ABSTRACT
BACKGROUND: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models. METHODS: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression. RESULTS: Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D. CONCLUSIONS: The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02833883.
Subject(s)
Benzamides , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant , Pyrazines , Triazoles , Male , Humans , Prostatic Neoplasms, Castration-Resistant/pathology , Prostate-Specific Antigen/therapeutic use , Mechanistic Target of Rapamycin Complex 1 , Phosphatidylinositol 3-Kinases , Nitriles/therapeutic use , DNA/therapeutic useABSTRACT
Background MLN0128 is a first-in-class, dual mTOR inhibitor with potential to outperform standard rapalogs through inhibition of TORC1 and TORC2. This phase II study was designed to assess antitumor activity of MLN0128 in metastatic castration-resistant prostate cancer (mCRPC). Methods Eligible patients had mCRPC previously treated with abiraterone acetate and/or enzalutamide. Five patients started MLN0128 at 5 mg once daily, subsequently dose reduced to 4 mg because of toxicity. Four subsequent patients started MLN0128 at 4 mg daily. Primary endpoint was progression-free survival at 6 months. Results Nine patients were enrolled and median time on treatment was 11 weeks (range: 3-30). Best response was stable disease. All patients had a rise in PSA on treatment, with a median 159% increase from baseline (range: 12-620%). Median baseline circulating tumor cell count was 1 cell/mL (range: 0-40); none had a decrease in cell count posttreatment. Grade ≤ 2 adverse events included fatigue, anorexia, and rash. The most common serious adverse events were grade 3 dyspnea and maculopapular rash. Eight patients discontinued treatment early because of radiographic progression (n = 1), grade 3 toxicity (n = 5), or investigator discretion (n = 2). Four patients had immediate PSA decline following drug discontinuation, suggesting MLN0128 could cause compensatory increase of androgen receptor (AR) activity. Correlative studies of pretreatment and posttreatment biopsy specimens revealed limited inhibition of AKT phosphorylation, 4EBP1 phosphorylation, and eIF4E activity. Conclusions Clinical efficacy of MLN0128 in mCRPC was limited likely due to dose reductions secondary to toxicity, PSA kinetics suggesting AR activation resulting from mTOR inhibition, and poor inhibition of mTOR signaling targets.
Subject(s)
Benzoxazoles/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Pyrimidines/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Aged , Benzoxazoles/adverse effects , Eukaryotic Initiation Factor-4E/metabolism , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplastic Cells, Circulating/pathology , Prostate-Specific Antigen/metabolism , Pyrimidines/adverse effects , Signal Transduction , Treatment OutcomeABSTRACT
INTRODUCTION: To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events. METHODS: The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers. RESULTS: The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications. CONCLUSIONS: Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.
Subject(s)
Cardiovascular Diseases , Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/drug therapy , Androgen Antagonists/adverse effects , Androgens/therapeutic use , Quality of Life/psychology , Cardiovascular Diseases/chemically inducedABSTRACT
PURPOSE: Improving clinical outcomes with novel drug combinations to treat metastatic castration-resistant prostate cancer (mCRPC) is challenging. Preclinical studies showed cabazitaxel had superior antitumor efficacy compared with docetaxel. Gene expression profiling revealed divergent effects of these taxanes in cycling cells. mCRPC are RB deficient rendering them hypersensitive to taxanes. These data suggested that upfront treatment with cabazitaxel with abiraterone may affect therapeutic response. We designed a phase II randomized noncomparative trial of abiraterone acetate/prednisone (AAP) or AAP and cabazitaxel (AAP + C) in men with mCRPC to address this hypothesis. METHODS: This trial of 81 men with mCRPC determined the radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) progression-free survival, overall objective response, and safety of AAP or AAP + C. Equally allocated patients received AAP followed by switching to cabazitaxel upon radiographic progression (arm 1) or upfront with AAP + C (arm 2). Patients were stratified into high-/low-risk groups by the Halabi nomogram. Real-time assessment of RB status and circulating tumor cell (CTC) analysis to correlate with clinical outcomes was exploratory. RESULTS: Both treatment arms were well-tolerated. Median rPFS in AAP was 6.4 months (95% CI, 3.8 to 10.6) and median overall survival (OS) 18.3 months (95% CI, 14.4 to 37.6), respectively. Fifty-six percent of patients showed ≥50% decline in PSA. Median rPFS in AAP + C was 14.8 months (95% CI, 10.6 to 16.4), and median OS 24.5 months (95% CI, 20.4 to 35.0). There was a ≥50% decline in PSA in 92.1% of men. Neither RB expression in pretherapy tumor biopsy, CTC, or tissue explants identified those who may benefit from AAP + C. CONCLUSION: AAP + C was safe with improved rPFS, OS duration, and a higher proportion of PSA declines. This suggests that AAP + C given earlier rather than sequentially may benefit some men. Further work is needed to identify this population.
