42 results on '"O'Bryant CL"'
Search Results
2. Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors.
- Author
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Miller C, Sommavilla R, O'Bryant CL, Barve M, Dowlati A, Luke JJ, Khatun M, Morris T, and Cullberg M
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Pyrroles pharmacokinetics, Pyrroles administration & dosage, Pyrroles adverse effects, Pyrimidines pharmacokinetics, Pyrimidines administration & dosage, Pyrimidines adverse effects, Aged, 80 and over, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Midazolam pharmacokinetics, Midazolam administration & dosage, Neoplasms drug therapy, Cytochrome P-450 CYP3A metabolism, Drug Interactions
- Abstract
Purpose: Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug-drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors., Methods: Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted., Results: Capivasertib-midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUC
inf and Cmax was 1.13 (0.97-1.32) and 1.15 (0.99-1.33) for day 8 versus day 1, and 1.75 (1.50-2.05) and 1.25 (1.08-1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment., Conclusion: The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population., Clinicaltrials: gov: NCT04958226., (© 2024. The Author(s).)- Published
- 2024
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3. A Phase Ib Expansion Cohort Evaluating Aurora A Kinase Inhibitor Alisertib and Dual TORC1/2 Inhibitor Sapanisertib in Patients with Advanced Solid Tumors.
- Author
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Davis SL, Messersmith WA, Purcell WT, Lam ET, Corr BR, Leal AD, Lieu CH, O'Bryant CL, Smoots SG, Dus ED, Jordan KR, Serkova NJ, Pitts TM, and Diamond JR
- Abstract
Background: This study further evaluated the safety and efficacy of the combination of alisertib and sapanisertib in an expansion cohort of patients, including a subset of patients with refractory pancreatic adenocarcinoma, with further evaluation of the pharmacodynamic characteristics of combination therapy., Methods: Twenty patients with refractory solid tumors and 11 patients with pancreatic adenocarcinoma were treated at the recommended phase 2 dose of alisertib and sapanisertib. Adverse events and disease response were assessed. Patients in the expansion cohort were treated with a 7-day lead-in of either alisertib or sapanisertib prior to combination therapy, with tumor tissue biopsy and serial functional imaging performed for correlative analysis., Results: Toxicity across treatment groups was overall similar to prior studies. One partial response to treatment was observed in a patient with ER positive breast cancer, and a patient with pancreatic cancer experienced prolonged stable disease. In an additional cohort of pancreatic cancer patients, treatment response was modest. Correlative analysis revealed variability in markers of apoptosis and immune cell infiltrate according to lead-in therapy and response., Conclusions: Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.
- Published
- 2024
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4. The emergence of targeted therapy for HER2-low triple-negative breast cancer: a review of fam-trastuzumab deruxtecan.
- Author
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Schreiber AR, O'Bryant CL, Kabos P, and Diamond JR
- Subjects
- Humans, Female, Trastuzumab, Camptothecin pharmacology, Receptor, ErbB-2, Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms drug therapy, Immunoconjugates adverse effects
- Abstract
Introduction: Metastatic triple-negative breast cancer (TNBC) is an aggressive sub-type of breast cancer. Despite recent advances, metastatic TNBC remains difficult to treat with limited targeted treatment options. Fam-trastuzumab deruxtecan (T-DXd), is a novel antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) and is composed of a unique linker bound to the topoisomerase I inhibitor DXd. T-DXd has significant anti-tumor activity in patients with HER2-low TNBC., Areas Covered: This review reports on the mechanism, pre-clinical/clinical studies, efficacy, and tolerability of T-DXd. A literature search was conducted via PubMed using keywords such as 'fam-trastuzumab deruxtecan,' 'Enhertu,' and 'HER2-low cancers.', Expert Opinion: The Phase III Destiny-Breast04 Trial showed benefit in progression-free and overall survival in patients with HER2-low metastatic breast cancers treated with T-DXd compared to treatment of physician's choice chemotherapy. T-DXd is the first pharmaceutical to effectively target a HER2-low population with clinically meaningful efficacy in patients with HER2-low TNBC. Compared to chemotherapy, T-DXd has a similar safety profile, with the additional need for close monitoring for interstitial lung disease. Given the clinical activity of T-DXd in TNBC, it is likely there will be continued efforts to refine HER2-low diagnostics and to develop additional ADCs with other protein targets.
- Published
- 2023
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5. Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment.
- Author
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Akce M, El-Khoueiry A, Piha-Paul SA, Bacque E, Pan P, Zhang ZY, Ewesuedo R, Gupta D, Tang Y, Milton A, Zajic S, Judson PL, and O'Bryant CL
- Subjects
- Aged, Area Under Curve, Dose-Response Relationship, Drug, Female, Humans, Indazoles administration & dosage, Indazoles blood, Liver physiopathology, Male, Middle Aged, Piperidines administration & dosage, Piperidines blood, Indazoles adverse effects, Indazoles pharmacokinetics, Liver drug effects, Piperidines adverse effects, Piperidines pharmacokinetics
- Abstract
Purpose: The purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI)., Methods: Patients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5-3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (< 77 kg, ≥ 77 kg)/platelets (< 150,000/µL, ≥ 150,000/µL). PK parameters included maximum concentration (C
max ), area under the curve to last measured concentration (AUClast ) and extrapolated to infinity (AUCinf ). Safety was assessed in both phases. Exposure-response (E-R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens., Results: In the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast , AUCinf ) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E-R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients., Conclusion: These findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI., Trial Registration: NCT03359850; registered December 2, 2017., (© 2021. The Author(s).)- Published
- 2021
- Full Text
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6. Evaluation of fosaprepitant-associated hypersensitivity reactions at a National Cancer Center.
- Author
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Laird CM, Glode AE, Schwarz K, Lam ET, and O'Bryant CL
- Subjects
- Academic Medical Centers methods, Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Drug Evaluation methods, Drug Hypersensitivity epidemiology, Female, Humans, Male, Middle Aged, Nausea chemically induced, Nausea drug therapy, Nausea epidemiology, Neoplasms epidemiology, Retrospective Studies, Risk Factors, Vomiting chemically induced, Vomiting drug therapy, Vomiting epidemiology, Young Adult, Antiemetics adverse effects, Cancer Care Facilities, Drug Hypersensitivity diagnosis, Morpholines adverse effects, Neoplasms drug therapy
- Abstract
Introduction: At our institution, an increased incidence of hypersensitivity reactions was reported following standardization of fosaprepitant as the preferred agent for the prophylaxis of chemotherapy induced nausea and vomiting (CINV) caused by highly emetogenic therapies. The purpose of this evaluation was to assess the incidence of systemic hypersensitivity reactions (HSRs) to fosaprepitant infusions compared to available literature., Methods: This evaluation is a retrospective review of electronic health records of adult patients who received their first dose of fosaprepitant for CINV prophylaxis beginning January 1, 2017 through June 30, 2017 at the University of Colorado Cancer Center outpatient infusion center. Subjects were identified using medication administration reports. Individual chart reviews were performed for all patients who received fosaprepitant during the specified timeframe and had a reaction reported on the same date., Results: A total of 868 patients received fosaprepitant in the outpatient infusion center during the study time period. Four patients (0.461%) had a systemic HSR attributed to fosaprepitant. Two of the reactions were reported as HSRs in the adverse reaction reporting system and two were found in provider notes during chart review. Due to the small sample size, risk factors for HSRs to fosaprepitant were not able to be determined., Conclusion: The incidence of HSRs to fosaprepitant at our institution was found to be consistent with the <1% incidence currently noted in literature. Based on these findings, opportunities have been identified for education on fosaprepitant-associated HSRs, proper documentation and patient-specific precautions.
- Published
- 2020
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7. Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors.
- Author
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Davis SL, Ionkina AA, Bagby SM, Orth JD, Gittleman B, Marcus JM, Lam ET, Corr BR, O'Bryant CL, Glode AE, Tan AC, Kim J, Tentler JJ, Capasso A, Lopez KL, Gustafson DL, Messersmith WA, Leong S, Eckhardt SG, Pitts TM, and Diamond JR
- Subjects
- Aged, Animals, Antineoplastic Combined Chemotherapy Protocols adverse effects, Aurora Kinase A antagonists & inhibitors, Aurora Kinase A metabolism, Azepines adverse effects, Benzoxazoles adverse effects, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Female, Humans, Male, Maximum Tolerated Dose, Mechanistic Target of Rapamycin Complex 1 antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 1 metabolism, Mechanistic Target of Rapamycin Complex 2 antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 2 metabolism, Mice, Middle Aged, Neoplasms pathology, Protein Kinase Inhibitors adverse effects, Pyrimidines adverse effects, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Azepines administration & dosage, Benzoxazoles administration & dosage, Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Pyrimidines administration & dosage
- Abstract
Purpose: The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors., Experimental Design: TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD)., Results: The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia., Conclusions: The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo , resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment., (©2020 American Association for Cancer Research.)
- Published
- 2020
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8. A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction.
- Author
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Takebe N, Beumer JH, Kummar S, Kiesel BF, Dowlati A, O'Sullivan Coyne G, Piekarz R, Rubinstein L, Fogli LK, Vaishampayan U, Goel S, O'Bryant CL, El-Rayes BF, Chung V, Lenz HJ, Kim R, Belani CP, Tuscano JM, Schelman W, Moore N, Doroshow JH, and Chen AP
- Subjects
- Adult, Aged, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Histone Deacetylase Inhibitors administration & dosage, Histone Deacetylase Inhibitors adverse effects, Humans, Hydroxamic Acids administration & dosage, Hydroxamic Acids adverse effects, Infusions, Intravenous, Liver physiopathology, Liver Diseases diagnosis, Liver Diseases etiology, Male, Maximum Tolerated Dose, Metabolic Clearance Rate physiology, Middle Aged, Neoplasm Staging, Neoplasms complications, Neoplasms pathology, Severity of Illness Index, Sulfonamides administration & dosage, Sulfonamides adverse effects, Histone Deacetylase Inhibitors pharmacokinetics, Hydroxamic Acids pharmacokinetics, Liver metabolism, Liver Diseases physiopathology, Neoplasms drug therapy, Sulfonamides pharmacokinetics
- Abstract
Aims: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic., Methods: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction., Results: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m
2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease., Conclusion: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2019
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9. Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients.
