PURPOSETo assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer.PATIENTS AND METHODSPatients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until Disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone.RESULTSFifty patients were entered onto the study: 48 with stage D2 and two with stage D1 Disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable Soft Tissue Disease. Forty-one (82%) had severe Disease. The overall response rate in 49 assessable...
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antitumor activity of suramin in hormone refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables
Cancer, 1995Co-Authors: Nancy A. Dawson, Donna Headlee, Alain Thibault, Charles E Myers, Raymond C. Bergan, Michael R Cooper, William D Figg, Edward A. Sausville, Seth M Steinberg, Oliver SartorAbstract:Background. A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. Methods. Fifty-four patients whose Disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose Disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 ρg/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and Soft-Tissue Disease response. Results. Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/ or a partial response of measurable Soft-Tissue Disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no Soft-Tissue Disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months. Conclusion. Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeatic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin. Cancer 1995; 76:453–62.
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surprising activity of flutamide withdrawal when combined with aminoglutethimide in treatment of hormone refractory prostate cancer
Journal of the National Cancer Institute, 1994Co-Authors: Oliver Sartor, Donna Headlee, Alain Thibault, Michael R Cooper, William D Figg, Seth M Steinberg, Anne Tompkins, M Weinberger, W M Linehan, Charles E MyersAbstract:BACKGROUND The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed. PURPOSE We investigated a combination of flutamide withdrawal and aminoglutethimide in suramin- and hydrocortisone-pretreated patients with "hormone-refractory" prostate cancer. METHODS Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminoglutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients. Because of suramin-induced adrenal insufficiency, all patients had previously received, and continued to receive, physiological doses of hydrocortisone. Treatment of all non-surgically castrated patients had previously failed; however, these patients continued to receive depot leuprolide. RESULTS In 14 (48%) of 29 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, Soft-Tissue masses, bone scans, and symptoms were also noted. Factors associated with response included prolonged flutamide pretreatment, a markedly elevated pretreatment PSA, and the absence of Soft-Tissue Disease. CONCLUSIONS Flutamide withdrawal, when combined with the simultaneous administration of aminoglutethimide, is a therapeutically active approach in patients with "hormone-refractory" prostate cancer. IMPLICATIONS On the basis of these and additional data, we hypothesize that prolonged exposure to flutamide results in the selective proliferation of cancer cells containing a mutant androgen receptor that aberrantly recognizes flutamide metabolites and nonandrogenic steroids as androgenic stimuli.
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suramin a novel growth factor antagonist with activity in hormone refractory metastatic prostate cancer
Journal of Clinical Oncology, 1992Co-Authors: Charles E Myers, Nancy A. Dawson, Michael R Cooper, Seth M Steinberg, C A Stein, Renato V Larocca, Mcclellan M Walther, G Weiss, Peter L Choyke, M UhrichAbstract:PURPOSESuramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy.PATIENTS AND METHODSSuramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2.RESULTSIn 17 patients with measurable Soft Tissue Disease, three had complete disappearance of Soft Tissue Disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable Disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). ...
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suramin a novel growth factor antagonist with activity in hormone refractory metastatic prostate cancer
Journal of Clinical Oncology, 1992Co-Authors: Charles E Myers, Nancy A. Dawson, Michael R Cooper, Seth M Steinberg, C A Stein, Renato V Larocca, Mcclellan M Walther, G Weiss, P Choyke, M M UhrichAbstract:Purpose Suramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy. Patients and methods Suramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2. Results In 17 patients with measurable Soft Tissue Disease, three had complete disappearance of Soft Tissue Disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable Disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). The remaining 21 patients had Disease limited to bone, and only one of these experienced resolution of more than 50% of all lesions on bone scan. Of these 21 patients, pretreatment PSA decreased by 75% or more in eight (38%) and normalized in five (25%). Median time to progression for all patients was 26.3 weeks, and median survival was 42.3 weeks. Patients with bone involvement alone exhibited a better survival than patients with Soft Tissue involvement (P2 = .02). Survival was strongly correlated (P2 = .0001) with a decline in the pretreatment PSA of greater than or equal to 75% by the eighth week on therapy, with nearly an 85% survival at 1 year compared with a 20% survival for those whose pretreatment PSA did not decline by that amount. Conclusion We conclude that suramin is an active agent in hormone-refractory prostate carcinoma.
