Biomedical subjects

Michael A Carducci

Publications and source records attributed to Michael A Carducci.

15 recordsLinked to original sources

PubMed2004

Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: recommendations from the Prostate-Specific Antigen Working Group.

PURPOSE: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). RESULTS HYPOTHESIS: A clinical states framework was used to address the hypothesis that definitive phase III trials could not be conducted in this patient population. PATIENT POPULATION: The Group focused on men with systemic (nonlocalized) recurrence and a defined risk of developing clinically detectable metastases. Models to define systemic versus local recurrence, and risk of metastatic progression were discussed. INTERVENTION: Therapies that have shown favorable effects in more advanced clinical states; meaningful biologic surrogates of activity linked with efficacy in other tumor types; and/or effects on a target or pathway known to contribute to prostate cancer progression in this state can be considered for evaluation. OUTCOMES: An intervention-specific posttherapy PSA-based outcome definition that would justify further testing should be described at the outset. Reporting: Trial reports should include a table showing the number of patients who achieve a specific PSA-based outcome, the number who remain enrolled onto the trial, and the number who came off study at different time points. The term PSA response should be abandoned. TRIAL DESIGN: The phases of drug development for this state are optimizing dose and schedule, demonstration of a treatment effect, and clinical benefit. To move a drug forward should require a high bar that includes no rise in PSA in a defined proportion of patients for a specified period of time at a minimum. Agents that do not produce this effect can only be tested in combination. The preferred end point of clinical benefit is prostate cancer-specific survival; the time to development of metastatic disease is an alternative. CONCLUSION: Methodology to show that an intervention alters the natural history of prostate cancer is described. At each stage of development, only agents with sufficient activity should be moved forward.

Clinical Trials as Topic↗

PubMed2004

Simultaneous analysis of docetaxel and the formulation vehicle polysorbate 80 in human plasma by liquid chromatography/tandem mass spectrometry.

An analytical procedure for the simultaneous determination of the anticancer agent docetaxel (Taxotere) and its formulation vehicle polysorbate 80 (Tween 80) in human plasma samples is described. Sample pretreatment involved a double liquid-liquid extraction step with a mixture of acetonitrile/n-butyl chloride (1/4, v/v). Separation of the compounds of interest, including the internal standard paclitaxel, was achieved on a reversed-phase Waters X-Terra mass spectrometry (MS) column (50 x 2.1mm internal diameter) packed with a 3.5-microm octadecyl stationary phase, using isocratic elution. Detection of docetaxel and polysorbate 80 was performed using tandem MS detection with electrospray ionization. Validation results indicated that the method is accurate and precise and has lower limits of quantitation of 0.500 nM (approximately 0.4 ng/ml) and 1.00 microg/ml for docetaxel and polysorbate 80, respectively. The method was subsequently used to measure concentrations of docetaxel and polysorbate 80 in plasma samples in support of a project to assess the influence of polysorbate 80 concentrations on the disposition and toxicity profile of docetaxel in cancer patients receiving Taxotere.

Chromatography, High Pressure Liquid↗

PubMed2004

Phase I and clinical pharmacology of a type I and II, 5-alpha-reductase inhibitor (LY320236) in prostate cancer: elevation of estradiol as possible mechanism of action.

OBJECTIVES: To study the safety, pharmacokinetics, biologic activity, and preliminary efficacy of the bispecific 5-alpha-reductase inhibitor (LY320236) in prostate cancer. METHODS: Fifty-one patients with recurrent or metastatic prostate cancer were sequentially (nonrandomly) assigned in cohorts to receive one of five single daily oral doses of LY320236 (10, 50, 150, 250, and 500 mg). Serial evaluations included serum testosterone, dihydrotestosterone, androstenediol glucuronide, estradiol, and pharmacokinetics on days 1, 29, and 57. Toxicity assessments, x-rays/scans, and blood tests, including serum prostate-specific antigen (PSA) determination, were done at regular intervals. RESULTS: Overall, treatment was well tolerated, with 3 of 51 patients developing reversible grade 3-4 toxicity (one diarrhea, two elevated liver enzymes). Peak blood levels (2 to 3 hours after drug administration) were greater for doses of 150 mg or greater compared with less than 150-mg doses with slow accumulation. Serum levels of testosterone, dihydrotestosterone, and androstenediol glucuronide did not change significantly during treatment; however, a statistically significant increase occurred in serum estradiol levels in both the castration and noncastration groups. One of 26 in the noncastration group and 4 (27%) of 15 in the castration group with baseline PSA levels of 5 ng/mL or greater had a 50% or greater PSA decline for 4 weeks or longer. CONCLUSIONS: LY320236 treatment is associated with modest reversible toxicity. An elevation of estradiol levels was seen in both castration and noncastration groups, although PSA declines were primarily seen in the castration group. The absence of cardiovascular toxicity suggests that this agent may be a promising alternative to exogenous estrogens in patients with prostate cancer who demonstrate evidence of disease progression after initial androgen deprivation treatment.

