11 results on '"Tolcher, A. W."'
Search Results
2. Novel compounds in the therapy of breast cancer: opportunities for integration with docetaxel.
- Author
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Tolcher AW
- Subjects
- Docetaxel, ErbB Receptors drug effects, Female, Humans, Oligonucleotides, Antisense therapeutic use, Paclitaxel therapeutic use, Antineoplastic Agents, Phytogenic therapeutic use, Breast Neoplasms drug therapy, Epidermal Growth Factor therapeutic use, Paclitaxel analogs & derivatives, Taxoids
- Abstract
Increasingly, novel agents are being developed specifically at inhibition of growth factor receptors and events within the signal transduction pathway. These agents include the epidermal growth factor tyrosine kinase inhibitors, the farnesyl transferase inhibitors, and bcl-2 antisense oligonucleotides. Along with these new approaches to molecular targeting, it will be necessary to develop new study designs for drug evaluation. Target validation in both normal surrogate tissues and tumor tissue becomes increasingly relevant in early clinical trials. Furthermore, antitumor efficacy may no longer correlate with normal hematological or nonhematological toxicity, and it may be more appropriate in phase I trials to identify the maximum target inhibition dose rather than the maximum tolerated dose. Moreover, measures of cytoreduction, such as complete and partial response, may be less relevant than disease stabilization for some of these novel agents which have limited cytotoxic effects and would be considered cytostatic agents. Assessment of single-agent activity and the future role in conjunction with cytostatic agents represents the single most important challenge facing the clinical development of these molecular targeted therapies.
- Published
- 2001
- Full Text
- View/download PDF
3. Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer.
- Author
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Tolcher AW, Cowan KH, Solomon D, Ognibene F, Goldspiel B, Chang R, Noone MH, Denicoff AM, Barnes CS, Gossard MR, Fetsch PA, Berg SL, Balis FM, Venzon DJ, and O'Shaughnessy JA
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis, ATP Binding Cassette Transporter, Subfamily B, Member 1 drug effects, Adult, Aged, Antibodies, Monoclonal, Antineoplastic Agents, Phytogenic administration & dosage, Biopsy, Breast Neoplasms blood, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cross-Over Studies, Drug Resistance, Neoplasm, Drug Therapy, Combination, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Middle Aged, Paclitaxel administration & dosage, Treatment Outcome, Verapamil blood, Verapamil therapeutic use, Antineoplastic Agents, Phytogenic pharmacokinetics, Breast Neoplasms drug therapy, Paclitaxel pharmacokinetics, Verapamil pharmacology
- Abstract
Purpose: We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer., Patients and Methods: Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy., Results: The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations., Conclusion: r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.
- Published
- 1996
- Full Text
- View/download PDF
4. Phase I study of paclitaxel in combination with cyclophosphamide and granulocyte colony-stimulating factor in metastatic breast cancer patients.
- Author
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Tolcher AW, Cowan KH, Noone MH, Denicoff AM, Kohler DR, Goldspiel BR, Barnes CS, McCabe M, Gossard MR, Zujewski J, and O'Shaughnessy JA
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Blood Cell Count drug effects, Cyclophosphamide administration & dosage, Diarrhea chemically induced, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Hypersensitivity drug therapy, Drug Hypersensitivity etiology, Equipment Failure, Erythrocyte Transfusion, Female, Granulocyte Colony-Stimulating Factor administration & dosage, Hematologic Diseases blood, Hematologic Diseases chemically induced, Hematologic Diseases therapy, Hematuria chemically induced, Hematuria drug therapy, Home Infusion Therapy instrumentation, Humans, Mesna therapeutic use, Middle Aged, Neoplasm Metastasis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms pathology, Breast Neoplasms therapy, Paclitaxel administration & dosage
- Abstract
Purpose: In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients., Patients and Methods: Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration., Results: Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels., Conclusion: Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.