- Author
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Ibrahim ME, Chang C, Hu Y, Hogan SL, Mercke N, Gomez M, O'Bryant CL, Bowles DW, George B, Wen X, Buckley B, Aleksunes L, and Joy MS
- Subjects
- Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Biomarkers urine, Cisplatin adverse effects, Cisplatin pharmacokinetics, Creatinine blood, Female, Glomerular Filtration Rate, Humans, Male, Middle Aged, Regression Analysis, Acute Kidney Injury chemically induced, Antineoplastic Agents administration & dosage, Cisplatin administration & dosage, Neoplasms drug therapy
- Abstract
Purpose: The ability to predict and detect clinical and subclinical nephrotoxicity early in the course of therapy has the potential to improve long-term outcomes in cancer patients receiving cisplatin chemotherapy. Pharmacokinetic parameters could serve as predictors of cisplatin-induced nephrotoxicity., Methods: Participants [n = 13] were treated with a 1-h cisplatin infusion [30-75 mg/m
2 ]. Blood was collected pre-dose and up to 6 h post-dose. Urinary biomarkers [KIM-1, calbindin, clusterin, GST-pi, β2M, albumin, NGAL, osteopontin, clusterin, MCP-1, cystatin C, and TFF3] were measured at baseline, days 3 and 10. Total and unbound platinum concentrations were measured using ICP/MS. Noncompartmental analysis was performed, and correlation and regression analyses evaluated the relationships between platinum pharmacokinetics and nephrotoxicity., Results: Peak platinum urinary concentrations correlated with urinary levels of KIM-1, calbindin, clusterin, GST-pi, β2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2 h also correlated with urinary clusterin, β2M, cystatin C, NGAL, osteopontin, and TFF3 at day 3. Regression analyses suggested 2-h total plasma platinum concentrations greater than 2000 ng/ml, and peak urinary platinum concentrations above 24,000 ng/ml may serve as potential approximations for elevated risk of nephrotoxicity. Platinum area under the plasma concentration time curve was associated with serum creatinine and estimated glomerular filtration rate., Conclusions: Peak plasma and urinary platinum concentrations and pharmacokinetic parameters were associated with risk of subclinical cisplatin-induced kidney injury as assessed using novel urinary biomarkers. Future studies will examine these relationships in larger clinical populations of cisplatin-induced acute kidney injury.- Published
- 2019
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10. Evaluation of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer.
- Author
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El-Khoueiry AB, Sarantopoulos J, O'Bryant CL, Ciombor KK, Xu H, O'Gorman M, Chakrabarti J, Usari T, and El-Rayes BF
- Subjects
- Adult, Aged, Area Under Curve, Case-Control Studies, Female, Follow-Up Studies, Humans, Liver Diseases diagnosis, Male, Middle Aged, Neoplasms pathology, Prognosis, Tissue Distribution, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Crizotinib pharmacokinetics, Crizotinib pharmacology, Liver Diseases metabolism, Neoplasms drug therapy, Severity of Illness Index
- Abstract
Purpose: This phase 1 study evaluated the effect of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer., Methods: Patients were dosed according to hepatic function classified by modified National Cancer Institute Organ Dysfunction Working Group criteria and group assignment [normal (A1 and A2), mild (B), moderate (C1 and C2), or severe (D)]. Primary pharmacokinetic endpoints included area under the concentration-time curve as daily exposure (AUC
daily ) and maximum plasma concentration (Cmax ) at steady state. Safety endpoints included types, incidence, seriousness, and relationship to crizotinib of adverse events., Results: The AUCdaily and Cmax in patients with normal liver function were 7107 ng h/mL and 375.1 ng/mL (A1) and 5422 ng h/mL and 283.9 ng/mL (A2), respectively. The AUCdaily and Cmax ratios of adjusted geometric means for Groups B, C2, and D versus Group A1 were 91.12 and 91.20, 114.08 and 108.87, and 64.47 and 72.63, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 75% of patients; grade 3/4 TRAEs occurred in 25%, including fatigue (6%), hyponatremia (5%), and hyperbilirubinemia (3%)., Conclusions: No adjustment to the approved 250 mg twice daily (BID) dose of crizotinib is recommended for patients with mild hepatic impairment. The recommended dose is 200 mg BID for patients with moderate hepatic impairment, and the dose should not exceed 250 mg daily for patients with severe hepatic impairment. Adverse events appeared consistent among the hepatic impairment groups., Clinical Trial Registration No: NCT01576406.- Published
- 2018
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11. Phase I Study of Enavatuzumab, a First-in-Class Humanized Monoclonal Antibody Targeting the TWEAK Receptor, in Patients with Advanced Solid Tumors.
- Author
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Lam ET, Eckhardt SG, Messersmith W, Jimeno A, O'Bryant CL, Ramanathan RK, Weiss GJ, Chadha M, Oey A, Ding HT, Culp PA, Keller SF, Zhao VY, Tsao LC, Singhal A, Holen KD, and Von Hoff D
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized pharmacology, Cell Line, Tumor, Female, Humans, Male, Middle Aged, Neoplasms pathology, Antibodies, Monoclonal metabolism, Antibodies, Monoclonal, Humanized therapeutic use, Neoplasms drug therapy, TWEAK Receptor metabolism
- Abstract
This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215-21. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2018
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12. Implementation of a pharmacist-managed clinic for patients with chronic nonmalignant pain.
- Author
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Norman JL, Kroehl ME, Lam HM, Lewis CL, Mitchell CN, O'Bryant CL, and Trinkley KE
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- Chronic Pain diagnosis, Humans, Pain Management methods, Primary Health Care methods, Chronic Pain therapy, Pain Management trends, Pharmaceutical Services trends, Pharmacists trends, Primary Health Care trends, Professional Role
- Abstract
Purpose: A pharmacist-managed chronic pain clinic (PMCPC) in a primary care setting is described., Summary: As primary care providers (PCPs) may be unprepared or lack time to manage high-risk patients receiving opioids for chronic nonmalignant pain, alternative models of care are needed. The University of Colorado PMCPC is integrated into an internal medicine outpatient clinic. The PMCPC is staffed by 1 clinical pharmacist, with pharmacy students and residents also performing clinic duties. The pharmacy team reviews health records to determine eligibility for PMCPC services and documents referral requests in the electronic health record (EHR); on PCP acceptance of a referral, the pharmacy team assumes primary responsibility for the patient's pain management under a collaborative practice agreement. Using a collaborative drug therapy management (CDTM) protocol, the pharmacy team conducts patient assessments, including an assessment for signs of aberrant drug-taking behaviors; provides initial and ongoing counseling and education; and makes recommendations to the PCP for opioid dosage adjustments and regimen additions and discontinuations. Experience at the clinic to date indicates that the PMCPC model is feasible and accepted by PCPs and patients., Conclusion: A PMCPC based in a primary care setting was established to improve the care of patients with chronic nonmalignant pain who are prescribed opioid therapy for a period of 3 months or longer. Clinic patients are referred to the clinic through the EHR and managed by a pharmacist under a CDTM protocol., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)
- Published
- 2017
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13. Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling.
- Author
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Dheeraj A, Rigby CM, O'Bryant CL, Agarwal C, Singh RP, Deep G, and Agarwal R
- Subjects
- Antineoplastic Agents pharmacology, Carcinoma, Basal Cell metabolism, Cell Death drug effects, Cell Line, Tumor, Drug Resistance, Neoplasm, Hedgehog Proteins metabolism, Humans, Skin Neoplasms metabolism, Carcinoma, Basal Cell pathology, Cell Proliferation drug effects, ErbB Receptors metabolism, Hedgehog Proteins antagonists & inhibitors, Mitogen-Activated Protein Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Silybin pharmacology, Skin Neoplasms pathology
- Abstract
Basal cell carcinoma (BCC) is the most common skin malignancy. Deregulated hedgehog signaling plays a central role in BCC development; therefore, hedgehog inhibitors have been approved to treat locally advanced or metastatic BCC. However, the development of resistance to hedgehog inhibitors is the major challenge in effective treatment of this disease. Herein, we evaluated the efficacy of a natural agent silibinin to overcome resistance with hedgehog inhibitors (Sant-1 and GDC-0449) in BCC cells. Silibinin (25-100 μm) treatment for 48 h strongly inhibited growth and induced death in ASZ001, Sant-1-resistant (ASZ001-Sant-1) and GDC-0449-resistant (ASZ001-GDC-0449) BCC cells. Furthermore, colony-forming ability of ASZ001, ASZ001-Sant-1 and ASZ001-GDC-0449 cells was completely inhibited by silibinin treatment. Molecular analysis showed that silibinin treatment decreased the level of phosphorylated EGFR (Tyrosine 1173) and total EGFR in ASZ001-Sant-1 cells, key signaling molecules responsible for BCC resistance toward hedgehog inhibitors. Further, silibinin treatment decreased the phosphorylated Akt (Serine 473), phosphorylated ERK1/2 (Threonine 202/Tyrosine 204), cyclin D1 and Gli-1 level but increased the SUFU expression in ASZ001-Sant-1-resistant cells. Silibinin treatment of ASZ001-Sant-1-resistant cells also decreased bcl-2 but increased cleaved caspase 3 and PARP cleavage, suggesting induction of apoptosis. Together, these results support silibinin use to target hedgehog inhibitor-resistant BCC cells., (© 2017 The American Society of Photobiology.)
- Published
- 2017
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14. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association.
