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Hester van Cruijsen,
Emile E Voest,
Cornelis J A Punt,
Klaas Hoekman,
Petronella O Witteveen,
Martijn R Meijerink, Thomas A Puchalski,
Jane Robertson,
Owain Saunders,
Juliane M Jürgensmeier,
Carla M L van Herpen,
Giuseppe Giaccone
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ABSTRACT: Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours.
Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics.
Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment.
Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration.
European journal of cancer (Oxford, England: 1990) 03/2010; 46(5):901-11. · 4.12 Impact Factor
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Scott A Laurie,
Isabelle Gauthier,
Andrew Arnold,
Frances A Shepherd,
Peter M Ellis,
Eric Chen,
Glenwood Goss,
Jean Powers,
Wendy Walsh,
Dongsheng Tu,
Jane Robertson, Thomas A Puchalski,
Lesley Seymour
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ABSTRACT: AZD2171 is a potent inhibitor of vascular endothelial growth factor receptors that showed broad antitumor activity in preclinical models. Doses of up to 45 mg/d of AZD2171 are tolerable when administered alone. This study evaluated escalating doses of AZD2171 in combination with standard chemotherapy in patients with advanced non-small-cell lung cancer.
Eligible patients received carboplatin targeted to an area under the concentration time curve of 6 mg . min/mL and paclitaxel 200 mg/m(2), both on day 1 of a 3-week cycle; daily oral AZD2171 at either 30 mg or 45 mg commenced day 2 of cycle 1. Pharmacokinetics of all drugs were performed, and tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST).
Twenty patients were enrolled. No dose-limiting toxicities were observed during cycle 1 at either dose. Fatigue, diarrhea, anorexia, and granulocytopenia were common; hypertension was manageable with a treatment algorithm designed for this protocol. No clinically significant drug-related bleeding was observed. At 45 mg/d, fatigue and diarrhea were increased, and headache and hoarseness were observed. Paclitaxel clearance decreased during cycle 2, but no other significant pharmacokinetic interactions were observed. After radiology review, confirmed responses were observed in nine patients (response rate, 45%; 95% CI, 23% to 68%); all but one enrolled patient showed evidence of tumor shrinkage, some with cavitation.
AZD2171 can be combined with standard doses of carboplatin/paclitaxel with encouraging antitumor activity. Toxicity is increased, but predictable and manageable.
Journal of Clinical Oncology 05/2008; 26(11):1871-8. · 18.37 Impact Factor
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Joachim Drevs,
Patrizia Siegert,
Michael Medinger,
Klaus Mross,
Ralph Strecker,
Ute Zirrgiebel,
Jan Harder,
Hubert Blum,
Jane Robertson,
Juliane M Jürgensmeier, Thomas A Puchalski,
Helen Young,
Owain Saunders,
Clemens Unger
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ABSTRACT: AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy.
In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed.
Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related.
Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.
Journal of Clinical Oncology 08/2007; 25(21):3045-54. · 18.37 Impact Factor
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Joseph P Eder,
Rocio Garcia-Carbonero,
Jeffrey W Clark,
Jeffrey G Supko, Thomas A Puchalski,
David P Ryan,
Pamela Deluca,
Antoinette Wozniak,
Angela Campbell,
John Rothermel,
Patricia LoRusso
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ABSTRACT: 4'- N -Benzoyl-staurosporine (PKC412) is an orally available staurosporine derivative that inhibits protein kinase C. The objectives of this phase I trial were to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetics of PKC412 when co-administered with 5-Fluorouracil (5-FU).
PKC412 was given daily with a 21-day continuous i.v. infusion of 5-FU 200 mg/m2/day, repeated every 4 weeks. The PKC412 dose was escalated by a modified continual reassessment method. The steady-state plasma pharmacokinetics of 5-FU, PKC412, and two of its circulating metabolites were determined during the first cycle of therapy.
A total of 33 patients were treated with 70 cycles (median: 2, range: 1-4) of PKC412 at doses ranging from 25 to 225 mg/day. No significant toxicities were encountered with doses up to 150 mg/day. Among nine patients treated with 225 mg/day of PKC412, one experienced grade 3 fatigue and nausea, another developed grade 3 hyperglycemia, and three had grade 2 emesis and stomatitis, leading to early treatment discontinuation. Minor responses consisting of a 40-45% tumor reduction were observed in two patients, one with gall bladder carcinoma and one with breast cancer. Mean values of steady-state pharmacokinetic variables for both PKC412 and 5-FU were comparable to single agent studies.