Subject(s)
Abiraterone Acetate , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Abiraterone Acetate/therapeutic use , Prostatic Neoplasms, Castration-Resistant/pathology , Prostate-Specific Antigen , Treatment Outcome , Taxoids/therapeutic use , Prednisone , Disease-Free Survival , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
PURPOSE: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. EXPERIMENTAL DESIGN: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m(2) daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily x 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. RESULTS: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m(2) on the daily x 5 schedule; 112 mg/m(2) on the daily x 3 schedule; and 220 mg/m(2) on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily x 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies. CONCLUSION: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.
Subject(s)
Benzoquinones/administration & dosage , Lactams, Macrocyclic/administration & dosage , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Benzoquinones/adverse effects , Benzoquinones/pharmacokinetics , Disease Progression , Dose-Response Relationship, Drug , Female , HSP70 Heat-Shock Proteins/metabolism , Humans , Lactams, Macrocyclic/adverse effects , Lactams, Macrocyclic/pharmacokinetics , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/metabolism , Neoplasms/pathology , Oncogene Protein v-akt/metabolism , Treatment OutcomeABSTRACT
PURPOSE: To investigate the safety and feasibility of rapid androgen cycling for men with progressive prostate cancer. EXPERIMENTAL DESIGN: Schedule 1 included a 4-week induction of androgen depletion, followed by 4-week treatment cycles of a monthly gonadotropin-releasing hormone agonist, testosterone on days 1 to 7, and an estrogen patch on days 8 to 21. Schedule 2 included a 12-week induction of androgen depletion followed by 4-week cycles of gonadotropin-releasing hormone agonist and testosterone, but no estrogens for patients with a prostate-specific antigen (PSA) nadir <1 ng/mL after induction. The primary end point was serially declining PSA trough values over six treatment cycles. RESULTS: Thirty-six patients were treated; 27 were evaluable after cycling, of whom 8 of 12 (67%) and 9 of 15 (60%) on schedules 1 and 2, respectively, reached the end point. Five patients with PSA >1 ng/mL following induction did not cycle. No patient progressed radiographically or clinically during cycling. Three posttherapy PSA patterns were observed: a decline followed by a rapid increase in trough levels, a sustained decline with a plateau at a detectable nadir, and a decline to an undetectable nadir. Mean testosterone levels were castrate at the time of trough and in the normal physiologic range following androgen repletion. Major toxicities included grades 1 and 2 fatigue, hepatitis, gynecomastia, and hot flashes. CONCLUSIONS: Rapid hormonal cycling is feasible and well tolerated, and successive declines in PSA troughs are achievable. Although the sample size was small, the proportion of patients achieving declining PSA at the end of six cycles was comparable with that reached with continuous androgen depletion therapy.
