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Byline: Albert Font (1), Jose Miguel Sanchez (1), Miquel Taron (1), Eva Martinez-Balibrea (1), Jose Javier Sanchez (2), Jose Luis Manzano (1), Mireia Margeli (1), Martin Richardet (1), Agusti Barnadas (1), Albert Abad (1), Rafael Rosell (1) Keywords: SN-38; CPT-11; pharmacogenetic screening Abstract: Purpose: Inherited variations in drug metabolizing enzymes may influence drug efficacy. This phase II study assesses the impact of second-line weekly irinotecan (CPT-11)/docetaxel in non-small cell lung cancer (NSCLC) patients, and gauges the uridine diphosphate glucuronosyl transferase (UGT1A1) polymorphism influence in toxicity and antitumor activity. Experimental Design: Fifty-one patients with NSCLC treated with at least one prior chemotherapy regimen were enrolled. Patients received irinotecan 70mg/m.sup.2 followed by docetaxel 25mg/m.sup.2. Both drugs were given on days 1, 8, and 15 every 28 days. UGT1A1 polymorphism were analyzed in blood samples of 47 patients. The UGT1A1 polymorphism are classified according to the number of TA repeats in the promoter region of this gene. Results: Three patients (6%) achieved a partial response and nineteen patients (37%) had stable disease. Median survival was 8 months (95% CI: 4.8--11.2) and 1-year survival 30%. Grade 3--4 hematologic toxicity was low (less than 10% of patients) 15% of patients had grade 3 asthenia and 25% of patients had grade 3/4 diarrhea. The frequency of UGT1A1 genotypes was as follows: 6/6 49%, 6/7 36%, and 7/7 15%. No differences in toxicity were observed according to UGT1A1 polymorphism. A nonsignificant improvement in time to progression (4 vs. 3 months) and median survival (11 vs. 8 months) was detected in patients with the variant alleles (6/7 and 7/7). Conclusions: This weekly irinotecan/docetaxel regimen has shown an acceptable toxicity profile while encouraging median and 1-year survival in heavily pretreated NSCLC patients. The tendency to better prognosis in patients carrying the variant genotypes 6/7 and 7/7 of UGT1A1 gene requires further validation. Author Affiliation: (1) Hospital Germans Trias i Pujol, Medical Oncology Service, Badalona, Barcelona, Spain (2) Department of Preventive Medicine, Free University of Madrid, Spain Article History: Registration Date: 06/10/2004

Byline: Ming-Sing Si (1), David K. Imagawa (2), Ping Ji (2), Xunbin Wei (2,3), Bari Holm (1), Jennifer Kwok (2), Michael Lee (2), Bruce A. Reitz (1), Dominic C. Borie (1) Keywords: docetaxel; immunosuppression; lymphocytes Abstract: Docetaxel is an antineoplastic taxoid that interferes with microtubule polymerization dynamics and is used clinically to treat advanced cancers. Because microtubules play significant roles in T lymphocyte activation and function we characterized the in vitro immunomodulatory properties of docetaxel. Effects of docetaxel on lectin-induced peripheral blood mononuclear cell (PBMC) proliferation were measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and proliferating cell nuclear antigen (PCNA) staining. In addition, apoptosis was measured by annexin V staining and cell activation by determination of CD25 and CD71 cell surface expression. Intracellular calcium kinetics in lectin-activated Jurkat T lymphocytes exposed to docetaxel were investigated. Th1 cytokine production was assessed in T lymphocytes by intracellular cytokine staining. Docetaxel significantly inhibited PBMC proliferation and promoted apoptosis of lectin-activated PBMCs. Docetaxel significantly decreased expression of CD71 but not that of CD25. Docetaxel altered intracellular calcium homeostasis but did not affect Th1 cytokine production in T lymphocytes. In conclusion we demonstrate that docetaxel, although exerting significant antiproliferative effects on lymphocytes and promoting activation-induced apoptosis does affect only partially lymphocyte activation and function and does not affect Th1 cytokine production. These results suggest maintenance of lymphocyte functions important for host tumor surveillance and suggest that this compound may have a role in the treatment of cancer arising organ transplant recipients. Author Affiliation: (1) Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA (2) UCI Transplantation Laboratory, Division of Hepatobiliary and Pancreas Surgery and Islet Cell Transplantation, Department of Surgery, University of California, Irvine, Orange, CA (3) Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA Article History: Registration Date: 06/10/2004