- Author
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Page RL 2nd, O'Bryant CL, Cheng D, Dow TJ, Ky B, Stein CM, Spencer AP, Trupp RJ, and Lindenfeld J
- Subjects
- Heart Failure epidemiology, Humans, United States epidemiology, American Heart Association, Heart Failure chemically induced, Heart Failure diagnosis, Practice Guidelines as Topic standards, Prescription Drugs adverse effects
- Abstract
Heart failure is a common, costly, and debilitating syndrome that is associated with a highly complex drug regimen, a large number of comorbidities, and a large and often disparate number of healthcare providers. All of these factors conspire to increase the risk of heart failure exacerbation by direct myocardial toxicity, drug-drug interactions, or both. This scientific statement is designed to serve as a comprehensive and accessible source of drugs that may cause or exacerbate heart failure to assist healthcare providers in improving the quality of care for these patients., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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15. Board-Certified Oncology Pharmacists: Their Potential Contribution to Reducing a Shortfall in Oncology Patient Visits.
- Author
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Ignoffo R, Knapp K, Barnett M, Barbour SY, D'Amato S, Iacovelli L, Knudsen J, Koontz SE, Mancini R, McBride A, McCauley D, Medina P, O'Bryant CL, Scarpace S, Stricker S, and Trovato JA
- Subjects
- Ambulatory Care, Humans, Neoplasms diagnosis, Neoplasms therapy, Medical Oncology, Pharmacists standards, Professional Role, Specialty Boards
- Abstract
Purpose: With an aging US population, the number of patients who need cancer treatment will increase significantly by 2020. On the basis of a predicted shortage of oncology physicians, nonphysician health care practitioners will need to fill the shortfall in oncology patient visits, and nurse practitioners and physician assistants have already been identified for this purpose. This study proposes that appropriately trained oncology pharmacists can also contribute. The purpose of this study is to estimate the supply of Board of Pharmacy Specialties-certified oncology pharmacists (BCOPs) and their potential contribution to the care of patients with cancer through 2020., Methods: Data regarding accredited oncology pharmacy residencies, new BCOPs, and total BCOPs were used to estimate oncology residencies, new BCOPs, and total BCOPs through 2020. A Delphi panel process was used to estimate patient visits, identify patient care services that BCOPs could provide, and study limitations., Results: By 2020, there will be an estimated 3,639 BCOPs, and approximately 62% of BCOPs will have completed accredited oncology pharmacy residencies. Delphi panelists came to consensus (at least 80% agreement) on eight patient care services that BCOPs could provide. Although the estimates given by our model indicate that BCOPs could provide 5 to 7 million 30-minute patient visits annually, sensitivity analysis, based on factors that could reduce potential visit availability resulted in 2.5 to 3.5 million visits by 2020 with the addition of BCOPs to the health care team., Conclusion: BCOPs can contribute to a projected shortfall in needed patient visits for cancer treatment. BCOPs, along with nurse practitioners and physician assistants could substantially reduce, but likely not eliminate, the shortfall of providers needed for oncology patient visits., (Copyright © 2016 by American Society of Clinical Oncology.)
- Published
- 2016
- Full Text
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16. Antibody-Drug Conjugates: A Clinical Pharmacy Perspective on an Emerging Cancer Therapy.
- Author
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Jerjian TV, Glode AE, Thompson LA, and O'Bryant CL
- Subjects
- Ado-Trastuzumab Emtansine, Aminoglycosides therapeutic use, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Brentuximab Vedotin, Female, Gemtuzumab, Humans, Leukemia, Myeloid, Acute drug therapy, Lymphoma drug therapy, Maytansine analogs & derivatives, Maytansine therapeutic use, Trastuzumab, Immunoconjugates therapeutic use, Neoplasms drug therapy
- Abstract
Antibody-drug conjugates (ADCs) combine highly specific monoclonal antibodies with potent cytotoxic drugs. Their synergy allows for targeted delivery of toxic drugs to cancer cells while sparing systemic exposure. In this review, we focus on the history and clinical applications of ADCs approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer and highlight new ADCs in the drug development pipeline. Three ADCs have received FDA approval thus far. Gemtuzumab ozogamicin, although withdrawn from the U.S. market, may still be an effective treatment modality in subsets of patients with acute myeloid leukemia. Brentuximab vedotin and ado-trastuzumab emtansine have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of advanced lymphoma and breast cancer, respectively. With a number of ADCs with promising preliminary data in the clinical trial pipeline, cancer therapy is moving forward from traditional chemotherapy to targeted treatment modalities driven by the specificity of monoclonal antibodies and advancing biotechnology., (© 2016 Pharmacotherapy Publications, Inc.)
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- 2016
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17. Claims analysis of hypertension occurrence, severity changes and patterns of antihypertensive use in cancer patients receiving vascular endothelial growth factor inhibitors.
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Thompson LA, Saseen JJ, O'Bryant CL, Allen RR, and Nair KV
- Subjects
- Adult, Cohort Studies, Female, Humans, Hypertension chemically induced, Hypertension diagnosis, Male, Middle Aged, Neoplasms drug therapy, Retrospective Studies, Antihypertensive Agents therapeutic use, Antineoplastic Agents adverse effects, Hypertension epidemiology, Insurance Claim Review statistics & numerical data, Neoplasms epidemiology, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
Background: Vascular endothelial growth factor inhibitors such as bevacizumab, sorafenib, and sunitinib are utilized in the treatment of multiple cancers. Although these agents are associated with hypertension, there is a lack of evidence describing patterns of antihypertensive use in patients with vascular endothelial growth factor inhibitor-associated hypertension in a non-trial, "real-world" setting., Objective: To describe the occurrence and severity of vascular endothelial growth factor inhibitor-associated hypertension, patterns of antihypertensive use and occurrence of cardiovascular complications in a non-trial population, and to describe patterns of initial antihypertensive therapy in patients developing hypertension during treatment with a vascular endothelial growth factor inhibitor., Methods: This retrospective cohort study utilized claims data from the Medstat MarketScan Commercial Claims and Encounter database to identify patients with claims for a vascular endothelial growth factor inhibitor and a diagnosis of cancer using International Classification of Diseases, 9th Revision, Clinical Modification codes, Healthcare Common Procedure Coding System J-codes and National Drug Codes. The study period encompassed claims from one year before the patient's first claim for a vascular endothelial growth factor inhibitor, and continued through one year after the initial vascular endothelial growth factor inhibitor claim. Patients meeting study criteria were classified into cohorts A1, patients with no hypertension throughout the study period; A2, patients without hypertension at baseline who developed hypertension after starting a vascular endothelial growth factor inhibitor; and cohort B, patients with hypertension prior to receiving a vascular endothelial growth factor inhibitor. We utilized medical and pharmacy claims data to describe the presence of hypertension, its severity, and the occurrence of cardiovascular complications throughout the study period. Initial antihypertensive use in cohort A2 was described., Results: In all, 2177 patients met study criteria and were categorized into cohorts A1 (n = 708), A2 (n = 333) and B (n = 1136). Approximately 32% of patients without hypertension at baseline had claims suggestive for hypertension during the study period. Life-threatening (Grade 4) hypertension increased throughout the study period for cohorts A1, A2, and B, to 3.4%, 10.2%, and 16.4%, respectively (p < 0.001 for all). Claims suggestive of Grade 3 hypertension occurred in more patients in cohort B (45.8%) than in cohort A2 (32.7%, p < 0.001). Cardiovascular complications occurred in 4.7%, 15.6%, and 22.7% of patients in cohorts A1, A2, and B, respectively. Initial antihypertensive agent selection did not impact the occurrence of cardiovascular complications in cohort A2., Conclusion: Our study provides valuable insight into non-trial patterns of vascular endothelial growth factor inhibitor-associated hypertension occurrence and severity, and is consistent with prior claims analysis. Identification of optimal strategies to manage vascular endothelial growth factor inhibitor-associated hypertension remain to be clarified with the advent of more comprehensive data sets., (© The Author(s) 2014.)
- Published
- 2015
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18. The need for PGY2-trained clinical pharmacy specialists.
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Ragucci KR, O'Bryant CL, Campbell KB, Buck ML, Dager WE, Donovan JL, Emerson K, Gubbins PO, Haight RJ, Jackevicius C, Murphy JE, and Prohaska E
- Subjects
- Delivery of Health Care, Integrated standards, Delivery of Health Care, Integrated trends, Humans, Pharmacists supply & distribution, Pharmacists trends, Pharmacy Residencies, Primary Health Care organization & administration, Quality of Health Care, Societies, Pharmaceutical, Students, Pharmacy, United States, Delivery of Health Care, Integrated organization & administration, Education, Pharmacy, Graduate methods, Pharmacists organization & administration, Specialization
- Abstract
The American College of Clinical Pharmacy and other stakeholder organizations seek to advance clinical pharmacist practitioners, educators, and researchers. Unfortunately, there remains an inadequate supply of residency-trained clinical specialists to meet the needs of our health care system, and nonspecialists often are called on to fill open specialist positions. The impact of clinical pharmacy specialists on pharmacotherapy outcomes in both acute care and primary care settings demonstrates the value of these specialists. This commentary articulates the need for postgraduate year two (PGY2)-trained clinical specialists within the health care system by discussing various clinical and policy rationales, interprofessional support, economic justifications, and their impact on quality of care and drug safety. The integrated practice model that has grown out of the American Society of Health-System Pharmacists Pharmacy Practice Model Initiative (PPMI) could threaten the growth and development of future clinical specialists. Therefore, the ways in which PGY2-trained clinical pharmacist specialists are deployed in the PPMI require further consideration. PGY2 residencies provide education and training opportunities that cannot be achieved in traditional professional degree programs or postgraduate year one residencies. These specialists are needed to provide direct patient care to complex patient populations and to educate and train pharmacy students and postgraduate residents. Limitations to training and hiring PGY2-trained clinical pharmacy specialists include site capacity limitations and lack of funding. A gap analysis is needed to define the extent of the mismatch between the demand for specialists by health care systems and educational institutions versus the capacity to train clinical pharmacists at the specialty level., (© 2014 Pharmacotherapy Publications, Inc.)
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- 2014
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19. Vismodegib: an inhibitor of the Hedgehog signaling pathway in the treatment of basal cell carcinoma.