Subject(s)
Androgens/metabolism , Carcinoma/drug therapy , Estrogens/administration & dosage , Gonadotropin-Releasing Hormone/administration & dosage , Prostatic Neoplasms/drug therapy , Testosterone/administration & dosage , Aged , Androgens/administration & dosage , Androgens/adverse effects , Androgens/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Agents, Hormonal/therapeutic use , Carcinoma/pathology , Drug Administration Schedule , Feasibility Studies , Gonadotropin-Releasing Hormone/agonists , Gonadotropin-Releasing Hormone/therapeutic use , Humans , Male , Middle Aged , Neoplasm Metastasis/drug therapy , Prostate-Specific Antigen/blood , Prostatic Neoplasms/pathology , Testosterone/bloodABSTRACT
PURPOSE: To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5. RESULTS: Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm. CONCLUSION: Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Epothilones/administration & dosage , Estramustine/administration & dosage , Prostatic Neoplasms/drug therapy , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/adverse effects , Antineoplastic Agents, Hormonal/adverse effects , Castration , Epothilones/adverse effects , Fatigue/chemically induced , Humans , Male , Middle Aged , Neoplasm Metastasis , Neutropenia/chemically induced , Peripheral Nervous System Diseases/chemically induced , Thrombosis/chemically inducedABSTRACT
PURPOSE: To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. PATIENTS AND METHODS: Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition. RESULTS: Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. CONCLUSIONS: Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.
Subject(s)
Enzyme Inhibitors/administration & dosage , Hematologic Neoplasms/drug therapy , Histone Deacetylase Inhibitors , Hydroxamic Acids/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Biological Availability , Drug Administration Schedule , Enzyme Inhibitors/pharmacokinetics , Female , Hematologic Neoplasms/metabolism , Humans , Hydroxamic Acids/pharmacokinetics , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/metabolism , VorinostatABSTRACT
BACKGROUND: Histone deacetylase inhibitors are a novel class of therapeutic agents that inhibit deacetylate histones and other proteins involved in the regulation of gene expression and cell cycle progression. Phase I trials of intravenous and oral formulations of one such agent, vorinostat (suberoylanilide hydroxamic acid [SAHA]), have shown that it is safe and tolerable, that it inhibits histone deacetylation in peripheral blood mononuclear cells, and that it has a broad range of antitumor activity. PATIENTS AND METHODS: Thirteen patients with mesothelioma were included in a phase I trial of oral SAHA. All but one had previously been treated with chemotherapy. RESULTS: Four patients completed > or = 6 cycles of therapy; 2 patients demonstrated a partial response. The toxicities in this cohort of patients were similar to those observed in the entire phase I trial: primarily fatigue, dehydration, nausea, and vomiting. CONCLUSION: Given the dearth of treatment options for patients with advanced mesothelioma who have progressed after first-line chemotherapy, these results are encouraging. A placebo-controlled, randomized phase III study of oral SAHA is now open for patients with mesothelioma in whom treatment with pemetrexed has failed.
Subject(s)
Enzyme Inhibitors/therapeutic use , Histone Deacetylase Inhibitors , Hydroxamic Acids/therapeutic use , Mesothelioma/drug therapy , Pleural Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Cohort Studies , Drug Administration Schedule , Female , Humans , Male , Mesothelioma/diagnostic imaging , Mesothelioma/pathology , Middle Aged , Pleural Neoplasms/diagnostic imaging , Pleural Neoplasms/pathology , Tomography, X-Ray Computed , Treatment Outcome , VorinostatABSTRACT
BACKGROUND: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored. PATIENTS AND METHODS: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed. RESULTS: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline. CONCLUSIONS: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Prostatic Neoplasms/drug therapy , Aged , Anemia/chemically induced , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Area Under Curve , Cell Line, Tumor , Cell Survival , Complement Activation , Dose-Response Relationship, Drug , Fatigue/chemically induced , Humans , Indium Radioisotopes , Male , Middle Aged , Neoplasm Metastasis , Orchiectomy , Pilot Projects , Prostate-Specific Antigen , Prostatic Neoplasms/blood , Prostatic Neoplasms/surgery , Thrombosis/chemically induced , Time Factors , Tissue Distribution , Treatment OutcomeABSTRACT
PURPOSE: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer. EXPERIMENTAL DESIGN: SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues. RESULTS: No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms. CONCLUSIONS: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.