- Published
- 1996
- Full Text
- View/download PDF
5. Interim results of a phase I/II study of biweekly paclitaxel and cisplatin in patients with metastatic breast cancer.
- Author
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Tolcher AW and Gelmon KA
- Subjects
- Adult, Aged, Alopecia chemically induced, Ambulatory Care, Antineoplastic Combined Chemotherapy Protocols adverse effects, Chemotherapy, Adjuvant, Cisplatin adverse effects, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Infusions, Intravenous, Injections, Intravenous, Middle Aged, Neoplasm Metastasis, Neutropenia chemically induced, Paclitaxel adverse effects, Remission Induction, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Cisplatin administration & dosage, Paclitaxel administration & dosage
- Abstract
Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered in a 3-hour infusion exhibits both a rapid decline to, and recovery from, the hematologic nadir. This suggests that a biweekly administration schedule of this agent either alone or in combination with agents that have limited hematologic toxicity may be possible. The objective of this study was to determine the tolerability and activity of biweekly administered paclitaxel in combination with cisplatin in patients with metastatic breast cancer. Patients with metastatic breast cancer who may have received up to one prior chemotherapy regimen in the adjuvant setting were eligible. Paclitaxel was administered intravenously by a 3-hour infusion followed by intravenous cisplatin every 2 weeks in the ambulatory setting. Twenty-nine patients have been entered in the study, of whom 27 had received prior adjuvant chemotherapy. Dose-limiting toxicity for the phase I study proved to be failure to recover the neutrophil count to more than 750 cells/microL by day 15; the maximum tolerated dose was therefore paclitaxel 90 mg/m2 and cisplatin 60 mg/m2 every 2 weeks. Nonhematologic toxicities were mild and included fatigue, arthralgias, peripheral neuropathy, and nausea and vomiting. At the present analysis, 234 cycles of treatment have been given. Among 27 patients evaluable for response (four of whom are still receiving therapy), three have had complete remissions and 18 partial responses, for an interim overall response rate of 78%. In summary, weekly paclitaxel and cisplatin is a safe and active combination in the treatment of metastatic breast cancer. Final determination of toxicity and activity will be published at the conclusion of this study.
- Published
- 1995
6. Paclitaxel administration using portable infusion pumps.
- Author
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Goldspiel BR, Kohler DR, Koustenis AG, Wilson WH, Tolcher AW, O'Shaughnessy JA, Wittes RE, and Chabner BA
- Subjects
- Equipment Design, Female, Humans, Ovarian Neoplasms drug therapy, Infusion Pumps, Paclitaxel administration & dosage
- Published
- 1993
7. A Randomized Phase II Trial Comparing 3-hour Versus 96-hour Infusion Schedules of Paclitaxel for the Treatment of Metastatic Breast Cancer
- Author
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Moulder, Stacy L., Holmes, Frankie A., Tolcher, Anthony W., Thall, Peter, Broglio, Kristine, Valero, Vicente, Buzdar, Aman U., Arbuck, Susan G., Seidman, Andrew, and Hortobagyi, Gabriel N.
- Subjects
Adult ,Aged, 80 and over ,Paclitaxel ,Breast Neoplasms ,Middle Aged ,Antineoplastic Agents, Phytogenic ,Article ,Disease-Free Survival ,Drug Administration Schedule ,Survival Rate ,Drug Resistance, Neoplasm ,Humans ,Female ,Neoplasm Metastasis ,Infusions, Intravenous ,Aged - Abstract
This study was performed to compare efficacy and toxicity profiles of paclitaxel using 3-hour versus 96-hour infusion schedules.Patients with metastatic breast cancer (MBC) were randomly assigned to receive paclitaxel starting at a dose of 250 mg/m(2) intravenously (iv) over 3 hours every 21 days or paclitaxel starting at a dose of 140 mg/m(2) iv over 96 hours every 21 days. Stratification variables included number of prior chemotherapy regimens and previous response to anthracyclines. Response was assessed every 2 cycles using bidimensional measurements. Patients were allowed to cross over at disease progression or therapy intolerance.A total of 214 patients received therapy (107 patients per arm). Response rates were similar: 23.4% in the 3-hour arm and 29.9% in the 96-hour arm (P = .28). The median duration of response (8.9 months vs 5.7 months; P = .75) and progression-free survival (5.0 months vs 3.8 months; P = .17) slightly favored the 96-hour arm. Overall survival was slightly longer in the 3-hour arm (14.2 months vs 12.7 months; P = .57). One patient who crossed over to the 96-hour arm (N = 18) developed a partial response; no response was noted with crossover to the 3-hour arm (N = 10). Myalgia/arthralgia and neuropathy were more frequent in the 3-hour arm, whereas mucositis, neutropenic fever/infection, and diarrhea were more common in the 96-hour arm.Paclitaxel given by 3-hour or 96-hour infusion was active in MBC. The 96-hour paclitaxel regimen did not significantly improve response or time to disease progression, was more cumbersome to administer, and was associated with greater myelosuppression (but less neuropathy and myalgia) compared with the 3-hour schedule.
- Published
- 2010
8. Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors.
- Author
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Rhoda Molife, L., Li Yan, Vitfell-Rasmussen, Joanna, Zernhelt, Adriane M., Sullivan, Daniel M., Cassier, Philippe A., Eric Chen, Biondo, Andrea, Tetteh, Ernestina, Siu, Lillian L., Patnaik, Amita, Papadopoulos, Kyriakos P., De Bono, Johann S., Tolcher, Anthony W., and Minton, Susan
- Subjects
PROTEINS ,CARBOPLATIN ,PACLITAXEL ,DOCETAXEL ,ERLOTINIB - Abstract
Background Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies. Methods Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m
2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested. Results MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ⩾6 months. Conclusion MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
9. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors.