5-alpha Reductase Inhibitors↗

PubMed2003

Phase 3 randomized trial evaluating second-line hormonal therapy versus docetaxel-estramustine combination chemotherapy on progression-free survival in asymptomatic patients with a rising prostate-specific antigen level after hormonal therapy for prostate cancer: an Eastern Cooperative Oncology Group (E1899), Intergroup/Clinical Trials Support Unit study.

Despite improvements in early detection of prostate cancer when it is clinically localized--and therefore most amenable to curative local therapies-- approximately 33% of men with early prostate cancer will develop biochemical failure with a rising prostate-specific antigen (PSA) during follow-up. The early use of androgen suppression in this group of men has changed the clinical picture of androgen-independent disease. Now, there are men on androgen suppression who will develop biochemical failure and remain free of clinical or radiographic evidence of metastatic disease for a period of time. There is no standard approach to this group of men, who have a rising PSA on androgen deprivation, because there are little or no data about strategies that may improve survival, delay time to progression, or improve quality of life. Therefore, current management of this population remains controversial. In an effort to determine which of these 2 approaches--second-line hormone therapy or chemotherapy--is optimal in delaying the time to progression, the Eastern Cooperative Oncology Group (ECOG) developed protocol E1899. Although both approaches offer the potential for response (reduction in PSA and prolonging the time to clinical progression), they have very different toxicity profiles, making impact on quality of life another important end point. This randomized trial evaluating second-line hormonal therapy using ketoconazole and hydrocortisone versus docetaxel and estramustine combination chemotherapy on progression-free survival in asymptomatic men with a rising PSA on androgen ablation for prostate cancer is the subject of this article.

Adenocarcinoma↗

PubMed2003

Phase I study of docosahexaenoic acid-paclitaxel: a taxane-fatty acid conjugate with a unique pharmacology and toxicity profile.

PURPOSE: Docosahexaenoic acid (DHA)-paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation. This Phase I trial examined its toxicity and pharmacokinetics (PKs). EXPERIMENTAL DESIGN: Patients with advanced refractory solid tumors received a 2-h i.v. infusion of DHA-paclitaxel every 3 weeks. Plasma and urine samples were obtained to characterize the pharmacological profile of DHA-paclitaxel and paclitaxel. RESULTS: Twenty-four patients received 78 cycles of DHA-paclitaxel over five dose levels (200-1100 mg/m(2)). Median number of cycles was 2 (range, 1-8). Myelosuppression was the principal toxicity observed (grade 3/4 neutropenia in 21%/53% of courses at 1100 mg/m(2)); during cycle 1, febrile neutropenia occurred in 1 of 9 patients treated at 1100 mg/m(2). Other grade 3 toxicities were infrequent. No patients developed alopecia, peripheral neuropathy > grade 1, or musculoskeletal toxicity > grade 1. At 1100 mg/m(2), DHA-paclitaxel had a mean (CV%) volume of distribution of 7.5 (64) liters, beta half-life of 112 (56) h, and clearance of 0.11 (30) liters/h. Paclitaxel PK parameters at 1100 mg/m(2) were: C(max), 282 (46) ng/ml; AUC, 10,705 (60) ng/ml x h; and terminal half-life, 85 (101) h. Paclitaxel plasma exposure represented < or =0.06% of DHA-paclitaxel exposure. Paclitaxel AUC was correlated with neutropenia. One partial response was observed. CONCLUSIONS: The starting dose recommended for subsequent studies is 1100 mg/m(2). DHA-paclitaxel dramatically alters the PK profile of derived paclitaxel compared with values observed after a 3-h infusion of paclitaxel (175 mg/m(2)). In addition, its favorable toxicity profile offers potential advantages over existing taxanes.

Adult↗

PubMed2003

Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial.

PURPOSE: To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma. PATIENTS AND METHODS: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers. RESULTS: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P =.13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P =.021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P =.002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan. CONCLUSION: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.

Acid Phosphatase↗

PubMed2003

Endothelin receptor antagonists in the treatment of prostate cancer.

The endothelin (ET) axis represents a novel and exciting target in the treatment of prostate cancer. ET-1, acting primarily through the endothelin A receptor (ET(A)), is integrally involved in multiple facets of prostate cancer progression, including cell growth, inhibition of apoptosis, angiogenesis, development and progression of bone metastases, and mediation of pain responses. Clinical trials with the ET(A) antagonist, atrasentan, have demonstrated good tolerability, with the most common adverse events being headache, rhinitis, and peripheral edema. These trials have demonstrated statistically significant improvements in pain measures, prostate-specific antigen (PSA) kinetics, biologic markers of bone changes, and development of bone metastases. There have also been consistent improvements in time to progression, although not always statistically significant. Ongoing studies in a variety of patient populations will better define the role of ET receptor antagonists in the treatment of men with prostate cancer. In this article, we review the biology and pathophysiology of the ET axis in prostate cancer, critically analyze the major clinical trials reported to date, and discuss some emerging data and how it may impact the way we proceed in the future with the development of this class of drugs in prostate cancer.