Subject(s)
Hematologic Neoplasms/drug therapy , Histone Deacetylase Inhibitors , Hydroxamic Acids/administration & dosage , Acetylation , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Biopsy , Dose-Response Relationship, Drug , Female , Histones/metabolism , Humans , Hydroxamic Acids/pharmacokinetics , Infusions, Intravenous , Male , Middle Aged , Skin/pathology , Time Factors , Treatment Outcome , VorinostatABSTRACT
BACKGROUND: Radium-223 dichloride, or radium-223, is a first-in-class alpha emitter that selectively targets bone metastases with high-energy, short-range alpha particles and is approved for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. Nurses are essential in educating patients about radium-223. OBJECTIVES: This article provides oncology nurses with information from the randomized phase III Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, as well as important handling, administration, and safety details unique to radium-223. METHODS: Data from the ALSYMPCA trial and related published information on radium-223 were reviewed. FINDINGS: Radium-223 is the only alpha-emitting radiopharmaceutical that has been shown to improve overall survival in patients with CRPC, as demonstrated in the ALSYMPCA trial. In addition, radium-223 delays time to first symptomatic skeletal event, and it is well tolerated with a low incidence of myelosuppression and gastrointestinal adverse events. Delivered on an outpatient basis, radium-223 requires universal precautions for handling and administration. Because of the potential for additive myelosuppression, the concomitant use of radium-223 with chemotherapy, other systemic radioisotopes, or hemibody external radiation therapy is not recommended.
Subject(s)
Antineoplastic Agents/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/nursing , Radium/therapeutic use , Clinical Trials, Phase III as Topic , Humans , Male , Occupational Exposure/prevention & control , Patient Education as Topic , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Radioisotopes/therapeutic use , Randomized Controlled Trials as TopicABSTRACT
PURPOSE: To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies. EXPERIMENTAL DESIGN: Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m(2). 17-AAG was administered over 1-2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m(2) in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot. RESULTS: Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m(2)-17-AAG 650 mg/m(2) due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed. CONCLUSIONS: The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m(2) and 17-AAG 500 mg/m(2).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzoquinones/administration & dosage , Benzoquinones/adverse effects , Docetaxel , Drug Administration Schedule , Female , Humans , Lactams, Macrocyclic/administration & dosage , Lactams, Macrocyclic/adverse effects , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/metabolism , Neoplasms/pathology , Taxoids/administration & dosage , Taxoids/adverse effectsABSTRACT
BACKGROUND: Growth of selected castration-resistant prostate cancer (CRPC) cell lines and animal models can be repressed by reexposure to androgens. Low doses of androgens, however, can stimulate tumor growth. OBJECTIVE: We performed a phase 1 clinical trial to determine the safety of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer (CRMPC). DESIGN, SETTING, AND PARTICIPANTS: Patients with progressive CRMPC who had been castrate for at least 1 yr received three times the standard replacement dose of transdermal testosterone. INTERVENTION: Cohorts of 3-6 patients received testosterone for 1 wk, 1 mo, or until disease progression. MEASUREMENTS: Toxicities, androgen levels, prostate-specific antigen (PSA) assays, computed tomography (CT) scans, bone scintigraphy, positron emission tomography (PET) scans, and metastatic tumor biopsy androgen receptor levels were assessed. RESULTS AND LIMITATIONS: Twelve patients were treated-three in cohorts 1 and 2 and six in cohort 3. No pain flares were noted. One patient came off study because of epidural disease, which was treated with radiation. Average testosterone levels were within normal limits, although dihydrotestosterone (DHT) levels on average were supraphysiologic in cohort 3. One patient achieved a PSA decline of >50% from baseline. No objective responses were seen. For cohort 3, median time on treatment was 84 d (range: 23-247 d). CONCLUSIONS: We have demonstrated that patients with CRMPC can be safely treated in clinical trials using high-dose exogenous testosterone. Patients did not, on average, achieve sustained supraphysiologic serum testosterone levels. Future studies should employ strategies to maximize testosterone serum levels, use contemporary methods of identifying patients with androgen receptor overexpression, and utilize PSA Working Group II Consensus Criteria clinical trial end points. TRIAL REGISTRATION: ClinicalTrials.gov; NCT00006044.