Howard I Scher - One of the best experts on this subject based on the ideXlab platform.
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end points and outcomes in castration resistant prostate cancer from clinical trials to clinical practice
Journal of Clinical Oncology, 2011Co-Authors: Howard I Scher, Michael J Morris, Ethan Basch, Glenn HellerAbstract:New therapeutic approaches for castration-resistant prostate cancer (CRPC) introduce new treatment dilemmas: how best to sequence these options to maximally benefit patients, what tests to perform before and after treatment to assess Disease status, and how to interpret the test results and use them to guide treatment. New and specific end points for different classes of drugs are needed to provide the information to guide these treatment decisions. In 2008, the Prostate Cancer Working Group 2 consensus criteria for early-phase clinical trials redefined clinical trial end points as first, to control, relieve, or eliminate Disease manifestations present when treatment is started and second, to prevent or delay future Disease manifestations. Disease manifestations include prostate-specific antigen (PSA), Soft-Tissue Disease (nodes and/or viscera), bone Disease (most common site of spread), and symptoms. Recent US Food and Drug Administration (FDA) approvals for CRPC therapies have been based on the prevent/delay end points that reflect unequivocal benefit to a patient: prolongation of life or reduction in skeletalrelated events (SREs). For the practicing oncologist, the control/relieve/eliminate outcomes should serve primarily to inform the decision of whether to continue therapy. In this review, we consider individual end points such as PSA, imaging, and patient-reported outcomes in the context of the control/relieve/eliminate and prevent/delay framework. We address the time-to-event end points of metastasis prevention, SRE, time to progression, and overall survival in the context of regulatory approvals. We also discuss circulating tumor cells measured with the CellSearch assay, recently cleared by the FDA for monitoring CRPC. J Clin Oncol 29:3695-3704. © 2011 by American Society of Clinical Oncology
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abstract cn02 03 circulating tumor cells as biomarkers in the development of the androgen receptor antagonist mdv3100
Molecular Cancer Therapeutics, 2009Co-Authors: Howard I Scher, Daniel C Danila, Aseem Anand, Celestia S. Higano, Tomasz M Beer, Dana E Rathkopf, Maryellen Taplin, Eleni Efstathiou, David T Hung, M HirmandAbstract:Background: Selecting targeted therapies and assessing outcome in patients (pts) with castration‐resistant prostate cancer (CRPC) are significant unmet medical needs. A proportion of CRPC remains dependent on androgen receptor (AR) activation. MDV3100, a second‐generation AR antagonist optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased AR expression blocks nuclear translocation of AR and DNA binding and has no known agonist activity when AR is overexpressed. Methods: Pts with progressive CRPC were enrolled in sequential cohorts of 3–6 pts at 30, 60, 150, 240, 360, 480 and 600 mg/day. Once the safety of a dose was established, enrollment was expanded at doses >60 mg/day to include 12 chemotherapy‐naive and 12 post‐chemotherapy pts per cohort. Antitumor effects were assessed using the Prostate Cancer Working Group (PCWG) 2 criteria reporting post‐therapy PSA changes from baseline, and radiologic imaging for Soft‐Tissue Disease by RECIST and osseous Disease on radionuclide bone scan as improved, progressed or no change. Circulating tumor cell (CTC) enumeration was performed with the FDA cleared analytically valid CellSearch assay (Veridex, LLC, Huntingdon Valley, PA) and reported as the number of cells per 7.5 ml of blood as previously described. Samples were collected at baseline, 4 weeks, and 12 weeks post‐treatment and at progression of Disease. Samples from outside Center were shipped overnight and processed in the CLIA certified MSKCC Clinical Chemistry laboratory. Results: A total of 140 pts were enrolled, of which 65 (46%) were chemotherapy‐naive, and 75 pts (54%) were in post‐chemotherapy setting. Maximal PSA decline from baseline of ≥ 50% was achieved in 40/65 (62%) chemotherapy‐naive and 38/75 (51%) post‐chemotherapy. At 12 weeks, radiographic control (no progression) was observed in 35/47 pts (74%) with evaluable Soft Tissue lesions per PCWG2 guidelines and 50/81 pts (62%) with bone lesions. At 600 mg/day, 2 of 3 pts had dose limiting toxicity (rash; seizure). Dose reductions due to fatigue were noted at 480 and 360 mg/day. The maximal tolerated dose was 240mg daily based on safety data. CTC counts were obtained from 128/140 (91%) pts enrolled; 16/60 pts chemotherapy‐naive and 35/68 pts post‐chemotherapy had ≥ 5 CTC/7.5 mL blood at baseline. CTC conversion from baseline CTC ≥ 5 (unfavorable) to CTC Conclusions: MDV3100 demonstrated favorable efficacy assessed by prostate‐specific antigen (PSA) decline and CTC enumeration. The efficacy comparable to that at higher doses and the better adverse event profile, led to the selection of 160 mg/day as the recommended dose for future studies. A prospective investigation of pre and post‐therapy CTC counts and clinical outcomes in a phase III randomized, double‐blind, placebo‐controlled efficacy trial of MDV3100 has been recently initiated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN02-03.