Androgen Antagonists↗

PubMed2003

Differentiation therapy.

Differentiation therapy is an area of oncology that is in its infancy. Theoretically, the concept of differentiation therapy involves turning a cancer cell "off" biologically and reverting to a more "benign" phenotype. Many agents have been studied over the past few years, with many already either in use clinically or showing future promise.

Antineoplastic Agents↗

PubMed2003

Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan.

PURPOSE: We examined the effects of atrasentan (endothelin-A receptor antagonist) on bone deposition and resorption markers and on bone scan index. MATERIALS AND METHODS: This double-blind, randomized, placebo controlled clinical trial of hormone refractory prostate cancer patients was done at 74 medical centers in the United States and Europe. A total of 288 asymptomatic patients with hormone refractory prostate adenocarcinoma and evidence of metastatic disease were randomized to 1 of 3 treatment groups, namely 2.5 mg. atrasentan, 10 mg. atrasentan or placebo administered orally daily until disease progression. The main outcomes measures were changes in bone deposition markers (total alkaline phosphatase and bone alkaline phosphatase) and bone resorption (N-telopeptides, C-telopeptides and deoxypyridinoline), and in the bone scan index. RESULTS: At baseline markers of bone deposition and resorption were elevated 1.4 to 2.7-fold above respective upper limits of normal. Subjects receiving placebo experienced a 58% elevation in mean total alkaline phosphatase and a 99% elevation in mean bone alkaline phosphatase (p < 0.001), whereas subjects receiving 10 mg. atrasentan maintained stable mean total alkaline phosphatase and bone alkaline phosphatase values compared with baseline. N-telopeptides, C-telopeptides and deoxypyridinoline elevation from baseline were consistently less in patients receiving 10 mg. atrasentan compared with placebo. Similar trends were observed in subjects who received 2.5 mg. atrasentan. Changes in clinical bone scan studies paralleled bone marker changes. CONCLUSIONS: Atrasentan suppressed markers of biochemical and clinical prostate cancer progression in bone and demonstrates clinical activity for hormone refractory prostate cancer.

Adenocarcinoma↗

PubMed2003

The evolving role of docetaxel in the management of androgen independent prostate cancer.

PURPOSE: Androgen independent prostate cancer is an advanced disease with an extremely poor outcome. In view of this fact, a great deal of interest has recently been generated in the potential use of chemotherapeutic agents, particularly docetaxel. We reviewed the evolving role of docetaxel as a chemotherapeutic agent for the management of this disease. MATERIALS AND METHODS: The main emphasis of this review is discussion of the various clinical trials that have investigated the use of docetaxel alone or combined with other agents for androgen independent prostate cancer. RESULTS: Docetaxel, which acts primarily by inhibiting microtubular depolymerization, in combination with other agents has consistently demonstrated a palliative response, a decrease in serum prostate specific antigen levels by 50% or greater in more than 60% of patients, a decrease in measurable disease and the suggestion of improved survival. CONCLUSIONS: Docetaxel based regimens are moderately well tolerated and they have shown promising results in various phase 2 trials. The completion of ongoing phase III randomized trials are eagerly awaited since they may determine whether a definite beneficial impact on overall survival can be achieved.

Antineoplastic Agents, Phytogenic↗

PubMed2003

Pharmacotherapy of hormone refractory prostate cancer: new developments and challenges.

Hormone refractory prostate cancer (HRPC) remains a challenge in the management of prostate cancer patients. With the widespread use of PSA (prostate specific antigen), recurrent disease after local treatment for localised prostate cancer is usually diagnosed long before evidence of metastatic disease. In many cases, hormonal manipulations are started at the time of biochemical relapse and therefore, patients become 'hormone refractory' earlier in the course of their disease, frequently with a good performance status, often with no evidence of metastatic disease, and they still face a considerably long life expectancy. Despite these changes, the need for more options in the treatment of HRPC is obvious. The pharmacological treatments that are in use and those that are under investigation for this group of patients will be discussed and include: cytotoxic agents including the microtubule inhibitors, alone and in combination with other conventional or experimental therapies such as calcitriol or thalidomide; treatment with epothilone analogues; endothelin receptor antagonists; palliative therapy with bisphosphonates, bone-targeted radiopharmaceuticals and other developing treatments such as vaccines, gene therapies and monoclonal antibodies.

Antineoplastic Agents↗

PubMed2002

Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.