Byline: Lisa Ann Kraus (1), Shanti K. Samuel (1), Steven M. Schmid (1), Donald J. Dykes (1), William R. Waud (1), Marie Christine Bissery (2) Keywords: bcl-2; docetaxel; Taxotere(r); xenografts Abstract: Docetaxel is a new taxoid compound with a broad spectrum of antitumor activity. Previous studies have shown that in vitro treatment of specific human tumor lines with docetaxel is associated with the phosphorylation and inactivation of the bcl-2 protein and the occurrence of apoptosis. The goal of this study was to examine whether bcl-2 expression is truly required for in vivo responsiveness to docetaxel. The expression and state of phosphorylation of bcl-2 was examined in human MX-1 breast or DU-145 prostate tumors explanted from nu/nu mice treated with docetaxel. The MX-1 cells accumulated in the G2/M phase of the cell cycle and exhibited phosphorylation of bcl-2 after treatment with docetaxel. By Western blot analysis DU-145 prostate tumor cells did not express bcl-2 protein before or following in vivo treatment with docetaxel. However, docetaxel was highly active against the DU-145 tumor xenograft model. Thus, docetaxel induces apoptosis and cell death through a different, bcl-2-independent mechanism in the DU-145 human prostate tumor, indicating that bcl-2 may not have prognostic value for treatment with docetaxel. Author Affiliation: (1) Southern Research Institute, 2000 9th Avenue South, Birmingham, Al, 35205 (2) Aventis Oncology, 13, quai Jules Guesde --, BP 14, 94403, Vitry-sur-Seine, Cedex, France Article History: Registration Date: 06/10/2004

Byline: Roger Kuhn (1), Arndt Hribaschek (1), Katrin Eichelmann (1), Stephan Rudolph (1), Joerg Fahlke (1), Karsten Ridwelski (1) Keywords: biliary tract carcinoma; chemotherapy; cholangiocarcinoma; docetaxel; gallbladder carcinoma; gemcitabine Abstract: Purpose. The prognosis of patients withbiliary tree carcinomas is very poor. Thediagnosis often occurs at an advancedstage, when curative resection is notpossible. We combined gemcitabine anddocetaxel to optimize the palliativetherapy for patients with gallbladder,biliary, and cholangio-carcinomas on anoutpatient basis. Patients and methods. Patients withhistologically proven biliary treecarcinomas and a WHO performance status&lt 2 received gemcitabine 1000 [mg/m.sup.2]followed by docetaxel 35 mg/m.sup.2 weekly for 3weeks followed by 1 week of rest. Results. Forty-three patients, 14males/29 females, with an average age of63.3 years (range, 41 to 78) have beenenrolled since 1998 37 have completedtreatment. So far, 168 cycles (range, 1 to16) have been administered. All 43 patientswere included in the response and toxicityassessments. There are no completeremissions however, 4 (9.3%) patientsachieved partial remission, 1 (2.3%) had aminimal remission, and 24 (55.8%)reached disease stabilization for a medianperiod of 5.2 months. Fourteen (32.6%)patients progressed. The median overallsurvival rate is currently 11.0 months. Grade 3 hematologic toxicities wereinfrequent, and there were no grade 4hematologic toxicities. Grade 3 leukopeniawas reported in 4 (9.3%) patients, grade 3thrombozytopenia in 1 (2.3%) patient, andgrade 3 anemia in 1 (2.3%) patient.Twenty-eight (65.1%) patients had grade3/4 alopecia, 8 (18.6%) hadnausea/vomiting, and 2 (4.6%) hadmucositis. Conclusion. The combination ofgemcitabine/docetaxel is an effective andwell tolerated therapy for patients withadvanced or metastatic gallbladder,biliary, and cholangio-carcinomas. Author Affiliation: (1) Clinic for General, Viscera and Vessel Surgery, Otto-von-Guericke-University, Magdeburg, Germany Article History: Registration Date: 10/10/2004