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abiraterone acetate and prednisone in patients pts with progressive metastatic castration resistant prostate cancer crpc after failure of docetaxel based chemotherapy
Journal of Clinical Oncology, 2008Co-Authors: Daniel C Danila, Aseem Anand, Lawrence H Schwartz, Martin Fleisher, Dana E Rathkopf, Susan F Slovin, M J Morris, K Farmer, Christopher M Haqq, Howard I ScherAbstract:5019 Background: A proportion of CRPC overexpress androgen synthetic enzymes and are dependent on androgens for growth. Abiraterone acetate (AA) inhibits 17 α-hydroxylase and C17,20-lyase to decrease serum androgen to undetectable levels. Methods: AA plus prednisone was studied in Pts with metastatic CRPC who had progressed on docetaxel based chemotherapy. Pts received oral AA 1000 mg QD, and prednisone 5 mg BID in 28 day cycles. The primary endpoint a >50% decline in PSA from baseline. Changes in bone and Soft Tissue Disease were also monitored, as were pre- and post-therapy circulating tumor cell (CTC) number. Results: 43 Pts were screened and 38 treated. The median (interquartile range) age was 73 years (64–81) and PSA 86.3 ng/mL (33–311.5) while 32 (84%) had > 5 CTC per 7.5 ml of blood at baseline. Prior systemic therapy included 3 or more hormone in 29 (76%), including ketoconazole in 17 (45%); while 26 (68%) received 1, and 12 (32%) 2 lines of chemotherapy. Sites of metastases were bone only in 10 (...
Dana E Rathkopf - One of the best experts on this subject based on the ideXlab platform.
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radiographic progression free survival as a clinically meaningful end point in metastatic castration resistant prostate cancer the prevail randomized clinical trial
JAMA Oncology, 2018Co-Authors: Dana E Rathkopf, Celestia S. Higano, Tomasz M Beer, Yohann Loriot, Andrew J Armstrong, Cora N Sternberg, Johann S De Bono, Bertrand Tombal, Teresa Parli, Suman BhattacharyaAbstract:IMPORTANCE Drug development formetastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. OBJECTIVE To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. DESIGN, SETTING, AND PARTICIPANTS PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. INTERVENTIONS Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic Disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. MAIN OUTCOMES AND MEASURES Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for Soft-Tissue Disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman rho and Kendall tau via Clayton copula. RESULTS In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman rho and 0.72 (95% CI, 0.68-0.77) by Kendall tau. CONCLUSIONS AND RELEVANCE Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients.
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cabozantinib in chemotherapy pretreated metastatic castration resistant prostate cancer results of a phase ii nonrandomized expansion study
Journal of Clinical Oncology, 2014Co-Authors: Matthew R Smith, Celestia S. Higano, Dana E Rathkopf, Christopher Sweeney, Paul G Corn, David C Smith, Maha Hussain, Daniel J George, Andrea L Harzstark, Oliver A SartorAbstract:Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until Disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n 93) or 40-mg (n 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable Soft Tissue Disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable Soft Tissue Disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group.