PURPOSE: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Adenocarcinoma↗

PubMed2002

Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma.

BACKGROUND: Recent clinical trials have shown antitumor activity with the combination of docetaxel plus estramustine phosphate (EMP) in the treatment of patients with androgen independent prostate carcinoma (AIPC). However, the most commonly employed treatment schedules with EMP have been associated with significant gastrointestinal, cardiovascular, and thromboembolic toxicity. The authors hypothesized that the therapeutic index of the combination of docetaxel plus EMP for patients with prostate carcinoma could be enhanced by reducing the incidence and severity of EMP-associated toxicity, which could be accomplished by shortening the duration of exposure to EMP. To preserve the therapeutic synergism between docetaxel and EMP, they designed a regimen employing higher doses of oral EMP administered on the day of the docetaxel infusion. METHODS: From June 1, 1998 through September 28, 2000, 42 patients with AIPC were registered to receive docetaxel (70 mg/m2 intravenously over 1 hour) and EMP (280 mg orally every 6 hours x 5 doses) every 21 days, up to a maximum of 6 cycles. Dexamethasone was administered prior to docetaxel and coumadin 2 mg orally every day was taken during the study treatment period. Patient characteristics included a median age of 68 years, a median Eastern Cooperative Oncology Group performance status of 1, a median prostate specific antigen (PSA) level at study entry of 110.5 ng/mL, and a median of 2 prior hormonal manipulations. Ten patients (25%) had received prior chemotherapy, and 14 patients (33%) had received prior palliative radiation therapy. RESULTS: Forty patients were evaluable for response and toxicity. Eighteen patients (45%; 95% confidence interval, 29-62%) had a decline > 50% in PSA level that lasted > 4 weeks with a median time to PSA progression and a median duration of PSA response of approximately 4.0 months. Four of 20 patients (20%) had partial soft tissue responses. Ten of 17 symptomatic patients (59%) had improvement in pain. The median survival for all patients was 13.5 months. The most prominent Grade 3 and 4 toxicities were reversible myelosuppression and fatigue. Nausea, emesis, diarrhea, and peripheral edema were minimal. No thromboembolic or hepatic complications were seen. CONCLUSIONS: Docetaxel plus 1 multidose day of oral EMP was active in patients with AIPC and was associated with an acceptable toxicity profile. Overall, the therapeutic index of this regimen compared favorably with regimens that employed a longer administration of EMP.

Adenocarcinoma↗

PubMed2002

Endothelin-1 as a target for therapeutic intervention in prostate cancer.

The endothelins, a family of potent vasoconstricting peptides, have been implicated in the pathophysiology of advanced prostate cancer. Two endothelin receptors, ET-A and ET-B are found in normal prostate tissue. Malignant prostate cells are notable for the loss of ET-B receptors and increased levels of endothelin-1 [ET-1]; this distortion of the endothelin system may be a significant factor in the progression of prostate cancer. Proposed roles for endothelin in prostate cancer include growth promotion, apoptosis inhibition, bone formation, and stimulation of nociceptive receptors. ET-1 can act alone as a mitogen, but its effects are greatest as a comitogen with a variety of growth factors, including basic fibroblast growth factor, insulin-like growth factors, and platelet derived growth factor. Although their exact functions are unclear, ET-1, in conjunction with vascular endothelial growth factor, appears to play a major role in tumor angiogenesis. By a variety of methods, ET-1 alters the balance of osteoblast and osteoclasts to the favor new bone formation that is characteristic of metastatic disease. Several studies indicate that the refractory pain of metastatic cancer is related to the direct nociceptive effects ET-1. These findings suggest that ET receptors are promising therapeutic targets for pharmacologic intervention. Early clinical trials indicate that the ET-A receptor antagonist used in prostate cancer is reasonably well tolerated with mild but pervasive symptoms related to ET-1's vasoconstrictive effects. Results of ongoing clinical trials are eagerly awaited in order to see if the hypothetical promise of ET antagonism will result in clinical success.

Apoptosis↗

PubMed2002

Pharmacological treatments for prostate cancer.

Recently, chemotherapy for prostate cancer has been primarily reserved for the palliation of symptoms secondary to prostate cancer. Chemotherapy regimens and new approaches are being developed that offer new hope of response and improved survival to men with prostate cancer. This paper discusses pharmacological strategies that are under investigation: cytotoxic agents and biological or targeted therapies, including the microtubule inhibitors (taxane/taxoids, vinorelbine) alone and in novel combinations with other experimental agents such calcitriol, thalidomide or flavopiridol (cell-cycle inhibitor) and treatment with epothilone analogues; endothelin receptor antagonists; other novel strategies such as vaccine therapy (GVAX; Cell Genesys) and prostate-specific membrane antibodies; and bisphosphonates.

Antibodies, Monoclonal↗