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Proctor AE, Thompson LA, and O'Bryant CL
- Subjects
- Anilides adverse effects, Anilides pharmacokinetics, Anilides pharmacology, Animals, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Drug Interactions, Hedgehog Proteins antagonists & inhibitors, Humans, Pyridines adverse effects, Pyridines pharmacokinetics, Pyridines pharmacology, Signal Transduction, Anilides therapeutic use, Antineoplastic Agents therapeutic use, Carcinoma, Basal Cell drug therapy, Pyridines therapeutic use, Skin Neoplasms drug therapy
- Abstract
Objective: To review vismodegib, the first Food and Drug Administration (FDA)-approved Hedgehog (Hh) signaling pathway inhibitor, in the treatment of advanced basal cell carcinoma (BCC)., Data Sources: MEDLINE and PubMed were searched using the terms vismodegib, GDC-0449, RG3616, and basal cell carcinoma for relevant clinical trials through September 2013. The FDA Web site, the National Clinical Trials registry, and abstracts from the American Society of Clinical Oncology (ASCO) were also evaluated to identify unpublished data and future clinical trials., Study Selection/data Extraction: All identified clinical and preclinical studies published in the English language were assessed, including selected references from the bibliographies of articles., Data Synthesis: Activation of the Hh signaling pathway is well documented in BCC. Vismodegib is a small-molecule inhibitor of Hh signaling that acts by antagonizing the protein Smoothened (SMO), thereby preventing downstream transcriptional activation of genes involved in cell proliferation and survival. Vismodegib was approved by the FDA in January 2012 for the treatment of recurrent, locally advanced BCC (laBCC), or metastatic BCC (mBCC) for which surgery or radiation cannot be utilized. A pivotal phase 2 trial evaluating 104 patients demonstrated that treatment with vismodegib, 150 mg orally once daily, resulted in a 30% and 43% objective response rate in patients with mBCC and laBCC, respectively. The most common adverse effects from vismodegib were mild to moderate and included muscle spasms, dysgeusia, decreased weight, fatigue, alopecia, and diarrhea. However, clinical studies noted a high incidence of discontinuation of therapy by patients for reasons other than disease progression., Conclusions: The approval of vismodegib represents the only targeted, prospectively studied treatment option for patients with advanced BCC. Further research assessing the utility of vismodegib in the treatment of other malignancies and the development of resistance patterns will more clearly define the role of Hedgehog inhibition in the broader scheme of oncological disorders.
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- 2014
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20. Crizotinib: a new treatment option for ALK-positive non-small cell lung cancer.
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O'Bryant CL, Wenger SD, Kim M, and Thompson LA
- Subjects
- Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung metabolism, Clinical Trials as Topic, Crizotinib, Drug Interactions, Drug Monitoring, Humans, Lung Neoplasms enzymology, Lung Neoplasms metabolism, Neoplasm Proteins antagonists & inhibitors, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors pharmacology, Pyrazoles adverse effects, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyridines adverse effects, Pyridines pharmacokinetics, Pyridines pharmacology, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Neoplasm Proteins metabolism, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyridines therapeutic use, Receptor Protein-Tyrosine Kinases metabolism
- Abstract
Objective: To review the characteristics and clinical trial data of crizotinib in ALK-positive non-small cell lung cancer (NSCLC)., Data Source: A literature search using PubMed/MEDLINE (up to December 2012) was performed using the terms crizotinib, ALK-positive, non-small cell lung cancer, and PF-02341066., Study Selection/data Extraction: Phase 1, 2, and 3 trials evaluating the safety and efficacy of crizotinib in a cohort of patients with ALK rearrangements and advanced NSCLC were evaluated. All peer-reviewed articles with clinically relevant information were reviewed., Data Synthesis: ALK rearrangement results in an aberrant EML4-ALK fusion oncogene that constitutively activates ALK tyrosine kinase, resulting in inhibition of apoptosis and promotion of tumor cell proliferation. Approximately 3-5% of NSCLC exhibit this rearrangement. Crizotinib is an oral selective inhibitor of ALK and mesenchymal epithelial growth factor tyrosine kinases. Early phase trials with crizotinib showed improved response rates of 50-57% and extended duration of response of 6-10 months. Results of these studies led to accelerated Food and Drug Administration (FDA) approval of crizotinib. Further clinical trial results confirmed improvement in response rates, duration of response, as well as progression-free survival in ALK-positive patients with NSCLC receiving crizotinib. The drug undergoes hepatic metabolism by CYP3A4 and demonstrates autoinhibition of CY3A4, thus predisposing it to drug interactions. The most frequent toxicities with crizotinib include mild visual disturbances, nausea, vomiting, diarrhea, constipation, edema, and generally reversible, sometimes severe, elevations in aspartate aminotransferase and alanine aminotransferase., Conclusions: Crizotinib is a novel targeted anticancer agent that appears to be a favorable treatment option for patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test.
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- 2013
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21. Romidepsin: a histone deacetylase inhibitor for refractory cutaneous T-cell lymphoma.
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Kim M, Thompson LA, Wenger SD, and O'Bryant CL
- Subjects
- Depsipeptides pharmacology, Drug Interactions, Histone Deacetylase Inhibitors pharmacology, Humans, Treatment Outcome, Depsipeptides therapeutic use, Histone Deacetylase Inhibitors therapeutic use, Lymphoma, T-Cell, Cutaneous drug therapy
- Abstract
Objective: To evaluate the efficacy and safety of romidepsin in refractory cutaneous T-cell lymphoma (CTCL)., Data Sources: An English-language literature search of PubMed and MEDLINE (Nov 2011-April 2012) was performed using the terms romidepsin, CTCL, and depsipeptide (FK228). The National Comprehensive Cancer Network guidelines, American Society of Clinical Oncology abstracts, American Society of Hematology abstracts, clinical trial registry, and prescribing information from the manufacturer were reviewed for additional information., Study Selection and Data Extraction: Phase 1 and 2 trials evaluating the efficacy and safety of romidepsin were reviewed with a specific focus on its use in cutaneous T-cell lymphoma. All peer-reviewed articles with clinically relevant information were evaluated for inclusion., Data Synthesis: In advanced stage CTCL, single or combination chemotherapy regimen responses are variable and lack durability. Romidepsin is a histone deacetylase inhibitor approved for refractory cutaneous T-cell lymphoma. Romidepsin has shown an improvement in duration of response and pruritus over traditional therapy. In 2 independent Phase 2 trials, romidepsin showed an overall response rate of 34% and durable response of 13-15 months in patients with refractory CTCL. The most frequent toxicities of romidepsin include nausea, vomiting, fatigue, or myelosuppression. Clinically insignificant QT interval changes have been observed but did not correlate with a decrease in left ventricular ejection fraction, or elevated laboratory markers of myocardial damage., Conclusions: Romidepsin is an effective, durable, and well-tolerated single-agent therapy in patients with refractory CTCL and should be considered for formulary addition in this population.
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- 2012
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22. Everolimus: a new treatment option for advanced pancreatic neuroendocrine tumors.
- Author
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Thompson LA, Kim M, Wenger SD, and O'Bryant CL
- Subjects
- Antineoplastic Agents pharmacology, Everolimus, Humans, Sirolimus pharmacology, Sirolimus therapeutic use, TOR Serine-Threonine Kinases antagonists & inhibitors, Antineoplastic Agents therapeutic use, Neuroendocrine Tumors drug therapy, Pancreatic Neoplasms drug therapy, Sirolimus analogs & derivatives
- Abstract
Objective: To present the current clinical evidence on everolimus for use in pancreatic neuroendocrine tumors (pNET)., Data Sources: A literature search was performed using PubMed and MEDLINE (1946-March 2012). Search terms were everolimus, RAD001, mTOR inhibitor, and pancreatic neuroendocrine tumors. Abstracts from the American Society of Clinical Oncology 2000-2012 meetings and Food and Drug Administration (FDA) reviews were searched to obtain otherwise unpublished data. The national clinical trials registry was searched for current and future studies of everolimus in pNET., Study Selection and Data Extraction: Clinical studies available in the English language describing the pharmacology, pharmacokinetics, clinical activity, and safety of everolimus in pNET were included. All peer-reviewed, clinically relevant publications were reviewed for inclusion., Data Synthesis: Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor approved by the FDA in May 2011 for the treatment of progressive, advanced pNET. Everolimus exerts its effect by inhibiting multiple downstream pathways of mTOR, which decreases cell proliferation, survival, and angiogenesis. Its pNET indication was based on the results of RADIANT-3, a Phase 3 trial demonstrating increased median progression-free survival (11 months) with everolimus 10 mg orally once daily compared to placebo (4.6 months). Everolimus was well tolerated in clinical trials. The most commonly reported adverse events included stomatitis, rash, diarrhea, fatigue, infections, nausea, and decreased appetite. Grade 3/4 events including anemia, thrombocytopenia, pneumonitis, and hyperglycemia occurred in approximately 5% of patients., Conclusions: Based on review of the available literature, everolimus is a safe and effective treatment option for patients with low- to intermediate-grade, unresectable or metastatic pNET that have progressed on prior therapies. Until results of head-to-head, randomized controlled trials are conducted to compare everolimus to other treatment options, it cannot be said whether everolimus is more efficacious or tolerable than other treatment options.
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- 2012
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23. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors.