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abstract cn02 03 circulating tumor cells as biomarkers in the development of the androgen receptor antagonist mdv3100
Molecular Cancer Therapeutics, 2009Co-Authors: Howard I Scher, Daniel C Danila, Aseem Anand, Celestia S. Higano, Tomasz M Beer, Dana E Rathkopf, Maryellen Taplin, Eleni Efstathiou, David T Hung, M HirmandAbstract:Background: Selecting targeted therapies and assessing outcome in patients (pts) with castration‐resistant prostate cancer (CRPC) are significant unmet medical needs. A proportion of CRPC remains dependent on androgen receptor (AR) activation. MDV3100, a second‐generation AR antagonist optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased AR expression blocks nuclear translocation of AR and DNA binding and has no known agonist activity when AR is overexpressed. Methods: Pts with progressive CRPC were enrolled in sequential cohorts of 3–6 pts at 30, 60, 150, 240, 360, 480 and 600 mg/day. Once the safety of a dose was established, enrollment was expanded at doses >60 mg/day to include 12 chemotherapy‐naive and 12 post‐chemotherapy pts per cohort. Antitumor effects were assessed using the Prostate Cancer Working Group (PCWG) 2 criteria reporting post‐therapy PSA changes from baseline, and radiologic imaging for Soft‐Tissue Disease by RECIST and osseous Disease on radionuclide bone scan as improved, progressed or no change. Circulating tumor cell (CTC) enumeration was performed with the FDA cleared analytically valid CellSearch assay (Veridex, LLC, Huntingdon Valley, PA) and reported as the number of cells per 7.5 ml of blood as previously described. Samples were collected at baseline, 4 weeks, and 12 weeks post‐treatment and at progression of Disease. Samples from outside Center were shipped overnight and processed in the CLIA certified MSKCC Clinical Chemistry laboratory. Results: A total of 140 pts were enrolled, of which 65 (46%) were chemotherapy‐naive, and 75 pts (54%) were in post‐chemotherapy setting. Maximal PSA decline from baseline of ≥ 50% was achieved in 40/65 (62%) chemotherapy‐naive and 38/75 (51%) post‐chemotherapy. At 12 weeks, radiographic control (no progression) was observed in 35/47 pts (74%) with evaluable Soft Tissue lesions per PCWG2 guidelines and 50/81 pts (62%) with bone lesions. At 600 mg/day, 2 of 3 pts had dose limiting toxicity (rash; seizure). Dose reductions due to fatigue were noted at 480 and 360 mg/day. The maximal tolerated dose was 240mg daily based on safety data. CTC counts were obtained from 128/140 (91%) pts enrolled; 16/60 pts chemotherapy‐naive and 35/68 pts post‐chemotherapy had ≥ 5 CTC/7.5 mL blood at baseline. CTC conversion from baseline CTC ≥ 5 (unfavorable) to CTC Conclusions: MDV3100 demonstrated favorable efficacy assessed by prostate‐specific antigen (PSA) decline and CTC enumeration. The efficacy comparable to that at higher doses and the better adverse event profile, led to the selection of 160 mg/day as the recommended dose for future studies. A prospective investigation of pre and post‐therapy CTC counts and clinical outcomes in a phase III randomized, double‐blind, placebo‐controlled efficacy trial of MDV3100 has been recently initiated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN02-03.
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abiraterone acetate and prednisone in patients pts with progressive metastatic castration resistant prostate cancer crpc after failure of docetaxel based chemotherapy
Journal of Clinical Oncology, 2008Co-Authors: Daniel C Danila, Aseem Anand, Lawrence H Schwartz, Martin Fleisher, Dana E Rathkopf, Susan F Slovin, M J Morris, K Farmer, Christopher M Haqq, Howard I ScherAbstract:5019 Background: A proportion of CRPC overexpress androgen synthetic enzymes and are dependent on androgens for growth. Abiraterone acetate (AA) inhibits 17 α-hydroxylase and C17,20-lyase to decrease serum androgen to undetectable levels. Methods: AA plus prednisone was studied in Pts with metastatic CRPC who had progressed on docetaxel based chemotherapy. Pts received oral AA 1000 mg QD, and prednisone 5 mg BID in 28 day cycles. The primary endpoint a >50% decline in PSA from baseline. Changes in bone and Soft Tissue Disease were also monitored, as were pre- and post-therapy circulating tumor cell (CTC) number. Results: 43 Pts were screened and 38 treated. The median (interquartile range) age was 73 years (64–81) and PSA 86.3 ng/mL (33–311.5) while 32 (84%) had > 5 CTC per 7.5 ml of blood at baseline. Prior systemic therapy included 3 or more hormone in 29 (76%), including ketoconazole in 17 (45%); while 26 (68%) received 1, and 12 (32%) 2 lines of chemotherapy. Sites of metastases were bone only in 10 (...