Subject(s)
Prostatic Neoplasms/drug therapy , Testosterone/administration & dosage , Aged , Gonadotropin-Releasing Hormone/analogs & derivatives , Humans , Male , Middle Aged , Neoplasm Metastasis , Orchiectomy , Prostatic Neoplasms/pathology , Treatment FailureABSTRACT
PURPOSE: Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam. PATIENTS AND METHODS: Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m(2) and (153)Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and (153)Sm-EDTMP was administered on day -1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression. RESULTS: Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of (153)Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 (153)Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption. CONCLUSION: Docetaxel and (153)Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms/drug therapy , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/adverse effects , Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Bone and Bones/drug effects , Docetaxel , Drug Resistance, Neoplasm , Humans , Male , Maximum Tolerated Dose , Middle Aged , Organometallic Compounds/administration & dosage , Organometallic Compounds/adverse effects , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/adverse effects , Prostate-Specific Antigen/blood , Prostate-Specific Antigen/drug effects , Prostatic Neoplasms/pathology , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/adverse effects , Taxoids/administration & dosage , Taxoids/adverse effectsABSTRACT
PURPOSE: We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers. PATIENTS AND METHODS: Noncastrate patients with Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage
, Prostatic Neoplasms/drug therapy
, Prostatic Neoplasms/metabolism
, Testosterone/metabolism
, Adult
, Aged
, Aged, 80 and over
, Cytochrome P-450 CYP3A
, Cytochrome P-450 Enzyme System/metabolism
, Docetaxel
, Humans
, Leuprolide/administration & dosage
, Male
, Middle Aged
, Prostate-Specific Antigen/blood
, Taxoids/administration & dosage
, Taxoids/pharmacokinetics
, Testosterone/administration & dosage
ABSTRACT
OBJECTIVES: In designing a Phase II trial, the acceptable clinical activity region for a new therapy is often developed using data from historically treated patients. This region incorrectly ignores the variability of this estimate, because the efficacy of the prior treatment lies somewhere around the estimate. The size of this interval is dependent on the sample size used. This report illustrates the use of a published method that accounts for this uncertainty and aids in the decision to proceed to a definitive trial. METHODS: A historical data set of low-risk patients with progressive castrate metastatic prostate cancer and a group of similar patients treated in a Phase II chemotherapy trial were used. The 1-year Kaplan-Meier estimate of survival was obtained for both. This approach uses the 75% upper confidence bound of the 1-year survival probability from the historical data set to define the lower limit of acceptable clinical activity. Use of this bound makes the approach more conservative, and hence the decision to proceed to a Phase III trial more difficult. RESULTS: In the low-risk historical patients, the 1-year Kaplan-Meier estimate of survival was 66.4% (75% upper confidence bound 71.0%). In the Phase II patients, the 1-year Kaplan-Meier estimate of survival was 89.5% (95% lower confidence bound 78.2%). CONCLUSIONS: A hypothesis test using the 75% upper confidence bound to define the lower limit of acceptable clinical activity demonstrates that the 1-year survival probability on Taxol/estramustine/carboplatin is greater than that of the historical population, and hence should be taken into a definitive trial. The design provides investigators increased confidence in making this decision.