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Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, Vo AC, Klucher K, Herbst RS, Eckhardt SG, Peterson S, Hausman DF, Kurzrock R, and Jimeno A
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Area Under Curve, Diarrhea chemically induced, Disease Progression, Dose-Response Relationship, Drug, Drug Administration Schedule, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Fatigue chemically induced, Female, Gonanes administration & dosage, Gonanes pharmacokinetics, Humans, Male, Metabolic Clearance Rate, Middle Aged, Mutation, Nausea chemically induced, Neoplasms metabolism, Neoplasms pathology, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Treatment Outcome, Vomiting chemically induced, Enzyme Inhibitors therapeutic use, Gonanes therapeutic use, Neoplasms drug therapy, Phosphoinositide-3 Kinase Inhibitors
- Abstract
Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers., Experimental Design: This was a phase I, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (arm 1; days 1-5 and 8-12 of a 28-day cycle) or continuous (arm 2; days 1-28 of a 28-day cycle) schedule. Additional patients were treated at the arm 2 MTD in a food effects substudy., Results: Eighty-four patients were treated in the arm 1 (n = 51), arm 2 (n = 20), and food effects (n = 13) cohorts. The most frequent study drug-related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n = 3) and grade III elevated aspartate aminotransferase (AST; n = 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866-associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (RECIST) was stable disease in 22% of evaluable patients in arm 1, 53% in arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months., Conclusions: This first-in-human study shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule.
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- 2012
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24. The intersection between cannabis and cancer in the United States.
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Bowles DW, O'Bryant CL, Camidge DR, and Jimeno A
- Subjects
- Animals, Biological Availability, Cannabinoids adverse effects, Cannabinoids pharmacokinetics, Humans, Mice, Neoplasms chemically induced, Pain drug therapy, Pain prevention & control, Palliative Care methods, United States, Cannabinoids therapeutic use, Cannabis chemistry, Marijuana Smoking legislation & jurisprudence, Neoplasms drug therapy, Phytotherapy
- Abstract
In the last 15 years there has been a major shift in the laws governing medical use of cannabis in the United States. Corresponding with this change there has been escalating interest in the role that cannabis, commonly referred to as marijuana, and cannabinoids play in the care of patients with cancer. This review will examine cannabis' and cannabinoids' current and potential roles in cancer care. Specifically, we will examine five areas of cannabis medicine: (1) pharmacologic properties of cannabis; (2) its potential role in the development of human cancers, particularly smoking-related malignancies; (3) cannabinoids' potential as anti-cancer therapies; (4) cannabis and cannabinoids in the palliation of common cancer-associated symptoms; (5) current legal status of cannabis for medical purposes in the United States., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2012
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25. An open-label study to describe pharmacokinetic parameters of erlotinib in patients with advanced solid tumors with adequate and moderately impaired hepatic function.
- Author
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O'Bryant CL, Haluska P, Rosen L, Ramanathan RK, Venugopal B, Leong S, Boinpally R, Franke A, Witt K, Evans J, Belani C, Gail Eckhardt S, and Ramalingam S
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents blood, Antineoplastic Agents therapeutic use, Cohort Studies, Dose-Response Relationship, Drug, ErbB Receptors antagonists & inhibitors, Erlotinib Hydrochloride, Female, Humans, Liver drug effects, Liver metabolism, Liver Function Tests, Male, Middle Aged, Neoplasm Invasiveness, Neoplasms metabolism, Neoplasms pathology, Neoplasms physiopathology, Protein Binding, Quinazolines adverse effects, Quinazolines blood, Quinazolines therapeutic use, Antineoplastic Agents pharmacokinetics, Liver physiopathology, Neoplasms drug therapy, Quinazolines pharmacokinetics
- Abstract
Purpose: To compare the pharmacokinetic (PK) parameters of a single dose of erlotinib in cancer patients with moderate hepatic impairment (MHI) to those of cancer patients with adequate hepatic function (AHF)., Methods: Cancer patients with either AHF or MHI were treated with a single 150 mg dose of erlotinib on day 1 only followed by 96 h of plasma sampling for PK assessment. From day 5, patients were allowed to continue daily erlotinib in a maintenance phase. Non-smoking patients were stratified into an AHF cohort (total bilirubin ≤ upper limit of normal [ULN] and ALT/AST ≤ 1.5 X ULN) or a MHI cohort (Child-Pugh score of 7-9). The frequency of adverse events and laboratory changes were assessed., Results: Thirty-six patients, 21 with AHF and 15 with MHI, received at least one dose of erlotinib. The PK of erlotinib was similar between the two cohorts with a median C (max) of 1.09 versus 0.828 μg/mL and corresponding median AUC(0-t ) 29.3 versus 30.5 μg h/mL for the AHF and MHI cohorts, respectively. Adverse events from erlotinib in cancer patients with MHI were consistent with the known safety profile., Conclusions: The PK and safety profiles of erlotinib in patients with MHI were similar to those with AHF. As a result, a reduced starting dose of erlotinib in patients with MHI is not required and treatment should be guided by patients' tolerability.
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- 2012
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26. A phase I study of bortezomib, etoposide and carboplatin in patients with advanced solid tumors refractory to standard therapy.
- Author
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Lieu C, Chow L, Pierson AS, Eckhardt SG, O'Bryant CL, Morrow M, Tran ZV, Wright JJ, and Gore L
- Subjects
- Adult, Aged, Anemia, Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor analysis, Boronic Acids adverse effects, Bortezomib, Carboplatin adverse effects, Dose-Response Relationship, Drug, Drug Administration Schedule, Etoposide adverse effects, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Nausea chemically induced, Neutropenia chemically induced, Pyrazines adverse effects, Thrombocytopenia chemically induced, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Boronic Acids administration & dosage, Carboplatin administration & dosage, Etoposide administration & dosage, Neoplasms drug therapy, Pyrazines administration & dosage
- Abstract
Purpose: To evaluate the toxicity, pharmacological, and biological properties of the combination of bortezomib, etoposide, and carboplatin in adults with advanced solid malignancies., Patients and Methods: Patients received escalating doses of bortezomib, etoposide, and carboplatin every 21 days. Surrogate markers of angiogenesis were evaluated., Results: Twenty-four patients received 64 courses of therapy. The most common treatment-related adverse events were myelosuppression. Dose-limiting grade 3 and 4 neutropenia and thrombocytopenia were observed when bortezomib was given on days 1, 4, 8, 11. With revised dosing, the maximum tolerated dose (MTD) of bortezomib 0.75 mg/m(2) (days 1, 8), etoposide 75 mg/m(2) (days 1-3), and carboplatin AUC 5 (day 1) was well tolerated, and are the recommended doses for further studies with this combination. No objective responses were observed, however stable disease was noted for greater or equal to four cycles in nine highly refractory patients.
- Published
- 2009
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27. A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state.
- Author
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O'Bryant CL, Lieu CH, Leong S, Boinpally R, Basche M, Gore L, Leonardi K, Schultz MK, Hariharan S, Chow L, Diab S, Gibbs A, and Eckhardt SG
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Area Under Curve, Biomarkers, Tumor blood, Chromatography, High Pressure Liquid, Cohort Studies, Female, Glycogen Synthase Kinase 3 blood, Glycogen Synthase Kinase 3 beta, Humans, Male, Middle Aged, Neoplasms genetics, Neoplasms physiopathology, Pharmacogenetics, Reference Standards, Sulindac administration & dosage, Sulindac adverse effects, Sulindac pharmacokinetics, Sulindac pharmacology, Tandem Mass Spectrometry, Antineoplastic Agents administration & dosage, Apoptosis drug effects, Fasting, Food, Neoplasms drug therapy, Sulindac analogs & derivatives
- Abstract
Purpose: To evaluate the safety, pharmacokinetics and determine the recommended dose of the selective apoptotic antineoplastic drug, OSI-461 administered on a twice-daily regimen to patients with advanced solid malignancies., Methods: In this phase I trial, 33 patients were treated with OSI-461 doses ranging from 400 to 1,200 mg given twice daily in 4-week cycles. Pharmacokinetic studies were performed to characterize the plasma disposition of OSI-461 and the effect of food intake on OSI-461 absorption. Secondary biomarker studies were performed to assess the biologic activity of OSI-461 including the measurement of pGSK-3beta, a PKG substrate, and pharmacogenetic studies to identify polymorphisms of CYP3A that influence drug metabolism and of ABCG2, involved in drug resistance., Results: Thirty-three patients were treated with 86 courses of OSI-461. The dose-limiting toxicities were grade 3 abdominal pain, found in one patient at the 1,000 mg BID fed dose level and all patients at the 1,200 mg BID fed dose level. There was also one episode each of grade 3 fatigue and grade 3 constipation at the 1,000 and 1,200 mg BID fed dose levels, respectively. Other common toxicities included mild to moderate fatigue, nausea, anorexia and mild elevation in bilirubin. Pharmacokinetic studies of OSI-461 revealed approximately a twofold increase in AUC(0-24) when OSI-461 was administered with food. An increase in pGSK-3beta post-dose was seen in the majority of patients and was greater at higher dose levels. No patients exhibited CYP3A4 polymorphisms, while 100% of patients were found to have the CYP3A5*3/CYP3A5*3 polymorphism. Two known polymorphisms of the ABCG2 gene, G34 --> A34 and C421 --> A421, occurred at frequencies of 11.76 and 29%, respectively., Conclusions: Toxicity and pharmacodynamic data show that the recommended oral dose of OSI-461 is 800 mg twice daily administered with food. The drug appears to be well-tolerated, and overall bioavailability appears to be markedly increased when the drug is administered with food. These results support further disease-directed evaluations of OSI-461 at a dose of 800 mg BID in combination with other chemotherapeutic agents.
- Published
- 2009
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28. A phase I study of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors.