The recommended phase II dose of PKC412 is 150 mg/day when combined with a continuous infusion of 200 mg/m2/day 5-FU. The dose limiting toxicity was grade 2 emesis and stomatitis and the regimen showed indications of activity. There was no evidence of a pharmacokinetic interaction between the two drugs.
Investigational New Drugs 05/2004; 22(2):139-50. · 3.36 Impact Factor
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Andrew X Zhu, Thomas A Puchalski,
Vincent P Stanton,
David P Ryan,
Jeffrey W Clark,
Steven Nesbitt,
Olga Charlat,
Patrick Kelly,
Elaine Kreconus,
Bruce A Chabner,
Jeffrey G Supko
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ABSTRACT: The causes of interpatient variation in severe toxicity resulting from treatment with weekly 5-fluorouracil (5-FU)/ leucovorin (LV) are poorly understood. This study was undertaken to examine the contribution of commonly occurring polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene to interpatient variability in 5-FU pharmacokinetics and toxicity. Patients with stage III/IV colorectal cancer were treated by bolus intravenous (I.V.) injection with 500 mg/m2 doses of 5-FU and LV once every week. The pharmacokinetics of 5-FU was determined on weeks 1 and 4. Genotyping assays were developed for 8 polymorphisms in the DPYD gene. A well-characterized functional polymorphism in the 5' untranslated region of the thymidylate synthase (TS) gene was also analyzed. A cohort of 22 patients (15 male, 7 female) with a median age of 61 years was evaluated. Although there was no relationship between the area under the plasma concentration time curve (AUC) for the first dose of 5-FU and worst-grade toxicity during the first cycle of therapy, 3 of the 4 patients in whom the AUC on week 4 was more than equal to 5 microgram/h/mL greater than the value for the first dose experienced grade 3/4 toxicity during subsequent treatment. Among the 8 polymorphisms in the DPYD gene, 7 were found to vary in the study population but none were significantly associated with the AUC of 5-FU. There was no relationship between the DPYD and TS genotypes examined and 5-FU toxicity. Extensive polymorphism in the DPYD gene was observed; however, no conclusive correlations existed between the DPYD and TS genotype and 5-FU pharmacokinetics or toxicity. Decreases in 5-FU clearance in certain patients may provide insight into the increased toxicity following repetitive cycles of treatment with weekly I.V. bolus 5-FU. The present study offers useful themes for undertaking larger prospective pharmacogenetic studies in the future.
Clinical Colorectal Cancer 03/2004; 3(4):225-34. · 1.68 Impact Factor
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Susanna M Campos,
Ursula A Matulonis,
Richard T Penson,
Hang Lee,
Ross S Berkowitz,
Linda R Duska,
Arlan F Fuller,
Kara S Wilson, Thomas A Puchalski,
Jeffrey G Supko,
Michael V Seiden
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ABSTRACT: Pegylated liposomally encapsulated doxorubicin (Doxil. Ortho-Biotech) and paclitaxel (Taxol, Bristol Myers Squibb) are both active against Müllerian malignancies. A phase II trial was performed to determine the toxicity and efficacy of these agents when administered in combination.
Patients were initially treated with 30 mg/m(2) of liposomal doxorubicin every 21 days and 70 mg/m(2) of paclitaxel every week for 18 weeks. The plasma pharmacokinetics of paclitaxel was determined when administered alone and concurrently with liposomal doxorubicin.
Forty women with recurrent gynecologic malignancies of Müllerian origin including 34 with ovary and primary peritoneal cancer (85%) were enrolled. Toxicity was evaluated for all 508 cycles of therapy. Paclitaxel and liposomal doxorubicin were delivered at 95% (66.4 mg/m(2)/week) and 77% (7.65 mg/m(2)/week) of their intended weekly dose intensities, respectively. Reductions in the dose of liposomal doxorubicin were frequently required for palmar plantar erythrodysesthesia during the latter cycles of therapy. There were 4 patients with a complete response and 7 with partial responses, for an overall objective response rate of 29%, among the 38 evaluable patients. Response rates for the subset of 13 women with tumor recurrence occurring at least 6 months after prior platinum-based therapy was 54%. The concurrent administration of liposomal doxorubicin did not alter the pharmacokinetic disposition of paclitaxel.