Subject(s)
Prostatic Neoplasms/drug therapy , Androgen Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Clinical Trials, Phase III as Topic , Cohort Studies , Decision Support Techniques , Estramustine/therapeutic use , Humans , Male , Paclitaxel/therapeutic use , Probability , Prostatic Neoplasms/mortality , Prostatic Neoplasms/secondary , Research Design/standards , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: The combination of paclitaxel, oral estramustine phosphate (EMP), and carboplatin (TEC) has shown antitumor activity in patients with castrate, metastatic prostate carcinoma. To improve the therapeutic efficacy and reduce the toxicity of TEC, the authors substituted intravenous (i.v.) EMP for oral EMP based on single-agent studies demonstrating an improved safety profile with i.v. EMP. METHODS: Patients with progressive, castrate, metastatic prostate carcinoma were treated with up to 6 4-week cycles of i.v. EMP (500-1500 mg/m(2) per week), paclitaxel (100 mg/m(2) per week), and carboplatin (target area under the curve = 6 mg/mL every 4 weeks). RESULTS: Thirty patients were treated in 6 dose cohorts. Deep venous thrombosis occurred in 5 of 30 patients (17%). Other common Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria) toxicities included hepatic toxicity (23%) and leukopenia (24%). Posttherapy prostate specific antigen declines > 50% were seen in 18 of 30 patients (60%), and declines > 80% were seen in 15 of 30 patients (50%). Eleven of 17 patients (65%) with measurable soft tissue disease achieved a partial response. Four of 27 patients (15%) with osseous metastases demonstrated improvement on bone scan. CONCLUSIONS: Intravenous EMP was administered safely with paclitaxel and carboplatin and produced clinical outcomes similar to the outcomes achieved with the TEC regimen. Substitution of i.v. EMP for the oral formulation was found to result in a lower incidence of severe nausea but increased hepatic toxicity.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Estramustine/administration & dosage , Paclitaxel/administration & dosage , Prostatic Neoplasms/drug therapy , Adenocarcinoma/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bone Neoplasms/secondary , Carboplatin/adverse effects , Disease-Free Survival , Drug Administration Schedule , Estramustine/adverse effects , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasm Metastasis , Paclitaxel/adverse effects , Prostate-Specific Antigen/blood , Prostatic Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND: Preclinical and clinical data have suggested that high-dose calcitriol (1,25-dihydroxycholecalciferol) has activity against prostate carcinoma. Pulse-dosed calcitriol and dexamethasone may maximize tolerability and efficacy. The authors examined the toxicity of pulse-dosed calcitriol with zoledronate and with the addition of dexamethasone at the time of disease progression. METHODS: Patients with progressive prostate carcinoma were eligible for the current study. In cohorts of 3-6 patients, calcitriol was administered for 3 consecutive days per week, starting at a dose of 4 microg per day. Doses were escalated to 30 microg per day. Intravenous zoledronate (4 mg) was administered monthly. Dexamethasone could be added to the regimen at disease progression. Toxicities, markers of bone turnover, plasma calcitriol levels, and clinical outcomes were recorded. RESULTS: Thirty-one patients were treated in cohorts that were defined by the calcitriol dose administered (4, 6, 8, 10, 14, 20, 24, or 30 microg). Seven patients received dexamethasone. Three patients had their doses reduced due to calcium-related laboratory findings. Patients tolerated therapy well, even in the 30 microg cohort; therefore, a maximum tolerated dose was not defined. Peak plasma levels observed in the 24 microg and 30 microg cohorts ranged from 391 to 968 pg/mL. Minimal antitumor effects were observed. CONCLUSIONS: Calcitriol was well tolerated at doses up to and including 30 microg 3 times per week in combination with intravenous zoledronate 4 mg monthly, with or without dexamethasone, in patients with progressive prostate carcinoma. Peak plasma levels in the 24 microg and 30 microg cohorts were greater than the levels associated with antitumor effects preclinically. Due to the cumbersome dosing schedule and the lack of significant activity observed, Phase II trials of this regimen are not planned.