- Author
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Lam ET, O'Bryant CL, Basche M, Gustafson DL, Serkova N, Baron A, Holden SN, Dancey J, Eckhardt SG, and Gore L
- Subjects
- Adult, Aged, Aged, 80 and over, Capecitabine, Celecoxib, Deoxycytidine administration & dosage, Female, Fluorouracil administration & dosage, Gefitinib, Humans, Male, Maximum Tolerated Dose, Middle Aged, Risk, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Deoxycytidine analogs & derivatives, Fluorouracil analogs & derivatives, Neoplasms drug therapy, Pyrazoles administration & dosage, Quinazolines administration & dosage, Sulfonamides administration & dosage
- Abstract
This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity profile of the combination of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors. Patients were treated with escalating doses of gefitinib once daily, capecitabine twice daily (14 of 28 days), and celecoxib twice daily. Plasma samples for biomarkers were obtained at baseline and weekly for the first 2 cycles. Pharmacokinetic variables were correlated with toxicity and presence of biological effect. Tumor biopsies from 5 patients were analyzed for changes in tumor metabolic activity by nuclear magnetic resonance spectroscopy. [18F]fluorodeoxyglucose positron emission tomography was done as a correlate in 6 patients at the MTD. Thirty-nine patients received 168 cycles of therapy. The dose-limiting toxicities observed included nausea, dehydration and nausea, diarrhea, and stomatitis. The MTD was 250 mg/d gefitinib (days 1-14) and 2,000 mg/m2/d capecitabine divided twice daily (days 8-21) every 28 days. Celecoxib was eliminated due to concerns of increased risk for cardiovascular toxicity, although no patients in this study had cardiac events. One patient with cholangiocarcinoma had a confirmed partial response. Fourteen of 39 (36%) patients maintained prolonged stable disease for a median of 4 months (range, 3-24 months). [18F]fluorodeoxyglucose positron emission tomography scan and metabolomic analyses revealed differences in metabolic response to gefitinib versus capecitabine. The combination of gefitinib and capecitabine is well tolerated and appears to have activity against certain advanced solid tumors, providing a rationale for further evaluation in advanced solid malignancies.
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- 2008
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29. A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies.
- Author
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Chow LQ, Gustafson DL, O'Bryant CL, Gore L, Basche M, Holden SN, Morrow MC, Grolnic S, Creese BR, Roberts KL, Davis K, Addison R, and Eckhardt SG
- Subjects
- Adult, Aged, Angiogenesis Inhibitors adverse effects, Angiogenesis Inhibitors immunology, Angiogenesis Inhibitors pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols adverse effects, Combined Modality Therapy, Docetaxel, Drug Administration Schedule, Fatigue chemically induced, Female, Fibroblast Growth Factor 2 urine, Gastrointestinal Diseases chemically induced, Glucuronidase antagonists & inhibitors, Heparin immunology, Humans, Male, Maximum Allowable Concentration, Middle Aged, Neoplasm Proteins antagonists & inhibitors, Neoplasms immunology, Neoplasms metabolism, Neoplasms therapy, Oligosaccharides administration & dosage, Oligosaccharides adverse effects, Oligosaccharides immunology, Oligosaccharides pharmacokinetics, Partial Thromboplastin Time, Platelet Factor 4 immunology, Taxoids administration & dosage, Taxoids adverse effects, Taxoids pharmacokinetics, Vascular Endothelial Growth Factor A urine, Angiogenesis Inhibitors therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasms drug therapy
- Abstract
Purpose: This study evaluated the safety, toxicity, pharmacological properties and biological activity of PI-88, a heparanase endoglycosidase enzyme inhibitor, with fixed weekly docetaxel in patients with advanced solid malignancies., Experimental Design: This was a phase I study to determine the maximal-tolerated dose of escalating doses of PI-88 administered subcutaneously for 4 days per week, along with docetaxel 30 mg/m(2) given on days 1, 8, 15 of a 28-day schedule., Results: Sixteen patients received a total of 42 courses of therapy. No dose-limiting toxicities were observed despite escalation to the highest planned dose level of PI-88 (250 mg/day). Frequent minor toxicities included fatigue (38%), dysgeusia (28.5%), thrombocytopenia (12%), diarrhea (14%), nausea (12%), and emesis (10%) in the 42 courses. No significant bleeding complications were observed. One patient developed a positive anti-heparin antibody test/serotonin releasing assay with positive anti-platelet factor 4/PI-88 antibodies and grade 1 thrombocytopenia in cycle 5, and was withdrawn from the study without any sequelae. PI-88 plasma concentrations (mirrored by APTT) and urinary elimination were linear and dose-proportional. Docetaxel did not alter the pharmacokinetic (PK) profile of PI-88, nor did PI-88 affect docetaxel PK. No significant relationship was determined between plasma or urine FGF-2, or plasma VEGF levels and PI-88 dose/response. Although no objective responses were observed; 9 of the 15 evaluable patients had stable disease for greater than two cycles of therapy., Conclusion: PI-88 administered at 250 mg/day for 4 days each week for 3 weeks with docetaxel 30 mg/m(2) on days 1, 8 and 15, every 28 days, was determined to be the recommended dose level for phase II evaluation. This combination was well tolerated without severe toxicities or PK interactions.
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- 2008
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30. A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors.
- Author
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Chow LQ, Eckhardt SG, O'Bryant CL, Schultz MK, Morrow M, Grolnic S, Basche M, and Gore L
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Cisplatin pharmacokinetics, Deoxycytidine administration & dosage, Deoxycytidine pharmacokinetics, Dose-Response Relationship, Drug, Farnesyltranstransferase blood, Fatigue chemically induced, Fatigue physiopathology, Female, HSP40 Heat-Shock Proteins blood, Humans, Male, Maximum Tolerated Dose, Middle Aged, Nausea chemically induced, Nausea physiopathology, Piperidines adverse effects, Piperidines pharmacokinetics, Pyridines adverse effects, Pyridines pharmacokinetics, Treatment Outcome, Vomiting chemically induced, Vomiting physiopathology, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cisplatin administration & dosage, Deoxycytidine analogs & derivatives, Farnesyltranstransferase antagonists & inhibitors, Piperidines administration & dosage, Pyridines administration & dosage
- Abstract
Purpose: This phase I study was conducted to evaluate the safety, tolerability, pharmacological properties and biological activity of the combination of the lonafarnib, a farnesylproteintransferase (FTPase) inhibitor, with gemcitabine and cisplatin in patients with advanced solid malignancies., Experimental Design: This was a single institution study to determine the maximal tolerated dose (MTD) of escalating lonafarnib (75-125 mg po BID) with gemcitabine (750-1,000 mg/m(2) on days 1, 8, 15) and fixed cisplatin (75 mg/m(2) day 1) every 28 days. Due to dose-limiting toxicities (DLTs) of neutropenia and thrombocytopenia in initial patients, these patients were considered "heavily pre-treated" and the protocol was amended to limit prior therapy and re-escalate lonafarnib in "less heavily pre-treated patients" on 28-day and 21-day schedules. Cycle 1 and 2 pharmacokinetics (PK), and farnesylation of the HDJ2 chaperone protein and FPTase activity were analyzed., Results: Twenty-two patients received 53 courses of therapy. Nausea, vomiting, and fatigue were frequent in all patients. Severe toxicities were observed in 91% of patients: neutropenia (41%), nausea (36%), thrombocytopenia (32%), anemia (23%) and vomiting (23%). Nine patients withdrew from the study due to toxicity. DLTs of neutropenia, febrile neutropenia, thrombocytopenia, and fatigue limited dose-escalation on the 28-day schedule. The MTD was established as lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) in heavily pre-treated patients. The MTD in the less heavily pre-treated patients could not be established on the 28-day schedule as DLTs were observed at the lowest dose level, and dose escalation was not completed on the 21-day schedule due to early study termination by the Sponsor. No PK interactions were observed. FTPase inhibition was not observed at the MTD, however HDJ-2 gel shift was observed in one patient at the 100 mg BID lonafarnib dose. Anti-cancer activity was observed: four patients had stable disease lasting >2 cycles, one subject had a complete response, and another had a partial response, both with metastatic breast cancer., Conclusion: Lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) day 1 on a 28-day schedule was established as the MTD. Lonafarnib did not demonstrate FTPase inhibition at these doses. Despite the observed efficacy, substantial toxicity and questionable contribution of anti-tumor activity of lonafarnib to gemcitabine and cisplatin limits further exploration of this combination.
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- 2008
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31. Screening and management of osteoporosis in breast cancer patients on aromatase inhibitors.
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Gibson K and O'Bryant CL
- Subjects
- Absorptiometry, Photon, Adult, Aged, Aged, 80 and over, Anastrozole, Androstadienes adverse effects, Androstadienes therapeutic use, Bone Diseases, Metabolic drug therapy, Bone Diseases, Metabolic etiology, Female, Humans, Letrozole, Middle Aged, Nitriles adverse effects, Nitriles therapeutic use, Osteoporosis diagnosis, Retrospective Studies, Triazoles adverse effects, Triazoles therapeutic use, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Aromatase Inhibitors adverse effects, Aromatase Inhibitors therapeutic use, Bone Density Conservation Agents therapeutic use, Breast Neoplasms complications, Breast Neoplasms drug therapy, Osteoporosis drug therapy, Osteoporosis therapy
- Abstract
Objective: Breast cancer patients are at an increased risk of osteoporosis due to age, cancer, chemotherapy, and aromatase inhibitor therapy. This retrospective review determined if patients treated with aromatase inhibitors received appropriate screening and management for osteoporosis., Design: University of Colorado Cancer Center breast cancer patients treated with aromatase inhibitor therapy during July 2005 through July 2006 were studied. Data was collected for each patient from the time of breast cancer diagnosis up to April 2007. The study endpoints included (1) appropriate screening for osteoporosis, (2) incidence of osteoporosis diagnosis, and (3) initiation of appropriate drug therapy for bone loss. Appropriate management was defined as adherence to the 2003 American Society of Clinical Oncology guidelines for bone health issues in women with breast cancer., Results: Of the 54 patients included in this study, 12 (22.2%) had no DEXA scans documented, 22 (40.7%) patients received a baseline DEXA scan and 8 (14.8%) patients received baseline and yearly DEXA scans. During the study timeline, 26 (48%) patients were diagnosed with osteopenia and 4 (7%) patients were diagnosed with osteoporosis. Forty-one (75.9%) patients received calcium and vitamin D therapy. Bisphosphonate therapy was received by less than one-third of the osteopenic patients and three-fourths of the osteoporotic patients., Conclusions: The majority of patients were not adequately screened which may have falsely lowered the diagnosis of osteoporosis resulting in omission of drug therapy. All high-risk patients should receive calcium and vitamin D therapy and be evaluated for bisphosphonate therapy. Screening and medical management for osteoporosis in breast cancer patients on aromatase inhibitors is an important area for clinical intervention.