Liposomal doxorubicin with weekly paclitaxel is active in Müllerian malignancies. The concurrent delivery of the weekly paclitaxel with liposomal doxorubicin may increase liposomal doxorubicin skin toxicity. Liposomal doxorubicin does not alter the pharmacokinetics of paclitaxel.
Gynecologic Oncology 10/2003; 90(3):610-8. · 3.89 Impact Factor
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Thomas A Puchalski,
David P Ryan,
Rocio Garcia-Carbonero,
George D Demetri,
Leah Butkiewicz,
David Harmon,
Michael V Seiden,
Robert G Maki,
Luis Lopez-Lazaro,
Jose Jimeno,
Cecilia Guzman,
Jeffrey G Supko
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ABSTRACT: Ecteinascidin 743 (ET-743) is a potent cytotoxic alkaloid of marine origin that has shown promising evidence of antitumor activity during phase I clinical trials. In the study reported here, the influence of clinical characteristics and pretreatment pathophysiological variables on the pharmacokinetics of ET-743 and their associations with drug-related toxicity was examined in sarcoma patients treated in three phase II clinical trials.
Adult patients with various histological subtypes of soft tissue sarcoma received 1.5 mg/m(2) of ET-743 by 24-h continuous i.v. infusion once every 3 weeks. Eligibility criteria were similar for each study, except for the histological subtype of the tumor or the extent of prior treatment with other anticancer agents, and all patients had normal or near-normal liver and renal function. The maximum plasma concentration (C(max)) and area under the plasma profile from time zero to infinity (AUC) of the drug were determined during the first cycle of therapy. Patients were evaluated for toxicity every week.
Geometric mean +/- SD values of the pharmacokinetic parameters in 69 patients were: C(max) 1.14 +/- 0.52 ng/ml, AUC 39.9 +/- 16.6 ng.h/ml, and total body clearance (CL) 36.7 +/- 16.4 l/h per m(2). The only significant correlation involving physical characteristics of the patients or pretreatment pathophysiological variables was a very weak relationship between alkaline phosphatase and AUC (r=0.39, P<0.01). The 15 patients with any baseline liver function test exceeding the upper limit of the normal ranges had a significantly greater (P=0.02) incidence of severe toxicity (80% vs 44%). Although the mean AUC of ET-743 in patients with elevated serum levels of hepatic enzymes was 17% greater than that in patients with normal pretreatment liver function tests, the difference was not significant ( P=0.22). In addition, there was no distinct relationship between the grade of the most severe drug-related toxicity that occurred during the first cycle of therapy and the AUC for the entire cohort. The CL of ET-743 was found to be 27% greater in patients concurrently receiving dexamethasone as a preventative antiemetic than in those who were not, but the difference did not achieve statistical significance (P=0.08). There were no significant associations between CL (liters per hour) and body surface area or any other variable related to body size.
The risk of developing severe toxicity was substantially enhanced in patients with relatively moderate indications of hepatic dysfunction without a coincident effect on the CL of ET-743. Dexamethasone cotreatment appeared to decrease the incidence of severe toxicity as well as the AUC of the drug. Delivering a fixed amount of drug without adjustment for the height or weight of the patient may be more appropriate than dose normalization due to the absence of an association between CL and body surface area. Optimizing dosing strategies to further enhance the therapeutic index of ET-743 may depend upon obtaining a better understanding of the metabolic fate of the drug in humans.
Cancer Chemotherapy and Pharmacology 11/2002; 50(4):309-19. · 2.83 Impact Factor
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Joseph P Eder,
Jeffrey G Supko,
Jeffrey W Clark, Thomas A Puchalski,
Rocio Garcia-Carbonero,
David P Ryan,
Lawrence N Shulman,
Joann Proper,
Moira Kirvan,
Barbara Rattner,
Susan Connors,
Mary T Keogan,
Milos J Janicek,
William E Fogler,
Lowell Schnipper,
Nancy Kinchla,
Carolyn Sidor,
Eric Phillips,
Judah Folkman,
Donald W Kufe
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ABSTRACT: To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors.
The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin.
There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies.
rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.
Journal of Clinical Oncology 10/2002; 20(18):3772-84. · 18.37 Impact Factor
