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Alain C Mita,
Anthony J Olszanski,
Richard C Walovitch, Raymond P Perez,
Kathleen MacKay,
David P Tuck,
Cecilia Simmons,
Susan Hammond,
Monica M Mita,
Muralidhar Beeram,
Anne J Stone,
Eric K Rowinsky,
Lionel D Lewis
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ABSTRACT: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a <30-min i.v. infusion without premedication every 3 weeks, determine the maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacokinetics of paclitaxel in this new formulation, and seek evidence of anticancer activity.
This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concentrations were measured by liquid chromatography-tandem mass spectrometry.
Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m(2). Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m(2) AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Pharmacokinetics of free and total paclitaxel showed biexponential plasma decay and dose proportionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas.
The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m(2). The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.
Clinical Cancer Research 07/2007; 13(11):3293-301. · 7.74 Impact Factor
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ABSTRACT: UCN-01, a Chk1 inhibitor, abrogates S and G(2) arrest and enhances cancer cell killing by DNA-damaging drugs in preclinical models. UCN-01 avidly binds alpha1-acid glycoprotein in plasma; whether sufficient drug concentrations are achieved in human tumors is unknown. A phase I trial tested the hypothesis that UCN-01 abrogates cisplatin-induced cell cycle arrest (in tumors) at tolerable doses.
Patients with advanced cancer received i.v. cisplatin, followed 22 hours later by UCN-01 (3-day continuous i.v. infusion of a 28-day cycle). Platinum was measured by atomic absorption, UCN-01 by high-performance liquid chromatography, and cell cycle progression in tumor biopsies by geminin immunostaining (biomarker for S/G(2) phases of cell cycle).
The first two patients treated with cisplatin (20 mg/m(2) plus UCN-01 45 mg/m(2)/d) experienced dose-limiting toxicities (subarachnoid hemorrhage, hyperglycemia, hypoxia, cardiac ischemia, and atrial fibrillation). Following 25% UCN-01 dose reduction, no toxicities greater than grade 2 were seen. Median plasma UCN-01 half-life (T(1/2)) was 405 hours. Salivary UCN-01 concentrations showed a rapid initial decline (median T(1/2alpha), 29.9 hours), followed by a terminal decay parallel to that in plasma. UCN-01 pharmacokinetics, and the timing of clinical toxicities, suggests that UCN-01 is bioavailable despite alpha1-acid glycoprotein binding. Marked suppression of cells in S/G(2) in tumor biopsies was seen by geminin immunohistochemistry, suggesting that UCN-01 is bioavailable at concentrations sufficient to inhibit Chk1.
Cisplatin (30 mg/m(2)), followed 22 hours later by UCN-01 (34 mg/m(2)/d for 3 days), is well tolerated clinically and yields UCN-01 concentrations sufficient to affect cell cycle progression in tumors.
Clinical Cancer Research 01/2007; 12(23):7079-85. · 7.74 Impact Factor
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ABSTRACT: The past 20 years have seen an explosion of information on the molecular changes that lead to cancer. The pathways that have been uncovered include many targets for the development of novel therapeutics. Several such drugs have been approved for clinical use and many additional drugs and targets are now being evaluated in preclinical studies. These new drugs may exhibit impressive therapeutic activity, but this is often restricted to a subpopulation of cancers with a particular molecular change. Moreover, toxicity or even antagonism may result from off-target effects of the drugs. Accordingly, it will be critical to stratify patients for treatment based on the propensity of their tumours to respond. In addition, defining the appropriate dose of targeted agents to administer is challenging; early clinical trial designs must include assays to define the effective biological dose, in addition to more traditional end-points such as the maximum tolerable dose. These and many other challenges exist in the preclinical and clinical development of these drugs.
British Journal of Clinical Pharmacology 08/2006; 62(1):5-14. · 2.96 Impact Factor
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Ramesh K Ramanathan,
Marwan Fakih,
Sridhar Mani,
Melvin Deutsch, Raymond P Perez,
Mark A Ritter,
Julie L Eiseman,
S Percy Ivy,
Donald L Trump,
Chandra P Belani,
Robert A Parise,
Douglas M Potter,
Merrill J Egorin
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ABSTRACT: To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated.
Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography.
Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion.
Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.
Cancer Chemotherapy and Pharmacology 05/2006; 57(4):465-74. · 2.83 Impact Factor
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J Marc Pipas,
Richard J Barth,
Bassem Zaki,
Michael J Tsapakos,
Arief A Suriawinata,
Michael A Bettmann,
Justin M Cates,
Gregory H Ripple,
John E Sutton,
Stuart R Gordon,
Carol E McDonnell, Raymond P Perez,
Nancy Redfield,
Louise P Meyer,
John F Marshall,
Bernard F Cole,
Thomas A Colacchio
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ABSTRACT: Pancreatic cancer remains highly lethal. Previous attempts with neoadjuvant therapy in this disease have been inconclusive, but a potential for benefit exists. We conducted a phase II trial of dose-intense docetaxel and gemcitabine followed by twice-weekly gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma.
Patients with stage I to III disease were eligible. Docetaxel 65 mg/m(2) intravenously over 1 hour and gemcitabine 4000 mg/m(2) given intravenously over 30 minutes were given on days 1, 15, and 29. On day 43, radiotherapy was begun at 50.4 Gy with gemcitabine 50 mg/m(2) intravenously over 30 minutes twice weekly for 12 doses. After treatment, patients were considered for resection.
Twenty-four assessable patients were recruited onto the trial. All but one patient completed a full 12 weeks of therapy. Grade 3 and 4 hematological and nonhematological toxicities were common but manageable, and neutropenic fever did not occur. No patient had local tumor progression. Twelve patients (50%) responded by Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria, including one radiographic complete response. Seventeen patients underwent resection after therapy. Margin-negative resections were performed in 13 patients, including 9 patients whose disease was borderline or unresectable before treatment. A treatment effect was seen in all resection specimens. There have been no local recurrences of tumor, and several patients remain alive without evidence of disease.
Docetaxel/gemcitabine followed by gemcitabine/radiotherapy is active in the treatment of pancreatic adenocarcinoma, with manageable toxicity. Tumor downstaging occurs in some patients to allow complete resection. Further investigation of this regimen is warranted.
Annals of Surgical Oncology 01/2006; 12(12):995-1004. · 4.17 Impact Factor
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ABSTRACT: Mitochondrial DNA-deficient (rho(0)) cells were generated following a 26-day incubation of MOLT-4 lymphoblastoid T cells in ethidium bromide (3,8-diamino-5-ethyl-6-phenylphenanthridinium bromide). The absence of mitochondrial DNA (mtDNA) in the resultant MOLT-4 rho(0) cells was confirmed by Southern analysis and quantitative polymerase chain reaction (PCR). MOLT-4 rho(0) cells proliferated more slowly than parental cells (wild type) and produced significantly more lactate (approximately fourfold increase; P < 0.001) with concomitantly reduced oxygen consumption (12.3% vs. 100%; P < 0.001) compared with the wild type. MOLT-4 rho(0) cells also showed reduced cytochrome c oxidase activity and a reduced cytochrome c oxidase/citrate synthase activity ratio compared to parental wild-type MOLT-4 cells (P < 10(-11)). Electron microscopy showed elongated mitochondria with parallel cristae in MOLT-4 cells although the mitochondria in MOLT-4 rho(0) cells appeared enlarged, some were vacuolated with either an absent or a grossly distorted cristae pattern. Vital staining with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) was used to image mitochondria in intact cells and study mitochondrial transmembrane potential (Deltapsi(m)). Flow cytometry using JC-1 indicated that MOLT-4 rho(0) had a lower Deltapsi(m) than MOLT-4. Sodium fluoride (an inhibitor of the glycolytic pathway) at a concentration of 20 mM further reduced the Deltapsi(m) in MOLT-4-rho(0) cells. This data suggested that a glycolytic pathway product, possibly ATP, was required for the maintenance of Deltapsi(m) in MOLT-4 rho(0) cells.
Toxicology and Applied Pharmacology 04/2004; 196(1):68-79. · 4.45 Impact Factor