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- 2008
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32. Bicalutamide-associated fulminant hepatotoxicity.
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O'Bryant CL, Flaig TW, and Utz KJ
- Subjects
- Humans, Male, Middle Aged, Androgen Antagonists adverse effects, Anilides adverse effects, Liver Failure, Acute chemically induced, Nitriles adverse effects, Prostatic Neoplasms drug therapy, Tosyl Compounds adverse effects
- Abstract
Abstract Bicalutamide is a nonsteroidal antiandrogen used extensively during the start of androgen deprivation therapy with a luteinizing hormone-releasing hormone agonist to reduce occurrence of the symptoms of tumor flare in patients with metastatic prostate carcinoma. The most common adverse effects of bicalutamide are induced by its pharmacologic property of competitive androgen receptor blockade and include gynecomastia, hot flashes, fatigue, and decreased libido. Although not as common, increases in liver function test results are also seen with bicalutamide therapy. These elevations are typically transient, and patients remain asymptomatic. We describe a 59-year-old man with metastatic prostate carcinoma treated with bicalutamide as part of androgen deprivation therapy before starting chemotherapy. At baseline, his liver function test results and serum creatinine concentration were within normal limits, and an abdominal computed tomographic scan did not demonstrate liver metastasis. After 4 days of bicalutamide therapy, the patient came to the emergency department with complaints of abdominal pain, distension, and tenderness. His liver function tests were abnormal, and bicalutamide was discontinued. After 2 days of increasing liver function tests and symptoms of hepatotoxicity, the patient developed tachycardia and hypotension that was resistant to fluid resuscitation. Multiorgan damage was manifested by an alanine aminotransferase level greater than 40 times the upper limit of normal, serum creatinine concentration of 4.2 mg/dl, and troponin I level of 18 ng/ml. The patient died 8 days after bicalutamide therapy was begun secondary to multiorgan failure, most likely as a result of fulminant hepatotoxicity. The Naranjo adverse drug reaction probability scale showed a probable (score of 5) causal relationship between bicalutamide and fulminant hepatotoxicity. Fulminant hepatotoxicity is a rare but potentially fatal adverse effect of bicalutamide. Liver function tests should be monitored before and during bicalutamide therapy, even for patients who have previously completed a course of this therapy with no signs or symptoms of toxicity.
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- 2008
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33. A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas.
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Gore L, Rothenberg ML, O'Bryant CL, Schultz MK, Sandler AB, Coffin D, McCoy C, Schott A, Scholz C, and Eckhardt SG
- Subjects
- Administration, Oral, Adult, Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Area Under Curve, Benzamides adverse effects, Benzamides pharmacokinetics, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Female, Histone Deacetylase Inhibitors, Humans, Male, Maximum Tolerated Dose, Middle Aged, Pyridines adverse effects, Pyridines pharmacokinetics, Antineoplastic Agents administration & dosage, Benzamides administration & dosage, Lymphoma drug therapy, Neoplasms drug therapy, Pyridines administration & dosage
- Abstract
Purpose: To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules., Experimental Design: Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined., Results: Twenty-seven patients received > or =149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for >5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation., Conclusions: MS-275 is well tolerated at doses up to 6 mg/m(2) every other week or 4 mg/m(2) weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m(2) given weekly for 3 weeks every 28 days or 2 to 6 mg/m(2) given once every other week.
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- 2008
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34. A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors.
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Camidge DR, Gail Eckhardt S, Gore L, O'Bryant CL, Leong S, Basche M, Holden SN, Musib L, Baldwin J, Darstein C, Thornton D, Finn RS, and Britten CD
- Subjects
- Adult, Aged, Antibiotics, Antineoplastic administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Area Under Curve, Capecitabine, Cohort Studies, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Dose-Response Relationship, Drug, Female, Floxuridine blood, Fluorouracil administration & dosage, Fluorouracil analogs & derivatives, Fluorouracil blood, Follow-Up Studies, Humans, Indoles administration & dosage, Male, Middle Aged, Monocytes drug effects, Monocytes enzymology, Neoplasms pathology, Phosphorylation, Protein Kinase C metabolism, Protein Kinase C beta, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasms drug therapy
- Abstract
Enzastaurin, an oral inhibitor of protein kinase Cbeta, affects signal transduction associated with angiogenesis, proliferation, and survival. Capecitabine is converted to 5-fluoruracil by thymidine phosphorylase, a putative angiogenic factor. The all-oral combination of the two drugs offers the potential for targeting angiogenesis in capecitabine-sensitive tumors with nonoverlapping toxicities. Patients with advanced cancer initially received single-agent enzastaurin to achieve steady-state concentrations (cycle 1). In subsequent 21-day cycles, enzastaurin was given orally, once daily, on days 1-21 and capecitabine orally, twice daily (b.i.d.), on days 1-14 in three dose-level cohorts. Three dose-escalation cohorts were studied: cohort 1 (n=8), 350 mg of enzastaurin +capecitabine (750 mg/m2 b.i.d.); cohort 2 (n=7), enzastaurin (350 mg)+capecitabine (1000 mg/m2 b.i.d.); cohort 3 (n=12), 525-mg capsules or 500-mg enzastaurin+capecitabine (1000 mg/m2 b.i.d.). Further dose escalation was not pursued because of emerging data that enzastaurin systemic exposure did not increase at doses above 525 mg. Although a traditional toxicity-based maximum tolerated dose was not achieved, the highest dosing cohort represented a biologically relevant dose of enzastaurin, on the basis of preclinical data and correlative pharmacodynamic biomarker assays of protein kinase Cbeta inhibition in peripheral blood mononucleocytes, in combination with a standard dose of capecitabine. For the 500/525-mg dose, ratios of total enzastaurin analyte geometric means (i.e. enzastaurin alone versus enzastaurin with capecitabine) reflected a trend toward decreased enzastaurin exposure, but did not reach statistical significance. The pharmacokinetic parameters of capecitabine with enzastaurin were similar to those previously reported for single-agent capecitabine. The regimen was well tolerated, without any consistent pattern of drug-related grade 3 or grade 4 toxicities being observed. Although no objective tumor responses were documented, five patients maintained stable disease for >or=6 months (range: 6-9.7 months). The recommended phase II dose of this combination, based on the results of this study, is enzastaurin at a daily dose of 500 mg (tablet formulation) and capecitabine (1000 mg/m2, b.i.d.) on days 1-14 every 21 days. Further disease-directed studies are warranted, such as in malignancies in the treatment of which both capecitabine and inhibitors of angiogenesis have previously been benchmarked as being effective.
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- 2008
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35. Inconsistencies in opioid equianalgesic ratios: clinical and research implications.
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O'Bryant CL, Linnebur SA, Yamashita TE, and Kutner JS
- Subjects
- Administration, Cutaneous, Administration, Oral, Adult, Delayed-Action Preparations administration & dosage, Female, Fentanyl administration & dosage, Humans, Male, Methadone, Middle Aged, Morphine administration & dosage, Neoplasms complications, Oxycodone administration & dosage, Pain complications, Randomized Controlled Trials as Topic statistics & numerical data, Analgesics, Opioid administration & dosage, Drug Dosage Calculations, Neoplasms drug therapy, Pain drug therapy
- Abstract
Cancer pain is common, occurring in up to 60% of patients and opioid conversion may be required for effective pain management. Conversion from one opioid to another can be problematic due to differences in equianalgesic ratios found in established resources. This study explores the implications of using various published equianalgesic ratios when converting to a common opioid unit. This secondary analysis includes 105 advanced cancer patients who reported use of transdermal fentanyl, long-acting oxycodone, or oral methadone. Common clinically used equianalgesic ratios were identified and utilized to calculate a parenteral morphine equivalent for each of the selected agents. When the equianalgesic ratios were applied to each drug, there were substantial differences in the calculated morphine equivalent for transdermal fentanyl (2-fold difference) and methadone (100-fold difference). The calculated difference for oxycodone was lower, with a 1.5-fold difference. This study demonstrates large variability in opioid conversions based on the use of common equianalgesic ratios for transdermal fentanyl, long-acting oxycodone, and methadone. These findings have important clinical and research implications. First, this study substantiates the use of these ratios as only guidelines for treatment. Second, it supports the need for well-designed, rigorous studies to evaluate opioid conversions. Third, this study demonstrates the need for a standard reporting system of opioid equianalgesic ratios employed in clinical trials.
- Published
- 2008
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36. Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors.
- Author
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Hariharan S, Gustafson D, Holden S, McConkey D, Davis D, Morrow M, Basche M, Gore L, Zang C, O'Bryant CL, Baron A, Gallemann D, Colevas D, and Eckhardt SG
- Subjects
- Angiogenesis Inhibitors pharmacokinetics, Apoptosis drug effects, Cell Adhesion Molecules blood, Cell Adhesion Molecules drug effects, Dose-Response Relationship, Drug, Endothelial Cells drug effects, Gene Expression drug effects, Humans, In Situ Nick-End Labeling, Neoplasms blood, Snake Venoms pharmacokinetics, Angiogenesis Inhibitors therapeutic use, Integrin alphaVbeta3 therapeutic use, Integrins therapeutic use, Neoplasms drug therapy, Receptors, Vitronectin therapeutic use, Snake Venoms therapeutic use
- Abstract
Background: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose., Patients and Methods: The doses of cilengitide were 600 or 1200 mg/m(2) as a 1-h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate., Results: Twenty patients received 50 courses of cilengitide with no dose-limiting toxic effects. The pharmacokinetic (PK) profile revealed a short elimination half-life of 4 h, supporting twice weekly dosing. Of the six soluble angiogenic molecules assessed, only E-selectin increased significantly from baseline. Analysis of tumor microvessel density and gene expression was not informative due to intrapatient tumor heterogeneity. Although several patients with evaluable tumor biopsy pairs did reveal posttreatment increases in tumor and endothelial cell apoptosis, these results did not reach statistical significance due to the aforementioned heterogeneity., Conclusions: Cilengitide is a well-tolerated antiangiogenic agent. The biomarkers chosen in this study underscore the difficulty in assessing the biological activity of antiangiogenic agents in the absence of validated biological assays.