- Author
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Vonderheide, Robert H., Burg, Jennifer M., Mick, Rosemarie, Trosko, Jennifer A., Dongguang Li, Naveed Shaik, M., Tolcher, Anthony W., and Hamid, Omid
- Subjects
CD40 antigen ,CARBOPLATIN ,PACLITAXEL ,TUMORS ,MONOCLONAL antibodies ,PATIENTS - Abstract
CD40 is a cell-surface molecule that critically regulates immune responses. CP -870,893 is a fully human, CD40-specific agonist monoclonal antibody (mAb) exerting clinical antineoplastic activity. Here, the safety of CP -870,893 combined with carboplatin and paclitaxel was assessed in a Phase I study. Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP -870,893 on day 3 (Schedule A) or day 8 (Schedule B), repeated every 21 d. The primary objective was to determine safety and maximum-tolerated dose (MTD) of CP -870,893. Secondary objectives included the evaluation of antitumor responses, pharmacokinetics and immune modulation. Thirty-two patients were treated with CP -870,893, 16 patients on each schedule. Two doselimiting toxicities were observed (grade 3 cytokine release and transient ischemic attack), each at the 0.2 mg/Kg dose level, which was estimated to be the MTD. The most common treatment-related adverse event was fatigue (81%). Of 30 evaluable patients, 6 (20%) exhibited partial responses constituting best responses as defined by REC IST. Following CP - 870,893 infusion, the peripheral blood manifested an acute depletion of B cells associated with upregulation of immune co-stimulatory molecules. T-cell numbers did not change significantly from baseline, but transient tumor-specific T-cell responses were observed in a small number of evaluable patients. The CD40 agonist mAb CP -870,893, given on either of two schedules in combination with paclitaxel and carboplatin, was safe for patients affected with advanced solid tumors. Biological and clinical responses were observed, providing a rationale for Phase II studies. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
10. A Randomized Phase 2 Trial Comparing 3-Hour Versus 96-Hour Infusion Schedules of Paclitaxel for the Treatment of Metastatic Breast Cancer.
- Author
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Moulder, Stacy L., Holmes, Frankie A., Tolcher, Anthony W., Thall, Peter, Broglio, Kristine, Valero, Vicente, Buzdar, Aman U., Arbuck, Susan G., Seidman, Andrew, and Hortobagyi, Gabriel N.
- Subjects
BREAST cancer treatment ,PACLITAXEL ,DRUG efficacy ,CANCER patients ,TOXICITY testing ,DRUG therapy - Abstract
The article presents a study which compares the toxicity and efficacy profile of 96-hour and three-hour infusion schedule of paclitaxel in treating metastatic breast cancer (MBC). The study evaluated the response of patients with MBC on chemotherapy regimens using bidimensional measurements. Results show that patients' response rate on both schedules was similar. It concludes that paclitaxel was active in MBC either in 96-hour and three-hour infusion schedules.
- Published
- 2010
- Full Text
- View/download PDF
11. Synthesis of a novel, sequentially active-targeted drug delivery nanoplatform for breast cancer therapy.
- Author
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Satsangi, Arpan, Roy, Sudipa S., Satsangi, Rajiv K., Tolcher, Anthony W., Vadlamudi, Ratna K., Goins, Beth, and Ong, Joo L.
- Subjects
- *
BREAST cancer treatment , *DRUG delivery systems , *CHEMICAL synthesis , *NANOMEDICINE , *CANCER-related mortality , *PACLITAXEL - Abstract
Breast cancer is the leading cause of cancer deaths among women. Paclitaxel (PTX), an important breast cancer medicine, exhibits reduced bioavailability and therapeutic index due to high hydrophobicity and indiscriminate cytotoxicity. PTX encapsulation in one-level active targeting overcomes such barriers, but enhances toxicity to normal tissues with cancer-similar expression profiles. This research attempted to overcome this challenge by increasing selectivity of cancer cell targeting while maintaining an ability to overcome traditional pharmacological barriers. Thus, a multi-core, multi-targeting construct for tumor specific delivery of PTX was fabricated with (i) an inner-core prodrug targeting the cancer-overexpressed cathepsin B through a cathepsin B-cleavable tetrapeptide that conjugates PTX to a poly(amidoamine) dendrimer, and (ii) the encapsulation of this prodrug (PGD) in an outer core of a RES-evading, folate receptor (FR)-targeting liposome. Compared to traditional FR-targeting PTX liposomes, this sequentially active-targeted dendrosome demonstrated better prodrug retention, an increased cytotoxicity to cancer cells (latter being true when FR and cathepsin B activities were both at moderate-to-high levels) and higher tumor reduction. This research may eventually evolve a product platform with reduced systemic toxicity inherent with traditional chemotherapy and localized toxicity inherent to single-target nanoplatforms, thereby allowing for better tolerance of higher therapeutic load in advanced disease states. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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