Byline: Elisabeth I. Heath (1), Susan Urba (2), John Marshall (3), Steven Piantadosi (1), Arlene A. Forastiere (1) Keywords: cancer of the esophagus; chemotherapy; docetaxel; paclitaxel Abstract: Background: Chemotherapy remains theprimary mode of treatment for metastaticcarcinoma of the esophagus. The efficacyof various chemotherapeutic regimens hasbeen studied predominantly in patients withsquamous cell carcinoma of the esophagus. In light of the increasing incidence ofadenocarcinoma of the esophagus, studiesevaluating newer chemotherapy agents, suchas docetaxel, in this patient populationare necessary. The objective of this trialwas to determine the complete and partialresponse rate of docetaxel in patients withincurable adenocarcinoma of theesophagus. Patients and methods: Eligiblepatients had histologically confirmedmetastatic adenocarcinoma of the esophagusor locally extensive disease not curablewith surgery or radiation therapy. Patients were either chemotherapy naive orpreviously treated with chemotherapy(including paclitaxel). Docetaxel wasadministered at a dose of 75 [mg/m.sup.2]every three weeks intravenously.Appropriate imaging studies/examinationswere obtained after every two cycles toevaluate response. Results: A total of 22 patients wereenrolled in the trial. Chemotherapy-naivepatients achieved a response rate of 18%(95% CI = 2.3 to 51.8) while patients whoreceived prior chemotherapy achieved a 0%response rate (95% CI = 0 to 25). Therewere no complete responses. The overallmedian survival time is 3.4 months and theone-year survival rate is 21%. Thetoxicities included febrile neutropenia(32%) as well as grade 3 and 4 fatigue(14%) and anorexia (9%). Conclusions: Although chemotherapy naivepatients achieved an 18% response rate andno responses were seen in previouslytreated patients, the limitations of thistrial does not allow for any definitiveconclusions to be made about the efficacyof single agent docetaxel chemotherapy inpatients with incurable esophagealcancer. Author Affiliation: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MP, USA (2) Department of Oncology, University of Michigan, Ann Arbor, MI, USA (3) Department of Oncology, Georgetown University Hospital, Washington, DC, USA Article History: Registration Date: 10/10/2004

Byline: Lucia Vigano (1), Alberta Locatelli (1), Giacomo Grasselli (1), Luca Gianni (1) Keywords: paclitaxel; docetaxel; combination therapy; pharmacokinetics; pharmacodynamics Abstract: The taxanes' interaction with otheranticancer drugs have been extensivelyinvestigated in in vitro and inanimal models as well as in humans due tothe outstanding antitumor activity in abroad range of malignancies. Paclitaxel anddocetaxel are endowed of a rich and complexpharmacology whereby differentpharmacodynamic effects are observeddepending on the sequence of theiradministration in respect with thecompanion drug, and the type of drug thatis combined. Pharmacokinetic interferenceis often but not always a basis of thepharmacodynamic effect. In addition, thevehicle of clinical formulation, especiallyCremophor EL for paclitaxel, influence thepharmacological effect. Finally, newinteraction based on as yet unknownmechanisms drive the two taxanes tomultiple additive/synergistic relationshipswith new signal transduction drugs, such asmodulators of the epidermal-growth-factorfamily of receptors andfarnesyl-transferase inhibitors. Theongoing effort to better understanding sucha rich pharmacology is worth continuing inview of designing new and bettercombinations of the taxanes. Author Affiliation: (1) Division of Medical Oncology A, Istituto Nazionale dei Tumori di Milano, Milan, Italy Article History: Registration Date: 11/10/2004

Byline: Rene Bruno (1,2), Nicole Vivier (1,2), Christine Veyrat-Follet (1,2), Guy Montay (1,2), Gerald R. Rhodes (1,2) Keywords: docetaxel; pharmacokinetics-pharmacodynamics; safety; efficacy Abstract: The population approach has been implemented prospectively inthe clinical development of docetaxel(Taxotere(r)). Overall 640 patients were evaluablefor the population PK/PD analysis. The PK analysis evidencedsignificant covariates explaining the inter-patientvariability of docetaxel clearance and the PK/PD analysisdemonstrated that the variability in clearance was asignificant predictor of several safety endpoints. In patientswith clinical chemistry suggestive of mild to moderate liverfunction impairment (SGOT and/or SGPT &gt 1.5 x ULNconcomitant with alkaline phosphatase &gt 2.5 x ULN),total body clearance was lowered by an average of 27%.Specific safety analyses demonstrated that these patients areat a significantly higher risk than others for the developmentof severe docetaxel-induced side effects. Population PK/PDdata were fully integrated into the regulatory dossier and inthe labeling of docetaxel worldwide. Population PK/PD modelsare being used to elaborate a simulation model to predict thesurvival of patients with non-small cell lung cancer treatedwith docetaxel. Author Affiliation: (1) Drug Metabolism and Pharmacokinetics, Aventis Pharma Recherche et Developpement, Antony, France (2) Collegeville, PA Article History: Registration Date: 11/10/2004