- Published
- 2007
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37. A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors.
- Author
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Chiappori AA, Eckhardt SG, Bukowski R, Sullivan DM, Ikeda M, Yano Y, Yamada-Sawada T, Kambayashi Y, Tanaka K, Javle MM, Mekhail T, O'bryant CL, and Creaven PJ
- Subjects
- Aged, Area Under Curve, Dose-Response Relationship, Drug, Female, Humans, Immunohistochemistry, Male, Matrix Metalloproteinase 2 drug effects, Matrix Metalloproteinase Inhibitors, Maximum Tolerated Dose, Middle Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Indoles adverse effects, Indoles pharmacokinetics, Matrix Metalloproteinase 9 drug effects, Neoplasms drug therapy, Thiophenes adverse effects, Thiophenes pharmacokinetics
- Abstract
Purpose: Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers., Experimental Design: The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival., Results: Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean C(max) and AUC(0-8) increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3. The negative mean inhibitory activity calculated for DL4 was due to one patient with a 397% MMP activity increase., Conclusion: S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.
- Published
- 2007
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38. A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.
- Author
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Gore L, Holden SN, Cohen RB, Morrow M, Pierson AS, O'Bryant CL, Persky M, Gustafson D, Mikule C, Zhang S, Palmer PA, and Eckhardt SG
- Subjects
- Adult, Aged, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Antimetabolites, Antineoplastic pharmacokinetics, Antimetabolites, Antineoplastic pharmacology, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols pharmacology, Capecitabine, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine pharmacokinetics, Deoxycytidine pharmacology, Drug-Related Side Effects and Adverse Reactions, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Fluorouracil blood, Fluorouracil pharmacokinetics, Fluorouracil pharmacology, HSP40 Heat-Shock Proteins metabolism, Humans, Male, Middle Aged, Neoplasm Staging, Protein Prenylation drug effects, Quinolones administration & dosage, Quinolones pharmacokinetics, Alkyl and Aryl Transferases antagonists & inhibitors, Deoxycytidine analogs & derivatives, Fluorouracil analogs & derivatives, Neoplasms drug therapy, Quinolones adverse effects, Quinolones pharmacology
- Abstract
Background: To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks., Patients and Methods: Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity., Results: Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease., Conclusions: Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks.
- Published
- 2006
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39. A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors.
- Author
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Basche M, Gustafson DL, Holden SN, O'Bryant CL, Gore L, Witta S, Schultz MK, Morrow M, Levin A, Creese BR, Kangas M, Roberts K, Nguyen T, Davis K, Addison RS, Moore JC, and Eckhardt SG
- Subjects
- Adult, Aged, Antibody Formation drug effects, Antineoplastic Agents pharmacology, Carcinoid Tumor drug therapy, Carcinoma, Renal Cell drug therapy, Colorectal Neoplasms drug therapy, Female, Fibroblast Growth Factors blood, Humans, Leiomyosarcoma drug therapy, Male, Maximum Tolerated Dose, Melanoma drug therapy, Middle Aged, Oligosaccharides blood, Oligosaccharides pharmacokinetics, Oligosaccharides toxicity, Partial Thromboplastin Time, Vascular Endothelial Growth Factor A blood, Antineoplastic Agents therapeutic use, Glucuronidase antagonists & inhibitors, Neoplasms drug therapy, Oligosaccharides therapeutic use
- Abstract
Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study., Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2)., Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C(max) correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >or=6 months., Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.
- Published
- 2006
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40. Safety and pharmacokinetic study of RPI.4610 (ANGIOZYME), an anti-VEGFR-1 ribozyme, in combination with carboplatin and paclitaxel in patients with advanced solid tumors.
- Author
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Kobayashi H, Eckhardt SG, Lockridge JA, Rothenberg ML, Sandler AB, O'Bryant CL, Cooper W, Holden SN, Aitchison RD, Usman N, Wolin M, and Basche ML
- Subjects
- Adult, Aged, Angiogenesis Inhibitors therapeutic use, Area Under Curve, Carboplatin pharmacokinetics, Carboplatin pharmacology, Carboplatin therapeutic use, Drug Interactions, Female, Humans, Male, Middle Aged, Neoplasms metabolism, Paclitaxel pharmacokinetics, Paclitaxel pharmacology, Paclitaxel therapeutic use, RNA, Catalytic adverse effects, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasms drug therapy, RNA, Catalytic pharmacokinetics
- Abstract
Purpose: RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial growth factor receptor 1. The purpose of this study was to evaluate the safety and pharmacokinetics of RPI.4610 in combination with carboplatin and paclitaxel in patients with advanced solid tumors., Methods: The study used a sequential treatment design evaluating a single dose level for all three drugs: paclitaxel 175 mg m-2 and carboplatin AUC=6 on day 1 of a 21-day cycle, and RPI.4610 100 mg m-2 day-1 beginning on day 8 and continuing daily thereafter. Pharmacokinetic samples were drawn on day 1 of courses 1 (chemotherapy alone) and 2 (chemotherapy+RPI.4610), and on day 8 of course 1 (RPI.4610 alone). Ratios were generated by comparing the pharmacokinetic parameters for the combination of carboplatin with paclitaxel when administered alone or together with RPI.4610., Results: Twelve patients were enrolled in this trial and received two to six courses of treatment each. The most common grade 3-4 toxicities were neutropenia (three patients), thrombocytopenia (three patients), pain (three patients), anemia (two patients) and fatigue (two patients). The ratio of the mean maximum plasma concentration (Cmax) for carboplatin when administered with paclitaxel alone versus when administered with paclitaxel and RPI.4610 was 1.07 (90% confidence interval, 0.77-1.37). Similarly, the ratio of the mean AUC0-last for carboplatin was 1.04 (0.73-1.35). For paclitaxel the ratio of the mean Cmax when administered with carboplatin alone versus with carboplatin and RPI.4610 was 1.17 (1.03-1.31), and the ratio of the mean AUC0-last was 1.17 (1.04-1.30). Objective tumor responses were observed and included one patient with a complete response (bladder cancer) and one patient with a partial response (esophageal cancer)., Conclusions: These results indicate that RPI.4610, carboplatin, and paclitaxel can be administered safely in combination without substantial pharmacokinetic interactions.
- Published
- 2005
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41. A phase I and pharmacokinetic study of exisulind and docetaxel in patients with advanced solid tumors.
- Author
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Witta SE, Gustafson DL, Pierson AS, Menter A, Holden SN, Basche M, Persky M, O'Bryant CL, Zeng C, Baron A, Long ME, Gibbs A, Kelly K, Bunn PA Jr, Chan DC, Pallansch P, and Eckhardt SG
- Subjects
- Adult, Aged, Antineoplastic Agents, Phytogenic pharmacokinetics, Apoptosis, Docetaxel, Dose-Response Relationship, Drug, Female, Gastrointestinal Tract drug effects, Humans, Male, Middle Aged, Time Factors, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Sulindac administration & dosage, Sulindac analogs & derivatives, Sulindac pharmacokinetics, Taxoids administration & dosage, Taxoids pharmacokinetics
- Abstract
Purpose: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study., Experimental Design: This study evaluated the toxicity and pharmacokinetics of combining exisulind (150-250 mg) given orally twice daily and docetaxel (30-36 mg/m2) administered intravenously on days 1, 8, and 15 of a 4-week cycle., Results: Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35-77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m2. Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed., Conclusions: The combination of docetaxel (36 mg/m2, weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non-small-cell lung cancer.
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- 2004
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42. Antiinflammatory and analgesic activity of an inhibitor of neuropeptide amidation.
- Author
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Ogonowski AA, May SW, Moore AB, Barrett LT, O'Bryant CL, and Pollock SH
- Subjects
- Amino Acid Sequence, Animals, Bradykinin, Carrageenan, Edema, Kinetics, Lyases metabolism, Male, Mice, Rats, Rats, Sprague-Dawley, Serotonin, Substance P chemistry, Substance P metabolism, Substrate Specificity, Amidine-Lyases, Analgesics pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Fatty Acids, Monounsaturated pharmacology, Inflammation prevention & control, Mixed Function Oxygenases antagonists & inhibitors, Multienzyme Complexes
- Abstract
4-Phenyl-3-butenoic acid (PBA) has been shown in vitro to be a turnover-dependent inactivator of peptidylglycine alpha-monooxygenase (PAM), the rate-limiting enzyme involved in the formation of amidated neuropeptides from their glycine-extended precursors. In the studies reported herein, we have shown that PBA produces a dose-dependent (50-500 mg/kg s.c.) inhibition of serum PAM activity in normal rats without affecting peptidylamidoglycolate lyase activity. Because amidated neuropeptides such as substance P and calcitonin gene-related peptide are involved in acute inflammation, we evaluated the effects of PBA on carrageenan-induced inflammation in rats. The acute administration of PBA (s.c. or i.p.) produced a dose-related inhibition of edema with maximum inhibition (67%) observed at 2 hr postphlogistic agent. In addition, the continuous administration of PBA to animals over a 7-day period using osmotic pumps not only inhibited hind paw swelling induced by carrageenan but also inhibited serum PAM activity and reduced tissue levels of substance P in hind paws. These results demonstrate for the first time a correlation between the antiinflammatory activity produced by an inhibitor of peptide amidation with its ability to inhibit serum PAM activity and lower endogenous tissue levels of substance P. Moreover, these results confirm our contention that PAM is an excellent pharmacological target for controlling the acute inflammatory response. We also demonstrate the ability of PBA to inhibit phenyl-p-quinone and acetylcholine-induced writhing in mice without affecting the spinally mediated tail immersion assay in rats. Because this analgesic effect was extremely rapid (within 15 min), PBA may be producing this effect by a mechanism other than peptide amidation.
- Published
- 1997
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