Byline: Mirte M. Malingre (1,2), Jos H. Beijnen (1,2,3), Jan H.M. Schellens (1,3) Keywords: paclitaxel; docetaxel; oral administration; bioavailability; P-glycoprotein; cytochrome P450 Abstract: Oral treatment with cytotoxic agents is tobe preferred as this administration routeis convenient to patients, reducesadministration costs and facilitates theuse of more chronic treatment regimens. Forthe taxanes paclitaxel and docetaxel,however, low oral bioavailability haslimited development of treatment by theoral route. Preclinical studies with mdr1aP-glycoprotein knock-out mice, which lackfunctional P-glycoprotein activity in thegut, have shown significant bioavailabilityof orally administered paclitaxel.Additional studies in wild-type micerevealed good bioavailability after oraladministration when paclitaxel was combinedwith P-glycoprotein blockers such ascyclosporin A or the structurally relatedcompound SDZ PSC 833. Based on theextensive preclinical research, thefeasibility of oral administration ofpaclitaxel and docetaxel in cancer patientswas recently demonstrated in our Institute.Co-administration of cyclosporin A stronglyenhanced the oral bioavailability of bothpaclitaxel and docetaxel. For docetaxel incombination with cyclosporin A an oralbioavailability of 90% was achieved withan interpatient variability similar to thatafter intravenous drug administration forpaclitaxel the oral bioavailability isestimated at approximately 50%. The safety of the oralroute for both taxanes is good. A phase IIstudy of weekly oral docetaxel incombination with cyclosporin A is currentlyongoing. Author Affiliation: (1) Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, The Netherlands (2) Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands (3) Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands Article History: Registration Date: 11/10/2004

Byline: Bastiaan Nuijen (1), Marjan Bouma (1), Jan H.M. Schellens (1), Jos H. Beijnen (1) Keywords: taxanes; paclitaxel; docetaxel; alternative formulation; co-solvents; surfactants; emulsions; micro-encapsulation systems; liposomes; cyclodextrines; prodrugs Abstract: The currently available taxanes paclitaxel(Taxol(r)) and docetaxel(Taxotere(r)) are clinically effectiveagainst advanced breast, ovarian andnon-small cell lung cancer. Due to theirlow aqueous solubility, both taxanes poseddifficulties to the pharmaceuticalscientists with respect to the developmentof an intravenous dosage form. At present,paclitaxel is formulated in a mixture of50:50% (v/v) Cremophor EL and dehydratedethanol. However, this formulation vehicleis associated with a number ofpharmacological, pharmacokinetic andpharmaceutical concerns amongst whichserious hypersensitivity reactions. Thisreview deals with the attempts made intothe development of alternative dosage formsof paclitaxel devoid of the CremophorEL/ethanol excipients and potential futuretaxane formulations. Author Affiliation: (1) Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands Article History: Registration Date: 11/10/2004

Byline: Corey J. Langer (1) Keywords: NSCLC; docetaxel; systemic therapy; combined modality Abstract: The treatment of advanced non-small cell lung carcinoma(NSCLC) has improved greatly over the past decade. With theadvent of new agents, in particular taxanes, gemcitabine, vinorelbine,and topoisomerase I inhibitors, response rates have improved from15--20% to 25--35%, with commensurate improvement in median and one year survival rates to 8--10 months and 35--45%, respectively. These improvements have proven statistically significant in multiple studies [1--4]. Docetaxel, either alone or in combination with platinols, hasshown particular promise and, in some arenas, it has become a standard component of our therapeutic armamentarium. We will review the preclinical data and single agent activity of docetaxel in treatment-naive and previously treated NSCLC patients, its activityin combination with cisplatin and carboplatin, as well as othernew agents, and finally focus on ongoing studies evaluating itsrole in locally advanced disease. Author Affiliation: (1) Fox Chase Cancer Center, Philadelphia, PA, USA Article History: Registration Date: 05/10/2004

Keywords: docetaxel; plasma assay; clinical trials; pharmacokinetics Abstract: We have developed a specific and sensitive method aiming atdocetaxel (Taxotere(r)) determination in plasma of treatedpatients. This involved solid-phase extraction of 1 ml of plasmaonto carboxylic acid (CBA) grafted silica cartridges followed byreversed-phase liquid chromatography with UV detection. The bestselectivity was obtained through the use of C18 Uptisphere(r) asstationary phase. The low limit of quantitation obtained (LOQ:5 ng/ml) allowed measurements of docetaxel up to 24 hours afterone-hour infusions with low dosages of drug (60 mg/m.sup.2). Themethod was applied successfully to monitor docetaxel plasma levelswithin two protocols associating fixed dosages of either methotrexate or gemcitabine with escalating doses of Taxotere(r). Article History: Registration Date: 02/10/2004